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Does treatment with egg antigens of Schistosoma mansoni ameliorate experimental colitis in mice through a colonic T-cell-dependent mechanism?

Helminth-derived molecules are being identified as a new therapeutic approach for immune-mediated diseases. We investigated the anti-inflammatory effect and the immunological mechanisms of Schistosoma mansoni soluble egg antigens (SmSEA) in a mouse model of chronic colitis. Colitis was induced in immunocompromised severe combined immunodeficiency mice by the adoptive transfer of CD4CD25CD62L T cells. Two weeks post-transfer, SmSEA treatments were started (study 1: 1 × 20 μg SmSEA per week 5 times; study 2: 2 × 20 μg SmSEA per week 3 times). From the start of the treatment (week 2), the clinical outcome and colonic inflammation were assessed at different time points by a clinical disease score and colonoscopy, respectively. At the end of the studies, the colons were harvested for macroscopic examination, and colonic lamina propria mononuclear cells were isolated for flow cytometric T-cell characterization. In both studies, administration of SmSEA in colitis mice improved all the inflammatory parameters studied. However in study 1, this beneficial effect on inflammation diminished with time, and the T-cell characterization of the lamina propria mononuclear cells, performed at week 6, revealed no immunological effects of the SmSEA treatment. In study 2, mice were killed earlier (week 4) and at that time point, we found a significant downregulation of the number of interleukin-17A-producing T cells and a significant upregulation of the number of interleukin-4-producing T cells in the colon of the SmSEA-treated colitis mice.

Our results demonstrated that the administration of SmSEA reduces the severity of colitis in the adoptive transfer mouse model characterized by an increased Th2 response and a suppressed Th17 response in the colon.

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Is abnormal left ventricular contractile response to exercise in the absence of obstructive coronary artery disease associated with resting left ventricular long-axis dysfunction?

The etiology of reduced left ventricular (LV) ejection fraction after exercise, without obstructive coronary artery disease or other established causes, is unclear. The aims of this study were to determine whether patients undergoing treadmill stress echocardiography with this abnormal LV contractile response to exercise (LVCRE) without established causes have resting LV long-axis dysfunction or microvascular dysfunction and to determine associations with this abnormal LVCRE. Of 5,275 consecutive patients undergoing treadmill stress echocardiography, 1,134 underwent cardiac computed tomography angiography or invasive angiography. Having excluded patients with obstructive coronary artery disease, hypertensive response, submaximal heart rate response, resting LV ejection fraction < 50%, and valvular disease, 110 with "abnormal LVCRE" and 212 with "normal LVCRE" were analyzed. Resting mitral annular velocities were measured to assess LV long-axis function. Myocardial blush grade and corrected Thrombolysis In Myocardial Infarction frame count were determined angiographically to assess microvascular function. Comparing normal LVCRE with abnormal LVCRE, age (mean, 59.7 ± 11.1 vs 61.4 ± 10.0 years), hypertension (53% vs 55%), diabetes (16% vs 20%), and body mass index (mean, 29.1 ± 5.4 vs 29.5 ± 6.4 kg/m(2)) were similar (P > .05). Abnormal LVCRE had reduced resting LV long-axis function with lower septal (mean, 6.1 ± 1.9 vs 7.7 ± 2.2 cm/sec) and lateral (mean, 8.1 ± 2.9 vs 10.4 ± 3.0 cm/sec) e' velocities (P < .001) and larger resting left atrial volumes (mean, 37.3 ± 10.1 vs 31.1 ± 7.2 mL/m(2), P < .001). On multivariate analysis, female gender (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.15-1.99; P < .001), exaggerated chronotropic response (OR, 1.49; 95% CI, 1.09-2.05; P < .001), resting left atrial volume (OR, 2.38; 95% CI, 1.63-3.47; P < .001), and resting lateral e' velocity (OR, 1.70; 95% CI, 1.22-2.49; P = .003) were associated with abnormal LVCRE, but not myocardial blush grade or corrected Thrombolysis In Myocardial Infarction frame count.

An abnormal LVCRE in the absence of established causes is associated with resting LV long-axis dysfunction and is usually seen in women.

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Is sleep efficiency ( but not sleep duration ) of healthy school-age children associated with grades in math and languages?

The objective of this study was to examine the associations between objective measures of sleep duration and sleep efficiency with the grades obtained by healthy typically developing children in math, language, science, and art while controlling for the potential confounding effects of socioeconomic status (SES), age, and gender. We studied healthy typically developing children between 7 and 11 years of age. Sleep was assessed for five week nights using actigraphy, and parents provided their child's most recent report card. Higher sleep efficiency (but not sleep duration) was associated with better grades in math, English language, and French as a second language, above and beyond the contributions of age, gender, and SES.

Sleep efficiency, but not sleep duration, is associated with academic performance as measured by report-card grades in typically developing school-aged children. The integration of strategies to improve sleep efficiency might represent a successful approach for improving children's readiness and/or performance in math and languages.

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Are vitamin D levels and bone turnover markers related to non-alcoholic fatty liver disease in severely obese patients?

Morbidly obese patients usually present vitamin D deficiency or secondary hyperparathyroidism. Low vitamin D levels have been recently related to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyse the relationship between vitamin D, bone turnover markers and non-alcoholic fatty liver disease and metabolic syndrome in severely obese patients. One hundred and ten patients who underwent bariatric surgery were included. Liver biopsy was taken during surgery. Two univariate analyses were carried out in order to i) analyse the relationship between liver histology and vitamin D-bone turnover markers (intact parathyroid hormone (PTH), osteocalcin and Carboxy-terminal collagen crosslinks) and ii) establish the association between metabolic syndrome components-insulin resistance (HOMA) and vitamin D-bone turnover markers. 70% of the patients had lower levels of vitamin D or secondary hyperparathyroidism. None of the components of liver histology were associated with levels of vitamin D or with bone turnover parameters. Patients with metabolic syndrome showed lower levels of PTH and osteocalcin (72,42 (29,47) vs 61.25(19.59) p-Value: 0.022; 19.79 (10.43) vs 16.87(10.25) p-Value: 0,028, respectively). HOMA was not related to Vitamin D or bone turnover markers.

Low levels of vitamin D or hyperparathyroidism are common in severely obese patients. Vitamin D and bone metabolism markers were associated neither to NAFLD nor with metabolic syndrome in our series of obese morbid patients.

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Are outcomes of abdominal wall reconstruction with acellular dermal matrix affected by wound contamination?

The optimal type of mesh for complex abdominal wall reconstruction has not been elucidated. We hypothesized that AWRs using acellular dermal matrix (ADM) experience low rates of surgical site occurrence (SSO) and surgical site infection, despite increasing degrees of wound contamination. We retrospectively reviewed prospectively collected data from consecutive abdominal wall reconstructions with ADM over a 9-year period. Outcomes of abdominal wall reconstructions were compared between patients with different CDC wound classifications. Univariate and multivariate logistic regression and Cox proportional hazard regression analyses identified potential associations and predictive/protective factors. The 359 patients had a mean follow-up of 28.3 ± 19.0 months. Reconstruction of clean wounds (n = 171) required fewer reoperations than that of combined contaminated (n = 188) wounds (2.3% vs 11.2%; p = 0.001) and trended toward experiencing fewer SSOs (19.9% vs 28.7%, p = 0.052). There were no significant differences between clean and combined contaminated cases in 30-day SSI (8.8% vs 8.0%), hernia recurrence (9.9% vs 10.1%), and mesh removal (1.2% vs 1.1%) rates. Independent predictors of SSO included body mass index ≥30 kg/m(2) (odds ratio [OR] 3.6; p < 0.001), 1 or more comorbidities (OR 2.5; p = 0.008), and defect width ≥15 cm (OR 1.8; p = 0.02).

Complex abdominal wall reconstructions using ADM demonstrated similar rates of complications between the different CDC wound classifications. This is in contradistinction to published outcomes for abdominal wall reconstruction using synthetic mesh that show progressively higher complication rates with increasing degrees of contamination. These data support the use of ADM rather than synthetic mesh for complex abdominal wall reconstruction in the setting of wound contamination.

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Does airway pressure release ventilation reduce conducting airway micro-strain in lung injury?

Improper mechanical ventilation can exacerbate acute lung damage, causing a secondary ventilator-induced lung injury (VILI). We hypothesized that VILI can be reduced by modifying specific components of the ventilation waveform (mechanical breath), and we studied the impact of airway pressure release ventilation (APRV) and controlled mandatory ventilation (CMV) on the lung micro-anatomy (alveoli and conducting airways). The distribution of gas during inspiration and expiration and the strain generated during mechanical ventilation in the micro-anatomy (micro-strain) were calculated. Rats were anesthetized, surgically prepared, and randomized into 1 uninjured control group (n = 2) and 4 groups with lung injury: APRV 75% (n = 2), time at expiration (TLow) set to terminate appropriately at 75% of peak expiratory flow rate (PEFR); APRV 10% (n = 2), TLow set to terminate inappropriately at 10% of PEFR; CMV with PEEP 5 cm H2O (PEEP 5; n = 2); or PEEP 16 cm H2O (PEEP 16; n = 2). Lung injury was induced in the experimental groups by Tween lavage and ventilated with their respective settings. Lungs were fixed at peak inspiration and end expiration for standard histology. Conducting airway and alveolar air space areas were quantified and conducting airway micro-strain was calculated. All lung injury groups redistributed inspired gas away from alveoli into the conducting airways. The APRV 75% minimized gas redistribution and micro-strain in the conducting airways and provided the alveolar air space occupancy most similar to control at both inspiration and expiration.

In an injured lung, APRV 75% maintained micro-anatomic gas distribution similar to that of the normal lung. The lung protection demonstrated in previous studies using APRV 75% may be due to a more homogeneous distribution of gas at the micro-anatomic level as well as a reduction in conducting airway micro-strain.

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Do a simplified method of preventing implant hex drive from aspiration or accidental swallowing during stage two implant recovery?

To prevent accidental ingestion of implant hex dive. Dental floss which is used to stabilize the hex drive is tied to the operator's finger ring to overcome sudden aspiration of fallen instrument. It showed excellent grip of the instrument during stage two uncover time and also saved operators time.

Accidental aspiration or swallowing of the dental instruments during routine implant surgeries can be prevented by tying the implant instruments to the operator's ring with silk ligatures or dental floss.

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Is late onset spinal motor neuronopathy caused by mutation in CHCHD10?

A study was undertaken to identify the responsible gene defect underlying late onset spinal motor neuronopathy (LOSMoN/SMAJ; Online Mendelian Inheritance in Man #615048), an autosomal dominant disease mapped to chromosome 22q11.2. The previous genetic linkage approach by microsatellite haplotyping was continued in new families. A whole genome sequencing was performed to find all possibly pathogenic mutations in the linked area. The detected variations were verified by Sanger sequencing. Six new SMAJ families were identified based on the unique founder haplotype. A critical recombination in 1 family restricted the linked area to 727kb between markers SHGC-106816 and D22S345. In whole genome sequencing a previously unknown mutation c.197G>T p.G66V in CHCHD10 was identified. The mutation was shown to segregate with the disease in 55 patients from 17 families.

Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ. During the preparation of this article other mutations were reported to cause frontotemporal dementia-amyotrophic lateral sclerosis syndrome, indicating that the CHCHD10 gene is largely important for the motor and cognitive neuronal systems.

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Does low perfusion index affect the difference in glucose level between capillary and venous blood?

In emergency cases, finger stick testing is primarily used to check the blood glucose value of patients since it takes longer to obtain the venous value. In critical patients, under conditions that cause an increase in metabolic state and level of stress, there occurs considerable difference in glucose levels between capillary and venous measurements. This study aimed to investigate the comparability of capillary and venous glucose values, according to the perfusion index level obtained with the Masimo Radical-7(®) device, in critical patients aged 18 years and over. We conducted this prospective and observational study in the emergency department of the Eskisehir Osmangazi University hospital between November 3, 2008 and February 2, 2009. The blood glucose of 300 critical patients was checked by finger stick in the emergency unit. The participants with normal vital signs had perfusion index between 0 and 5; the results obtained by the two methods were more consistent for perfusion index values of 6 and over. The results were most consistent in aged participants with normal vital sign findings and low perfusion index and in young patients with high perfusion index. In the cases where at least one of the vital signs was abnormal, the glucose values obtained by the two methods were more consistent when the perfusion index was 6 or over. In this group, independently from the perfusion index value, the consistency was higher in younger patients compared with aged patients.

In the emergency department, perfusion index value measured by Masimo Radical-7 and capillary blood glucose levels can serve in blood sugar management in critically ill patients.

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Are multiple pathways responsible for anti-inflammatory and cardiovascular activities of Hordeum vulgare L?

Hordeum vulgare L. (HV or barley) is used by traditional healers to treat various inflammatory and cardiovascular diseases, without the knowledge of pharmacologic rationale behind its actions. This study was designed to explore the potential scientific mechanism(s) that could explain the use of Hordeum vulgare in traditional medicine as a treatment for various inflammatory and cardiovascular diseases. A crude extract and its three fractions were prepared from HV and screened for the inhibition of platelet aggregation and various metabolites of cyclooxygenase (COX), lipoxygenase (LOX) pathways of arachidonic acid (AA) metabolism as well as for its effects on certain antioxidant enzymes. Platelet aggregation was monitored using turbidometric principle, AA metabolism through radioimmunoassay and antioxidant enzymes by commercial kits using spectrophotometer. Results show that HV exhibited activities against all human platelet agonists used except adenine diphosphate, and inhibited both COX and LOX pathways of AA metabolism. It also elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). However, these activities were distributed in various fractions of HV. Aqueous fraction was most potent in elevating SOD activity; chloroform fraction had concentrated compounds responsible for COX inhibition while n-hexane seems to possess compounds responsible for LOX inhibition as well as the only fraction enhancing the activity of GPx.

These results suggest the likely mechanisms responsible for observed anti-inflammatory and cardiovascular effects of HV in traditional medicine.

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Does [ ITF increase the transcriptional activity of ITF promoter via the JAK-STAT3 signal transduction pathway ]?

To investigate the eff ect of intestinal trefoil factor (ITF) on the transcriptional activity of ITF promoter and to explore the regulatory mechanism of Janus kinase/signal transducers and activators of transcription (JAK/STAT) on ITF promoter. The 5' flanking sequence of the ITF gene was cloned from human whole blood genomic DNA by PCR. ITF promoter fragment was cloned and inserted into the pGL3-Basic vector to construct recombinant vector. ITF promoter vector was stimulated with ITF at various concentrations and the luciferase activity was measured. The JAK-STAT3 signal transduction pathway was then blocked by a specific inhibitor AG490 to determine the signal pathway involved in ITF promoter activity. Restriction endonuclease analysis and DNA sequencing confirmed that the recombinant plasmid, containing ITF promoter, was constructed successfully. After transient transfection, the activity of ITF promoter was increased significantly in the presence of ITF (P<0.05). Blockage of the JAK-STAT3 signal transduction pathway with AG490 significantly reduced the ITF promoter activity (P<0.05).

ITF increases the transcriptional activity of ITF promoter via the JAK-STAT3 signal transduction pathway.

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Does clinical evaluation of pazopanib eye drop versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration?

To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported.

Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

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Does long-term treadmill exercise attenuate tau pathology in P301S tau transgenic mice?

Recent epidemiological evidence suggests that modifying lifestyle by increasing physical activity could be a non-pharmacological approach to improving symptoms and slowing disease progression in Alzheimer's disease and other tauopathies. Previous studies have shown that exercise reduces tau hyperphosphorylation, however, it is not known whether exercise reduces the accumulation of soluble or insoluble tau aggregates and neurofibrillary tangles, which are both neuropathological hallmarks of neurodegenerative tauopathy. In this study, 7-month old P301S tau transgenic mice were subjected to 12-weeks of forced treadmill exercise and evaluated for effects on motor function and tau pathology at 10 months of age. Exercise improved general locomotor and exploratory activity and resulted in significant reductions in full-length and hyperphosphorylated tau in the spinal cord and hippocampus as well as a reduction in sarkosyl-insoluble AT8-tau in the spinal cord. Exercise did not attenuate significant neuron loss in the hippocampus or cortex. Key proteins involved in autophagy-microtubule-associated protein 1A/1B light chain 3 and p62/sequestosome 1 -were also measured to assess whether autophagy is implicated in the exercised-induced reduction of aggregated tau protein. There were no significant effects of forced treadmill exercise on autophagy protein levels in P301S mice.

Our results suggest that forced treadmill exercise differently affects the brain and spinal cord of aged P301S tau mice, with greater benefits observed in the spinal cord versus the brain. Our work adds to the growing body of evidence that exercise is beneficial in tauopathy, however these benefits may be more limited at later stages of disease.

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Does alpha and beta EEG power reflect L-dopa acute administration in parkinsonian patients?

To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients. We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson's disease (PD). Each patient underwent Unified Parkinson's Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores. Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor.

Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients.

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Does subclinical left ventricular dysfunction by echocardiographic speckle-tracking strain analysis relate to outcome in sarcoidosis?

Limited data exist on the risk of developing cardiac sarcoidosis (CS) and/or adverse events in sarcoidosis patients. Using LV global longitudinal strain (GLS), an emerging sensitive parameter of LV function, we evaluated the prevalence of subclinical cardiac dysfunction in sarcoidosis and investigated whether LVGLS predicts adverse outcomes in this population. A total of 130 patients with proven sarcoidosis undergoing echocardiography at our referral centre were identified. Following exclusion of those with evidence of CS (n = 14) or other pre-existing structural heart disease (n = 16), 100 patients (55 ± 13 years, 48% male, 90% pulmonary involvement) and 100 age- and gender-matched controls were included. LVGLS was measured by speckle-tracking analysis. The primary endpoint was a composite of all-cause mortality, heart failure hospitalization, device implantation, new arrhythmias, or future development of CS on advanced cardiac imaging modalities. LVGLS was significantly impaired in sarcoidosis patients compared with controls (-17.3 ± 2.5 vs. -20.0 ± 1.6%, P < 0.001). Overall, 27 patients (27%) reached the endpoint during a median follow-up of 35 months. On Cox proportional hazards model analysis, abnormal 24-h Holter, larger LV end-diastolic diameters, and more impaired LVGLS were significantly associated with the endpoint; however, only LVGLS remained independently associated on multivariate analysis [hazard ratio (HR) 1.4, 95% confidence interval (CI) 1.1-1.7, P = 0.006]. Patients with LVGLS less than -17.3% were significantly more likely to be free of the primary endpoint (log-rank P = 0.01).

LVGLS is impaired in sarcoidosis patients, suggesting subclinical cardiac dysfunction despite the absence of conventional evidence of cardiac disease, and is independently associated with occurrence of cardiac events and/or development of CS.

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Are guanine quadruplexes formed by specific regions of human transposable elements?

Transposable elements form a significant proportion of eukaryotic genomes. Recently, Lexa et al. (Nucleic Acids Res 42:968-978, 2014) reported that plant long terminal repeat (LTR) retrotransposons often contain potential quadruplex sequences (PQSs) in their LTRs and experimentally confirmed their ability to adopt four-stranded DNA conformations. Here, we searched for PQSs in human retrotransposons and found that PQSs are specifically localized in the 3'-UTR of LINE-1 elements, in LTRs of HERV elements and are strongly accumulated in specific regions of SVA elements. Circular dichroism spectroscopy confirmed that most PQSs had adopted monomolecular or bimolecular guanine quadruplex structures. Evolutionarily young SVA elements contained more PQSs than older elements and their propensity to form quadruplex DNA was higher. Full-length L1 elements contained more PQSs than truncated elements; the highest proportion of PQSs was found inside transpositionally active L1 elements (PA2 and HS families).

Conservation of quadruplexes at specific positions of transposable elements implies their importance in their life cycle. The increasing quadruplex presence in evolutionarily young LINE-1 and SVA families makes these elements important contributors toward present genome-wide quadruplex distribution.

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Is circulating soluble LR11 , a novel marker of smooth muscle cell proliferation , enhanced after coronary stenting in response to vascular injury?

Restenosis after vascular intervention remains a major clinical problem. Circulating LR11 has been shown a novel marker of intimal smooth muscle cell (SMC) proliferation in human and animal studies. The present study was performed to clarify the clinical significance of circulating LR11 in patients with stable angina pectoris after coronary stenting. We firstly investigated the circulating sLR11 levels for 28 days after arterial injury in mice, and then assessed time-dependent change in circulating sLR11 level after coronary stenting in a clinical study. Mouse sLR11 levels rapidly increased to 4.0-fold of the control value without cuff placement at postoperative day (POD) 14, and the levels gradually declined to 3.1-fold of the control value until POD 28 in mice. The circulating soluble LR11 levels were measured (before and at 14, 60 and 240 days after coronary stenting in a clinical study of 102 consecutive patients with stable angina pectoris who were treated with percutaneous coronary intervention. Circulating sLR11 levels were significantly increased on days 14 and 60 after the procedure and positively associated with the angiographic late loss index.

Our study suggested that circulating sLR11 levels may be a potential marker for angiographic late loss in patients after coronary stenting. Further mechanistic studies are expected to know the clinical significance of sLR11 as a novel marker for intimal SMC.

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Are de novo donor-specific HLA antibodies associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation?

The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001).

Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.

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Does a systematic review identify valid comorbidity indices derived from administrative health data?

To conduct a systematic review of studies reporting on the development or validation of comorbidity indices using administrative health data and compare their ability to predict outcomes related to comorbidity (ie, construct validity). We conducted a comprehensive literature search of MEDLINE and EMBASE, until September 2012. After title and abstract screen, relevant articles were selected for review by two independent investigators. Predictive validity and model fit were measured using c-statistic for dichotomous outcomes and R(2) for continuous outcomes. Our review includes 76 articles. Two categories of comorbidity indices were identified: those identifying comorbidities based on diagnoses, using International Classification of Disease codes from hospitalization or outpatient data, and based on medications, using pharmacy data. The ability of indices studied to predict morbidity-related outcomes ranged from poor (C statistic ≤ 0.69) to excellent (C statistic >0.80) depending on the specific index, outcome measured, and study population. Diagnosis-based measures, particularly the Elixhauser Index and the Romano adaptation of the Charlson Index, resulted in higher ability to predict mortality outcomes. Medication-based indices, such as the Chronic Disease Score, demonstrated better performance for predicting health care utilization.

A number of valid comorbidity indices derived from administrative data are available. Selection of an appropriate index should take into account the type of data available, study population, and specific outcome of interest.

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Do comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production?

The consumption of an agrarian diet is associated with a reduced risk for many diseases associated with a 'Westernised' lifestyle. Studies suggest that diet affects the gut microbiota, which subsequently influences the metabolome, thereby connecting diet, microbiota and health. However, the degree to which diet influences the composition of the gut microbiota is controversial. Murine models and studies comparing the gut microbiota in humans residing in agrarian versus Western societies suggest that the influence is large. To separate global environmental influences from dietary influences, we characterised the gut microbiota and the host metabolome of individuals consuming an agrarian diet in Western society. Using 16S rRNA-tagged sequencing as well as plasma and urinary metabolomic platforms, we compared measures of dietary intake, gut microbiota composition and the plasma metabolome between healthy human vegans and omnivores, sampled in an urban USA environment. Plasma metabolome of vegans differed markedly from omnivores but the gut microbiota was surprisingly similar. Unlike prior studies of individuals living in agrarian societies, higher consumption of fermentable substrate in vegans was not associated with higher levels of faecal short chain fatty acids, a finding confirmed in a 10-day controlled feeding experiment. Similarly, the proportion of vegans capable of producing equol, a soy-based gut microbiota metabolite, was less than that was reported in Asian societies despite the high consumption of soy-based products.

Evidently, residence in globally distinct societies helps determine the composition of the gut microbiota that, in turn, influences the production of diet-dependent gut microbial metabolites.

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Is disruption of SOX6 associated with a rapid-onset dopa-responsive movement disorder , delayed development , and dysmorphic features?

Sox6 is a transcription factor that is crucial for the differentiation and development of cortical interneurons and dopaminergic neurons of the substantia nigra pars compact. Loss-of-function mutations might thus result in complex paroxysmal diseases such as epilepsy syndromes or movement disorders. We present a 15-year-old boy with delayed speech development and attention deficit hyperactivity disorder who presented with a rapid-onset generalized dopa-responsive dystonia. Neurological examination revealed generalized dystonic and frequent athetoid movements of the arms, trunk, and neck. Gait was severely impaired secondary to frequent dystonic postures. Both a resting tremor and action tremors were observed in both hands. Speech was dysarthric but language comprehension was unimpaired. Testing for saccadic dysfunction revealed hypometric horizontal and vertical saccades. Physical examination was otherwise significant for a pectus carinatum and splenomegaly. Laboratory studies, brain magnetic resonance imaging, and electroencephalography were unremarkable. Treatment with levodopa/carbidopa led to a complete and sustained remission of neurological symptoms. Genetic testing revealed a mono-allelic de novo 84-kb deletion on chromosome 11p15.2 encompassing exons 14-16 of the SOX6 gene (chr11: 15944880-16029095, NCBI 37/hg19).

This is the first report of a dopa-responsive movement disorder associated with SOX6 disruption. SOX6 mutations should be considered in the differential diagnosis of unexplained dopa-responsive dystonia syndromes.

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Does capsular closure affect development of heterotopic ossification after hip arthroscopy?

The purpose of this study was to evaluate the role of capsular closure after hip arthroscopy in reduction of the incidence of heterotopic ossification (HO). One hundred (50 study group, 50 control group) consecutive hip arthroscopy procedures with radiographic follow-up of more than 9 weeks were included in the study. The study group consisted of 50 patients in whom capsular closure with 2 No. 1 polydioxanone (PDS) sutures was performed, and a control group consisted of 50 patients in whom the capsule remained open after capsulotomy. HO was assessed by radiographs using the Brooker classification. Statistical analysis of the data was carried out with the χ-square or Fisher exact test and Student t test, when appropriate, at a significance level of .05. Thirty-six (36%) patients had radiographic evidence of postoperative HO (14 patients in the capsular closure group). No significant difference was found regarding sex, side of operation, age, or HO rate between the study and the control groups (P = .778, P = .123, P = .744, and P = .144, respectively). Furthermore, no significant difference was found in the rate of HO with potential clinical significance (Brooker classification > I) between the control and study groups (P = .764).

Capsular closure did not seem to alter the rate of HO when compared with a control group of patients in whom the capsulotomy was not repaired.

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Do smoking and unstable hinge fractures cause delayed gap filling irrespective of early weight bearing after open wedge osteotomy?

The purpose of this study was to examine the osteotomy gap filling rate with new bone after open wedge high tibial osteotomy (HTO) without bone graft and the effects of smoking, lateral hinge fracture, and early full weight bearing. A prospective series (N = 70) of open wedge HTOs with the TomoFix plate (DePuy Synthes, Umkirch, Germany) was performed. Radiologic follow-up examinations took place postoperatively, after 6 and 12 weeks, and after 6, 12, and 18 months to measure osteotomy gap filling at each follow-up. Bone healing was compared in smokers versus nonsmokers who underwent open wedge HTOs with intact lateral hinges. Fractured lateral hinges were classified according to the Takeuchi classification and separately analyzed regarding bone healing. Patients were randomly assigned to undergo early (11 days) or standard (6 weeks) full-weight-bearing rehabilitation. A delay in the osteotomy gap filling rate between smokers and nonsmokers could be observed at all follow-up periods, but differences were not significant. A fracture of the lateral hinge was found in 39% of the patients. A type I fracture was observed in 14% of patients, a type II fracture was observed in 13%, and a type III fracture was found in 6%. The highest increase in the osteotomy gap filling rate was observed between 12 weeks and 6 months after surgery in patients with intact lateral hinges. For patients with unstable type II fractures, the highest increase in the gap filling rate was delayed until 6 to 12 months. Early full weight bearing had no effect on the gap filling rate in any of the patient groups evaluated.

This study shows that osteotomy gap filling after open wedge HTO is delayed in smokers and in patients in whom opening of the gap resulted in unstable lateral hinge fractures. Early full weight bearing did not have a significant effect on the gap filling rate.

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Is topical clobetasol in conjunction with topical tretinoin effective in preventing scar formation after superficial partial-thickness burn ulcers of the skin : A retrospective study?

Deep erythema and inflammation after re-epithelialization of superficial wounds is a sign of scar formation. Corticosteroids may prevent scarring by suppression of inflammation and fibroblast activity. Tretinoin may increase the efficacy of corticosteroids in this setting. To evaluate the efficacy of corticosteroids plus tretinoin for prevention of scars after superficial wounds. In a retrospective study of patients with superficial partial thickness thermal skin burn, we compared the patients who received clobetasol plus tretinoin after re-epithelialization with patients who did not receive any medication. Clobetasol propionate 0.05% ointment was used twice daily with overnight occlusive dressing in conjunction with twice weekly topical tretinoin 0.05% cream. Among 43 patients who had light pink or no erythema after re-epithelialization and consequently did not receive clobetasol + tretinoin, no scar was developed. Among patients who had deep erythema after re-epithelialization, rate of scar formation was significantly higher in 14 patients who did not receive clobetasol + tretinoin than in 21 patients who received clobetasol + tretinoin (64% and 19%, respectively; p = 0.01).

Clobetasol + tretinoin can significantly decrease the incidence of scar formation in patients with inflammation after re-epithelialization of superficial wounds.

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Does the rate of hypo-osmotic challenge influence regulatory volume decrease ( RVD ) and mechanical properties of articular chondrocytes?

Osteoarthritis (OA) is associated with a gradual reduction in the interstitial osmotic pressure within articular cartilage. The aim of this study was to compare the effects of sudden and gradual hypo-osmotic challenge on chondrocyte morphology and biomechanics. Bovine articular chondrocytes were exposed to a reduction in extracellular osmolality from 327 to 153 mOsmol/kg applied either suddenly (<5 s) or gradually (over 180 min). Temporal changes in cell diameter and the existence of regulatory volume decrease (RVD) were quantified along with changes in cortical actin and chromatin condensation. The cellular viscoelastic mechanical properties were determined by micropipette aspiration. In response to a sudden hypo-osmotic stress, 66% of chondrocytes exhibited an increase in diameter followed by RVD, whilst 25% showed no RVD. By contrast, cells exposed to gradual hypo-osmotic stress exhibited reduced cell swelling without subsequent RVD. There was an increase in the equilibrium modulus for cells exposed to sudden hypo-osmotic stress. However, gradual hypo-osmotic challenge had no effect on cell mechanical properties. This cell stiffening response to sudden hypo-osmotic challenge was abolished when actin organization was disrupted with cytochalasin D or RVD inhibited with REV5901. Both sudden and gradual hypo-osmotic challenge reduced cortical F-actin distribution and caused chromatin decondensation.

Sudden hypo-osmotic challenge increases chondrocyte mechanics by activation of RVD and interaction with the actin cytoskeleton. Moreover, the rate of hypo-osmotic challenge is shown to have a profound effect on chondrocyte morphology and biomechanics. This important phenomenon needs to be considered when studying the response of chondrocytes to pathological hypo-osmotic stress.

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Does liver-specific deletion of augmenter of liver regeneration accelerate development of steatohepatitis and hepatocellular carcinoma in mice?

Augmenter of liver regeneration (ALR, encoded by GFER) is a widely distributed pleiotropic protein originally identified as a hepatic growth factor. However, little is known about its roles in hepatic physiology and pathology. We created mice with liver-specific deletion of ALR to study its function. We developed mice with liver-specific deletion of ALR (ALR-L-KO) using the albumin-Cre/LoxP system. Liver tissues were collected from ALR-L-KO mice and ALR(floxed/floxed) mice (controls) and analyzed by histology, reverse-transcription polymerase chain reaction, immunohistochemistry, electron microscopy, and techniques to measure fibrosis and lipids. Liver tissues from patients with and without advanced liver disease were determined by immunoblot analysis. Two weeks after birth, livers of ALR-L-KO mice contained low levels of ALR and adenosine triphosphate (ATP); they had reduced mitochondrial respiratory function and increased oxidative stress, compared with livers from control mice, and had excessive steatosis, and hepatocyte apoptosis. Levels of carbamyl-palmitoyl transferase 1a and ATP synthase subunit ATP5G1 were reduced in livers of ALR-L-KO mice, indicating defects in mitochondrial fatty acid transport and ATP synthesis. Electron microscopy showed mitochondrial swelling with abnormalities in shapes and numbers of cristae. From weeks 2-4 after birth, levels of steatosis and apoptosis decreased in ALR-L-KO mice, and numbers of ALR-expressing cells increased, along with ATP levels. However, at weeks 4-8 after birth, livers became inflamed, with hepatocellular necrosis, ductular proliferation, and fibrosis; hepatocellular carcinoma developed by 1 year after birth in nearly 60% of the mice. Hepatic levels of ALR were also low in ob/ob mice and alcohol-fed mice with liver steatosis, compared with controls. Levels of ALR were lower in liver tissues from patients with advanced alcoholic liver disease and nonalcoholic steatohepatitis than in control liver tissues.

We developed mice with liver-specific deletion of ALR, and showed that it is required for mitochondrial function and lipid homeostasis in the liver. ALR-L-KO mice provide a useful model for investigating the pathogenesis of steatohepatitis and its complications.

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Does transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveal proton pump inhibitor-reversible allergic inflammation?

Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery. In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities. We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE. The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment.

These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.

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Is a high normal thyroid-stimulating hormone associated with arterial stiffness , central systolic blood pressure , and 24-hour systolic blood pressure in males with treatment-naïve hypertension and euthyroid?

We compared the results of laboratory examinations, echocardiography, arterial stiffness, central blood pressure (BP) and ambulatory BP monitoring (ABPM) between treatment-naïve patients with low normal thyroid-stimulating hormone (TSH) and those with high normal TSH levels. A total of 285 consecutively-eligible patients with both treatment-naïve hypertension and euthyroid were divided into two groups: those with low-normal TSH (0.40-1.99 μIU/mL, group 1) and high-normal TSH (2.00-4.50 μIU/mL, group 2) and compared according to group and gender. Males were divided into group 1 (n = 113, 68.9%) and group 2 (n = 51, 31.1%) and females were divided into group 1 (n = 71, 58.7%) and group 2 (n = 50, 41.3%). Multivariate analyses revealed that the augmentation index (71.0 [adjusted mean] ± 1.7 [standard error] vs. 78.8 ± 2.5%, P = 0.045), central systolic BP (SBP) (143.3 ± 2.1 vs. 153.0 ± 3.2 mmHg, P = 0.013), systemic vascular resistance (SVR, 21.4 ± 0.6 vs. 23.9 ± 0.9 mmHg/L/min, P = 0.027), SBP during daytime (144.1 ± 1.4 vs. 151.6 ± 2.1 mmHg, P=0.004) and nighttime (130.4 ± 1.6 vs. 138.5 ± 2.5 mmHg, P=0.008), and nighttime pulse pressure (PP, 47.2 ± 0.9 vs. 51.7 ± 1.4 mmHg, P = 0.010) were significantly higher while cardiac output (5.4 ± 0.1 vs. 4.8 ± 0.2L/min, P = 0.043) and PP amplification (1.02 ± 0.02 vs. 0.94 ± 0.03, P = 0.039) were significantly lower in the male group 2 than in the male group 1. However, there were no significant differences between the two groups in females.

Treatment-naïve hypertensive males with high normal TSH and euthyroid showed higher arterial stiffness, central SBP, SVR, and SBP in ABPM and lower cardiac output and PP amplification as compared to the the low normal TSH group, but not females.

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Does rotenone impair autophagic flux and lysosomal functions in Parkinson 's disease?

Rotenone is an environmental neurotoxin that induces accumulation of α-synuclein and degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc), but the molecular mechanisms are not fully understood. We investigated whether rotenone induced impairment of autophagic flux and lysosomal functions. Autophagy flux, accumulation of α-synuclein, lysosomal membrane integrity and neurodegeneration were assessed in the rotenone-treated rat model and PC12 cells, and the effects of the autophagy inducer trehalose on rotenone's cytotoxicity were also studied. Rotenone administration significantly reduced motor activity and caused a loss of tyrosine hydroxylase in SNpc of Lewis rats. The degeneration of nigral dopaminergic neurons was accompanied by the deposition of α-synuclein aggregates, autophagosomes and redistribution of cathepsin D from lysosomes to the cytosol. In cultured PC12 cells, rotenone also induced increases in protein levels of α-synuclein, microtubule-associated protein 1 light chain 3-II, Beclin 1, and p62. Rotenone increased lysosomal membrane permeability as evidenced by leakage of N-acetyl-beta-d-glucosaminidase and cathepsin D, the effects were blocked by reactive oxygen species scavenger tiron. Autophagy inducer trehalose enhanced the nuclear translocation of transcription factor EB, accelerated the clearance of autophagosomes and α-synuclein and attenuated rotenone-induced cell death of PC12 cells. Meanwhile, administration of trehalose to rats in drinking water (2%) decreased rotenone-induced dopaminergic neurons loss in SNpc.

These studies indicate that the lysosomal dysfunction contributes to rotenone's neurotoxicity and restoration of lysosomal function could be a new therapeutic strategy for Parkinson's disease.

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Is interleukin-6 associated with obesity , central fat distribution , and disease severity in patients with acute pancreatitis?

Acute pancreatitis (AP) is a systemic inflammatory disease, and cytokines are suggested to be related to the course of AP. Obesity and central fat distribution are considered to have been associated with severe AP. This study investigated the profile of inflammatory cytokines in AP to determine how they are related to obesity, central fat distribution, and AP severity. Fifty-nine patients with AP were prospectively enrolled in the study. Body mass index and waist circumference were obtained at admission. Serum levels of inflammatory cytokines, IL-Iβ, IL-1ra, IL-6, TNF-α, sTNFR-I, and sTNFR-II, were measured on day 1 and 2 of AP. Of the patients included in the study, 19 (32%) were overweight, 23 (39%) had central fat distribution, and 23 (39%) had moderate AP. IL-1ra and IL-6 were significantly higher in overweight patients compared with non-overweight patients. IL-1ra, IL-6, TNF-α, and sTNFR-I were significantly higher in patients with central fat distribution compared with patients with non-central fat distribution. IL-6, sTNFR-I, and sTNFR-II were significantly higher in patients with moderate pancreatitis compared to those with mild pancreatitis. Among the six cytokines, IL-6 was commonly elevated in patients with central fat distribution, overweight, and moderate AP. The areas under the receiver operating characteristic curves of IL-6 for predicting the association with overweight, central fat distribution, and AP severity were 0.678, 0.716, and 0.801, respectively (P < 0.05).

IL-6 is a good marker for AP severity and is associated with obesity and central fat distribution in AP patients.

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Is platelet activation associated with myocardial infarction in patients with pneumonia?

Troponins may be elevated in patients with pneumonia, but associations with myocardial infarction (MI) and with platelet activation are still undefined. The aim of this study was to investigate the relationship between troponin elevation and in vivo markers of platelet activation in the early phase of hospitalization of patients affected by community-acquired pneumonia. A total of 278 consecutive patients hospitalized for community-acquired pneumonia, who were followed up until discharge, were included. At admission, platelet activation markers such as plasma soluble P-selectin, soluble CD40 ligand, and serum thromboxane B2 (TxB2) were measured. Serum high-sensitivity cardiac troponin T levels and electrocardiograms were obtained every 12 and 24 h, respectively. Among 144 patients with elevated high-sensitivity cardiac troponin T, 31 had signs of MI and 113 did not. Baseline plasma levels of soluble P-selectin and soluble CD40 ligand and serum TxB2 were significantly higher in patients who developed signs of MI. Logistic regression analysis showed plasma soluble CD40 ligand (p < 0.001) and soluble P-selectin (p < 0.001), serum TxB2 (p = 0.030), mean platelet volume (p = 0.037), Pneumonia Severity Index score (p = 0.030), and ejection fraction (p = 0.001) to be independent predictors of MI. There were no significant differences in MI rate between the 123 patients (45%) taking aspirin (100 mg/day) and those who were not aspirin treated (12% vs. 10%; p = 0.649). Aspirin-treated patients with MIs had higher serum TxB2 compared with those without MIs (p = 0.005).

MI is an early complication of pneumonia and is associated with in vivo platelet activation and serum TxB2 overproduction; aspirin 100 mg/day seems insufficient to inhibit thromboxane biosynthesis. (MACCE in Hospitalized Patients With Community-acquired Pneumonia; NCT01773863).

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Is fasting serum dipeptidyl peptidase-4 activity independently associated with alanine aminotransferase in type 1 diabetic patients?

Dipeptidyl peptidase-4 (DPP4) was recently proposed as a novel adipokine linked to insulin resistance (IR). As IR represents a cluster of disorders in hepatic and muscle cell insulin signalisation, we aimed to assess the possible correlation between fasting serum DPP4 activity, IR and liver enzymes in order to elucidate the question of hepatic contribution to serum DPP4 activity. This cross-sectional study comprised 44 T1DM patients aged 18 to 65years. IR was estimated using the equation derived from euglycemic-hyperinsulinemic clamp studies-estimated glucose disposal rate (eGDR). DPP4 serum activity was determined spectrophotometrically as a rate of cleavage of 7-amino-4-methyl coumarin (AMC) from H-Gly-Pro-AMC. The patients were divided into two groups according to the mean value of fasting serum DPP4 activity (31.42U/L). The group with lower fasting serum DPP4 activity had lower mean rate of liver biomarkers alanine aminotransferase (ALT) (p=0.001) and aspartate aminotransferase (AST) (p=0.002) while higher eGDR (p=0.003) compared to group with higher DPP4 activity. DPP4 activity showed positive correlation with AST (r=0.358, p=0.017) and ALT (r=0.364, p=0.015) while negative correlation with eGDR (r=-0.612, p<0.001). ALT remained positively associated with fasting serum DPP4 activity after controlling for age, gender, diabetes duration, the use of statins and antihypertensives (p=0.025).

Fasting serum DPP4 activity might be associated with hepatic IR in T1DM patients and a part of soluble DPP4 activity might be of a hepatic origin. Further study investigation is warranted to elucidate this topic.

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Is initial combination therapy with metformin , pioglitazone and exenatide more effective than sequential add-on therapy in subjects with new-onset diabetes . Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes ( EDICT ) : a randomized trial?

To test our hypothesis that initiating therapy with a combination of agents known to improve insulin secretion and insulin sensitivity in subjects with new-onset diabetes would produce greater, more durable reduction in glycated haemoglobin (HbA1c) levels, while avoiding hypoglycaemia and weight gain, compared with sequential addition of agents that lower plasma glucose but do not correct established pathophysiological abnormalities. Drug-naïve, recently diagnosed subjects with type 2 diabetes mellitus (T2DM) were randomized in an open-fashion design in a single-centre study to metformin/pioglitazone/exenatide (triple therapy; n = 106) or an escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin (conventional therapy; n = 115) to maintain HbA1c levels at <6.5% for 2 years. Participants receiving triple therapy experienced a significantly greater reduction in HbA1c level than those receiving conventional therapy (5.95 vs. 6.50%; p < 0.001). Despite lower HbA1c values, participants receiving triple therapy experienced a 7.5-fold lower rate of hypoglycaemia compared with participants receiving conventional therapy. Participants receiving triple therapy experienced a mean weight loss of 1.2 kg versus a mean weight gain of 4.1 kg (p < 0.01) in those receiving conventional therapy.

The results of this exploratory study show that combination therapy with metformin/pioglitazone/exenatide in patients with newly diagnosed T2DM is more effective and results in fewer hypoglycaemic events than sequential add-on therapy with metformin, sulfonylurea and then basal insulin.

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Does diet-induced obesity prevent the development of acute traumatic coagulopathy?

Obesity and hemorrhagic shock following trauma are predictors of mortality but have conflicting effects on coagulation. Following hemorrhage, tissue injury and hypoperfusion lead to acute traumatic coagulopathy (ATC), producing a hypocoagulable state. Inversely, obesity promotes clotting and impairs fibrinolysis to yield a hypercoagulable state. High rates of venous thromboembolism, organ failure, and early mortality may be caused by hypercoagulability in obese patients. We hypothesize that obesity prevents the development of ATC following injury-induced hemorrhagic shock. Male Sprague-Dawley rats (250-275 g) were fed a high-fat diet (32%kcal from fat) for 4 weeks to 6 weeks and diverged into obesity-resistant (OR, n = 9) and obesity-prone (OP, n = 9) groups. Age-matched control (CON) rats were fed normal diet (10% kcal from fat, n = 9). Anesthetized rats were subjected to an uncontrolled hemorrhage by a Grade V splenic injury to a mean arterial pressure (MAP) of 40 mm Hg. Hypotension (MAP, 30-40 mm Hg) was maintained for 30 minutes to induce shock. MAP, heart rate, lactate, base excess, cytokines, blood loss, and thrombelastography (TEG) parameters were measured before and after hemorrhagic shock. At baseline, OP rats exhibited a shorter time to 20-mm clot (K), and higher rate of clot formation (α angle), clot strength (maximal amplitude), and coagulation index, compared with the CON rats (p < 0.05), indicating enhanced coagulation. Physiologic parameters following shock were similar between groups. In the CON and OR rats, shock prolonged the time to clot initiation (R) and K and decreased α angle and coagulation index (all p < 0.05 vs. baseline). In contrast, shock had no effect on these TEG parameters in the OP rats. Maximal amplitude was the only TEG parameter affected by shock in the OP rats, which was decreased in all groups.

Obesity prevents the development of ATC following hemorrhage shock. Complications associated with obesity following hemorrhagic shock may be attributed to the preserved hypercoagulable state.

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Do endothelial progenitor cells induce transplant arteriosclerosis via VEGFR-1/2 activity?

Acute rejection (AR) after organ transplantation results in transplant arteriosclerosis (TA). Endothelial progenitor cells (EPCs) are involved in tissue repair and blood vessel formation but are suspected to be a cause of TA. In this study, we introduced a syngeneic and allogeneic abdominal aortic transplant model with C57BL/6 and BALB/c mice. Syngeneic and allogeneic grafts were histopathologically analyzed after transplantation. Bone marrow-derived EPCs were injected into transplant model animals to observe their distribution and temporal concentration changes. Changes of vascular endothelial growth factor receptor 1 (VEGFR-1), phosphorylated VEGFR-1 (pVEGFR-1), VEGFR-2, pVEGFR-2, protein kinase B (Akt), pAkt, extracellular signal-regulated kinase 1 (Erk1), pErk1 levels in EPCs upon VEGF165 and the VEGFR inhibitor Vandetanib exposure were analyzed in vitro with western blotting. In the allogeneic transplant group, two weeks after transplantation, formations of new intima layers could be observed, and its proliferation gradually increased to four and six weeks post-transplantation (p < 0.05), accompanied by significant arterial stenoses. Exogenous EPCs mainly localized to the damaged sites of the transplant arteries. In vivo, Vandetanib caused a significant dose dependent decrease of transplant hyperplasia (p < 0.05) and inhibited VEGF related proliferation, migration and adhesion of EPCs.

Vandetanib treatment can reduce arteriosclerosis induced by abdominal aorta transplantation by blocking VEGFRs in EPCs.

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Are elevated beta2-glycoprotein I-low-density lipoprotein levels associated with the presence of diabetic microvascular complications?

To investigate serum beta2-glycoprotein I-low-density lipoprotein (β2-GPI-LDL) and oxidized low-density lipoprotein (ox-LDL) levels in type 2 diabetes mellitus (T2DM) patients, and to further evaluate the associations of β2-GPI-LDL with ox-LDL in vivo and with the presence of diabetic microvascular complications. We determined β2-GPI-LDL, ox-LDL and small dense low density lipoprotein cholesterol (sdLDL-C) levels in 236 T2DM patients with or without microvascular complications and 75 controls. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. Compared with controls, β2-GPI-LDL and ox-LDL levels were significantly elevated in both groups of T2DM patients and those with microvascular complications exhibited the more significant increase than those without complications. Serum β2-GPI-LDL levels were positively correlated with ox-LDL as well as sdLDL-C levels in T2DM patients. Multiple linear regression analyses showed that ox-LDL was one of the independent determinants of β2-GPI-LDL levels. Logistic regression analyses indicated that elevated β2-GPI-LDL and ox-LDL levels had significant predictive values for diabetic microvascular complications.

Elevated serum β2-GPI-LDL levels may be a serological hallmark of enhanced LDL oxidation in vivo and closely associated with the presence of diabetic microvascular complications.

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Is bone marrow from blotchy mice dispensable to regulate blood copper and aortic pathologies but required for inflammatory mediator production in LDLR-deficient mice during chronic angiotensin II infusion?

The blotchy mouse caused by mutations of ATP7A develops low blood copper and aortic aneurysm and rupture. Although the aortic pathologies are believed primarily due to congenital copper deficiencies in connective tissue, perinatal copper supplementation does not produce significant therapeutic effects, hinting additional mechanisms in the symptom development, such as an independent effect of the ATP7A mutations during adulthood. We investigated if bone marrow from blotchy mice contributes to these symptoms. For these experiments, bone marrow from blotchy mice (blotchy marrow group) and healthy littermate controls (control marrow group) was used to reconstitute recipient mice (irradiated male low-density lipoprotein receptor -/- mice), which were then infused with angiotensin II (1,000 ng/kg/min) for 4 weeks. By using Mann-Whitney U test, our results showed that there was no significant difference in the copper concentrations in plasma and hematopoietic cells between these 2 groups. And plasma level of triglycerides was significantly reduced in blotchy marrow group compared with that in control marrow group (P < 0.05), whereas there were no significant differences in cholesterol and phospholipids between these 2 groups. Furthermore, a bead-based multiplex immunoassay showed that macrophage inflammatory protein (MIP)-1β, monocyte chemotactic protein (MCP)-1, MCP-3, MCP-5, tissue inhibitor of metalloproteinases (TIMP)-1, and vascular endothelial growth factor (VEGF)-A production was significantly reduced in the plasma of blotchy marrow group compared with that in control marrow group (P < 0.05). More important, although angiotensin II infusion increased maximal external aortic diameters in thoracic and abdominal segments, there was no significant difference in the aortic diameters between these 2 groups. Furthermore, aortic ruptures, including transmural breaks of the elastic laminae in the abdominal segment and lethal rupture in the thoracic segment, were observed in blotchy marrow group but not in control marrow group; however, there was no significant difference in the incidence of aortic ruptures between these 2 groups (P = 0.10; Fisher's exact test).

Overall, our study indicated that the effect of bone marrow from blotchy mice during adulthood is dispensable in the regulation of blood copper, plasma cholesterol and phospholipids levels, and aortic pathologies, but contributes to a reduction of MIP-1β, MCP-1, MCP-3, MCP-5, TIMP-1, and VEGF-A production and triglycerides concentration in plasma. Our study also hints that bone marrow transplantation cannot serve as an independent treatment option.

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Are maternal salivary cortisol levels during pregnancy positively associated with overweight children?

Animal and human studies suggest that programing of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the development of obesity, but human studies of biological indicators of HPA axis activity are lacking. We studied the association between levels of the stress hormone cortisol during pregnancy and overweight offspring during childhood into adolescence. Salivary samples from 655 Danish pregnant women with singleton pregnancies (1989-1991) were collected once in the morning and once in the evening in their second and third trimester. We followed the offspring from two to 16 years of age with at least one measurement of height and weight, and classified their body mass index into overweight and normal weight. The adjusted relative difference in median salivary cortisol (with 95% confidence interval (CI)) during pregnancy (the four samples), in second and third trimester (morning and evening samples) between overweight and normal weight offspring was estimated. Furthermore, the adjusted median ratio between morning and evening maternal salivary cortisol level was estimated for normal weight and overweight children. All the analyses were stratified into the equal age groups: 2-6, 7-11, and 12-16 years. We found non-significant higher maternal cortisol levels during pregnancy in offspring that were overweight at the age of 2-6, 7-11 and 12-16 years than in normal weight peers; adjusted relative difference in median salivary cortisol 11% (95% CI: -2; 25), 6% (95% CI: -7; 20), and 9% (95% CI: -4; 24), respectively. A statistically significantly higher level of maternal cortisol was found in the second trimester in 2-6-year-old and 12-16-year-old overweight offspring; relative difference 19% (95% CI: 3; 37), and 20% (95% CI: 3; 41), respectively. The median ratio between morning and evening maternal salivary cortisol level was similar for overweight and normal weight children; e.g. at age 2-6 years in third trimester 4.31 (95% CI: 4.05; 4.60)nmol/l and 4.28 (95% CI: 3.60; 5.09)nmol/l, respectively (P=0.93).

Our findings suggest a relatively consistent association between pregnancy cortisol levels and overweight offspring, especially in the second trimester.

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Is less advanced disease at initiation of salvage androgen deprivation therapy associated with decreased mortality following biochemical failure post-salvage radiation therapy?

The optimal clinical context for initiation of salvage androgen deprivation therapy (SADT) following the biochemical recurrence of localized prostate cancer remains controversial. We chose to investigate if disease burden at time of SADT initiation is associated with clinical outcomes following biochemical failure (BF) post-salvage radiation therapy (SRT). Medical records of 575 patients receiving SRT at a single institution from 1986-2010 were retrospectively reviewed. Of 250 patients experiencing BF post-SRT, 172 had a calculable prostate-specific antigen doubling time (PSADT) prior to SADT initiation. These patients comprise the analyzed cohort and were divided into four groups based on characteristics at SADT initiation: those with PSADTs >3 months without distant metastasis (DM) (group 1 [less advanced disease], n=62), those with PSADTs <3 months without DM (group 2 [more advanced disease], n=28), those with DM (group 3 [more advanced disease], n=32), and those not receiving SADT during follow-up (group 4, n=50). Endpoints included prostate cancer-specific mortality (PCSM) and overall mortality (OM). Kaplan-Meier methods were used to estimate survival, and Cox proportional hazards models were used for multivariate analysis. Median follow-up post-SRT was 7.9 years. Patients starting SADT with more advanced disease were at significantly increased risk for PCSM (hazard ratio [HR]:2.8, 95% confidence interval [CI]: 1.4-5.6, p=0.005) and OM (HR:1.9, 95% CI: 1.0-3.5, p=0.04) compared to those receiving SADT with less advanced disease. PCSM and OM did not significantly differ between groups 1 and 4 or groups 2 and 3. Of note, patients in group 4 had very long PSADTs (median = 27.0 months) that were significantly longer than those of group 1 (median = 6.0 months) (p<0.001). Multivariate analysis including groups 1-3 found a pre-SADT PSADT <3 months to be the most significant predictor of PCSM (HR:4.2, 95% CI: 1.6-11.1, p=0.004) and the only significant predictor of OM (HR:2.9, 95% CI: 1.3-6.7, p=0.01).

Less advanced disease at initiation of SADT is associated with decreased PCSM and OM following BF post-SRT; however, observation may be reasonable for patients with very long PSADTs. A PSADT <3 months prior to SADT initiation significantly predicts an increased risk of PCSM and OM in this patient demographic.

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Is low postoperative platelet count associated with negative outcome after liver resection for hepatocellular carcinoma?

Hepatocellular carcinoma is one of the most common malignancies worldwide. The only curative treatment is surgery. As hepatocellular carcinoma is often associated with liver cirrhosis, patients are at risk for postoperative liver failure. In the recent years, platelets are thought to play an important role in liver regeneration.The aim of this study was to discover the relevance of postoperative platelet counts after liver resection for hepatocellular carcinoma. Data of 68 patients who underwent liver resection for hepatocellular carcinoma between July 2007 and July 2012 in a single centre were analysed. Postoperative morbidity and mortality were evaluated in regard to postoperative platelet counts. Comparative analysis between patients with platelet counts ≤100 2x109/ l and >100 x109/ l at d1 was performed in regard to postoperative outcome. Within this cohort, 43 patients (63%) suffered from histologically proven liver cirrhosis. Postoperative mortality was statistically significant associated with postoperative reduced platelet counts. Comparative analysis showed significantly elevated postoperative bilirubin levels and lower prothrombin time in patients with platelet counts ≤ 100 1x109/ l at d1.

Postoperative low platelet counts are associated with poor outcome after hepatic resection for hepatocellular carcinoma.

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Does early menarche increase the risk of Type 2 diabetes in young and middle-aged Korean women?

To investigate the association between early menarche (menarche age < 12 years) and Type 2 diabetes mellitus in young and middle-aged Korean women. We analysed data for 4657 women aged 20-50 years from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) (2007-2009). The prevalence of Type 2 diabetes was 2.8%. Women with early menarche had a higher prevalence of impaired fasting glucose than did women with later menarche (age ≥ 12 years) in the 20-30 age group (7.4% vs. 3.0%), and a higher prevalence of diabetes in the 30-40 (6.3% vs. 1.7%) and 40-50 (18.5% vs. 4.4%) age groups. The odds ratio (OR) of Type 2 diabetes in women with early menarche was 3.61 [95% confidence interval (CI), 1.90-6.88] after adjusting for age. In multivariate regression, the OR of Type 2 diabetes decreased to 2.52 (95% CI, 1.29-4.94) after further adjusting for BMI. However, the OR decreased to 2.04 (95% CI, 0.95-4.39) without significance after adjusting for HOMA-IR.

Early menarche increased the risk of Type 2 diabetes in young and middle-aged Korean women although adulthood adiposity attenuated the relationship. Knowledge of age at menarche is important in identifying women at risk for diabetes.

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Does twenty-four hour in-hospital congenital cardiac surgical coverage improve perioperative ECMO support outcomes?

Extracorporeal membrane oxygenation (ECMO) support is often required in the management of perioperative congenital heart surgery (CHS) patients. However, 24-hour in-hospital congenital cardiac surgical coverage (24-CCSC) is not available at all institutions. The purpose of this study is to evaluate the effect of 24-CCSC on perioperative ECMO outcomes in CHS patients. An institutional review board approved, retrospective review of 128 perioperative CHS ECMO patients at a single, quaternary care children's hospital between January 2003 and December 2012 was performed. Primary endpoints evaluated were mortality in children supported with ECMO after undergoing cardiac surgery and ECMO-related morbidity after initiation of 24-CCSC with advanced congenital cardiac surgical fellows. Patients were divided into 2 groups based on whether 24-CCSC was absent (cohort 1: January 2003 to July 2007) or present (cohort 2: August 2007 to December 2012) at the time of ECMO management. The surgical procedures performed were similar in both cohorts based on STAT Mortality Categories (5 Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Categories). The overall mortality rate in children supported with ECMO after undergoing cardiac surgery was 53%. This mortality was significantly reduced from 68% to 43% (p = 0.007) with 24-CCSC. Multivariate logistic regression analysis revealed that 24-CCSC (p = 0.009) and lower STAT Mortality Category (p = 0.042) were independent predictors of operative survival. Cardiac arrhythmias (36% to 16%; p = 0.012) and pulmonary complications (32% to 8%; p < 0.001) were significantly reduced with 24-CCSC.

The presence of 24-CCSC significantly decreased the rate of mortality in children supported with ECMO after undergoing cardiac surgery, as well as cardiac arrhythmias and pulmonary complications for perioperative CHS patients receiving ECMO support. This study demonstrates that CHS programs would benefit from 24-CCSC in the care of this critically ill patient population.

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Does early primary repair of tetralogy of Fallot lead to increased postoperative resource utilization?

Although early primary repair of tetralogy of Fallot has gained wider acceptance, there is some speculation that repair at a younger age may be associated with increased morbidity and resource utilization. A retrospective review of all consecutive patients undergoing tetralogy of Fallot repair between September 2004 and December 2011 was performed. Primary end points were hospital charges, and surrogates of postoperative hospital resource utilization, including ventilation time, intensive care unit (ICU) stay, and hospital stay. The secondary end point was operative death. Logistic regression analysis was used to determine factors associated with increased postoperative hospital resource utilization. Among 164 patients in the study, there was 1 hospital death (0.6%). After excluding 9 patients who had palliative procedures before their repair, 155 comprised the primary repair group. Multivariate linear regression analysis revealed prematurity (p = 0.018), a nonelective operation (p < 0.001), and major extracardiac anomalies (p = 0.003) were independent predictors of increased postoperative hospital charges. Prematurity (p < 0.002), low birth weight (p = 0.047), and major extracardiac anomalies (p < 0.001) were significant predictors of increased ventilation time. Prematurity (p < 0.001), a nonelective operation (p < 0.001), and low birth weight (p = 0.048) significantly increased ICU length of stay. A nonelective operation (p = 0.025) and major extracardiac anomalies (p < 0.001) were predictors of an increased hospital stay. Younger age at repair was not associated with any increase in ventilation time, ICU stay, hospital stay, or with an increase in hospital charges.

Extracardiac anomalies, prematurity, low birth weight, and nonelective surgical intervention are predictors of increased morbidity and increased hospital resource utilization and impose a significant cost burden to the care of these patients. Early primary repair of tetralogy of Fallot can be safely performed without any increase in morbidity or increased hospital resource utilization.

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Are aggregate National Early Warning Score ( NEWS ) values more important than high scores for a single vital signs parameter for discriminating the risk of adverse outcomes?

The Royal College of Physicians (RCPL) National Early Warning Score (NEWS) escalates care to a doctor at NEWS values of ≥5 and when the score for any single vital sign is 3. We calculated the 24-h risk of serious clinical outcomes for vital signs observation sets with NEWS values of 3, 4 and 5, separately determining risks when the score did/did not include a single score of 3. We compared workloads generated by the RCPL's escalation protocol and for aggregate NEWS value alone. Aggregate NEWS values of 3 or 4 (n=142,282) formed 15.1% of all vital signs sets measured; those containing a single vital sign scoring 3 (n=36,207) constituted 3.8% of all sets. Aggregate NEWS values of either 3 or 4 with a component score of 3 have significantly lower risks (OR: 0.26 and 0.53) than an aggregate value of 5 (OR: 1.0). Escalating care to a doctor when any single component of NEWS scores 3 compared to when aggregate NEWS values ≥5, would have increased doctors' workload by 40% with only a small increase in detected adverse outcomes from 2.99 to 3.08 per day (a 3% improvement in detection).

The recommended NEWS escalation protocol produces additional work for the bedside nurse and responding doctor, disproportionate to a modest benefit in increased detection of adverse outcomes. It may have significant ramifications for efficient staff resource allocation, distort patient safety focus and risk alarm fatigue. Our findings suggest that the RCPL escalation guidance warrants review.

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Are plant communities on infertile soils less sensitive to climate change?

Much evidence suggests that plant communities on infertile soils are relatively insensitive to increased water deficit caused by increasing temperature and/or decreasing precipitation. However, a multi-decadal study of community change in the western USA does not support this conclusion. This paper tests explanations related to macroclimatic differences, overstorey effects on microclimate, variation in soil texture and plant functional traits. A re-analysis was undertaken of the changes in the multi-decadal study, which concerned forest understorey communities on infertile (serpentine) and fertile soils in an aridifying climate (southern Oregan) from 1949-1951 to 2007-2008. Macroclimatic variables, overstorey cover and soil texture were used as new covariates. As an alternative measure of climate-related change, the community mean value of specific leaf area was used, a functional trait measuring drought tolerance. We investigated whether these revised analyses supported the prediction of lesser sensitivity to climate change in understorey communities on infertile serpentine soils. Overstorey cover, but not macroclimate or soil texture, was a significant covariate of community change over time. It strongly buffered understorey temperatures, was correlated with less change and averaged >50 % lower on serpentine soils, thereby counteracting the lower climate sensitivity of understorey herbs on these soils. Community mean specific leaf area showed the predicted pattern of less change over time in serpentine than non-serpentine communities.

Based on the current balance of evidence, plant communities on infertile serpentine soils are less sensitive to changes in the climatic water balance than communities on more fertile soils. However, this advantage may in some cases be lessened by their sparser overstorey cover.

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Does licochalcone-A sensitize human esophageal carcinoma cells to TRAIL-mediated apoptosis by proteasomal degradation of XIAP?

Esophageal carcinoma is one of the most aggressive human cancers, and novel treatment modality is required. Although expressing adequate levels of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, significant proportion of esophageal cancer cells exhibit resistance to the cytotoxic effect of this ligand. Licochalcone-A (LA), a flavonoid present in a variety of edible plants, exhibits a wide spectrum of pharmacologic properties such as anticancer, antioxidant, and anti-inflammatory activities. Eca109 and TE1 cells were cultured and transfected, then their viability was detected using MTT assay. Immunoprecipitation and immunoblotting analysis and RT-PCR analysis were also performed. In this study, we found that LA synergistically caused the TRAIL-induced apoptosis in Eca109 and TE1 cells. Such potentiation was achieved through inhibiting Akt activation and promoting proteasomal degradation of X-linked Inhibitor of Apoptosis Protein (XIAP) which mediated the survival signals and allow the cells to escape from apoptosis in various human cancers.

The combination of TRAIL and LA might be a novel therapeutic strategy for esophageal carcinoma patients who fail to respond to standard chemotherapy.

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Is intranodal cytokeratin particles a predictive marker of efficacy for neoadjuvant therapies in patients with squamous cell carcinoma of the esophagus?

Lymph node metastasis is one of the most important prognostic factors in patients with esophageal squamous cell carcinoma (ESCC). Neoadjuvant treatment can reduce micrometastasis in lymph nodes to enable curative resection by down staging. The aim of this study was to evaluate the histological effect of neoadjuvant therapy on lymph node metastasis of ESCC by performing immunohistochemistry for cytokeratin staining. A total of 3061 lymph nodes were examined from 62 patients who received neoadjuvant treatment followed by esophagectomy with lymphadenectomy. We observed positive staining for cytokeratin in 276 (9.0%) lymph nodes, which included overt metastasis, micrometastasis and hyalinized cytokeratin particles (HCP). Patients with HCPs in lymph nodes had better outcomes than patients without HCPs in lymph node. A significant prognostic difference between the patients with HCPs and without HCPs was observed in a subgroup of patients with nodal metastasis.

Our findings suggest that HCP might reflect a degenerative change of cancer cells in lymph nodes and can predict the response to neoadjuvant therapy.

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Does iNKT/CD1d-antitumor immunotherapy significantly increase the efficacy of therapeutic CpG/peptide-based cancer vaccine?

Therapeutic cancer vaccines aim to boost the natural immunity against transformed cancer cells, and a series of adjuvants and co-stimulatory molecules have been proposed to enhance the immune response against weak self-antigens expressed on cancer cells. For instance, a peptide/CpG-based cancer vaccine has been evaluated in several clinical trials and was shown in pre-clinical studies to favor the expansion of effector T versus Tregs cells, resulting in a potent antitumor activity, as compared to other TLR ligands. Alternatively, the adjuvant activity of CD1d-restricted invariant NKT cells (iNKT) on the innate and adaptive immunity is well demonstrated, and several CD1d glycolipid ligands are under pre-clinical and clinical evaluation. Importantly, additive or even synergistic effects have been shown upon combined CD1d/NKT agonists and TLR ligands. The aim of the present study is to combine the activation and tumor targeting of activated iNKT, NK and T cells. Activation and tumor targeting of iNKT cells via recombinant α-galactosylceramide (αGC)-loaded CD1d-anti-HER2 fusion protein (CD1d-antitumor) is combined or not with OVA peptide/CpG vaccine. Circulating and intratumoral NK and H-2Kb/OVA-specific CD8 responses are monitored, as well as the state of activation of dendritic cells (DC) with regard to activation markers and IL-12 secretion. The resulting antitumor therapy is tested against established tumor grafts of B16 melanoma cells expressing human HER2 and ovalbumin. The combined CD1d/iNKT antitumor therapy and CpG/peptide-based immunization leads to optimized expansion of NK and OVA-specific CD8 T cells (CTLs), likely resulting from the maturation of highly pro-inflammatory DCs as seen by a synergistic increase in serum IL-12. The enhanced innate and adaptive immune responses result in higher tumor inhibition that correlates with increased numbers of OVA-specific CTLs at the tumor site. Antibody-mediated depletion experiments further demonstrate that in this context, CTLs rather than NK cells are essential for the enhanced tumor inhibition.

Altogether, our study in mice demonstrates that αGC/CD1d-antitumor fusion protein greatly increases the efficacy of a therapeutic CpG-based cancer vaccine, first as an adjuvant during T cell priming and second, as a therapeutic agent to redirect immune responses to the tumor site.

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Is pseudomonas aeruginosa in CF and non-CF homes found predominantly in drains?

For patients with cystic fibrosis (CF) Pseudomonas aeruginosa infection is a major contributor to progressive lung disease. While colonizing strains are thought to be primarily environmental, which environments are important in lung colonization is unclear. We took 11,674 samples from a broad range of sites over 3-8 visits to homes with (7) and without (8) CF patients. Twenty-eight percent of sampled drains yielded P. aeruginosa at least once, and a general mixed linear model estimated that 6.3% of samples from drains yield P. aeruginosa. This is more than eight times the estimated recovery from any other type of household environment.

These findings implicate drains as important potential sources of P. aeruginosa infection. They suggest that maximizing P. aeruginosa control efforts for drains would reduce exposure with minimal extra burden to CF patients and families.

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Is increased expression of pleiotrophin a prognostic marker for patients with gastric cancer?

BACKGROUND/AIMs: Pleiotrophin (PTN) have been demonstrated to play an important role in the development of human gastric cancer. However, the prognostic value remains unclear. The aim of this study was to investigate whether expression of PTN has prognostic relevance in human gastric cancer. Immunohistochemistry was used to investigate the expression of PTN proteins in 178 patients with gastric cancer. The level of PTN mRNA in gastric cancer tissues and paratumor tissues were evaluated in 52 paired cases by quantitative real-time polymerase chainreaction(qRT-PCR). Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. The expression level of PTN in gastric cancer tissues was significantly higher (P<0.001) than those in paratumor tissues according to the immunohistochemistry analysis, which was confirmed by qRT-PCR analysis. Additionally, the overexpression of PTN was significantly associated with the tumor site (P=0.001), Lauren’s classification (P<0.001),histologic differentiation(P=0.014),depth of invasion(P<0.001), TNM stage (P=0.003),and lymph node metastasis (P=0.002). Moreover, the Cox proportional- hazards regression analysis revealed that the increased expression of PTN was an independent prognostic factor for poor recurrence-free survival(RFS) and overall survival(OS)(both P<0.001).

These findings indicated that the expression of PTN is significantly correlated with prognosis in gastric cancer patients, suggesting that the expression of PTN may be used as an independent prognostic marker.

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Does the CC-genotype of the cyclooxygenase-2 gene associate with decreased risk of nasopharyngeal carcinoma in a Tunisian population?

The cyclooxygenase-2 (cox-2) pathway is now recognized to be important in human cancer development and progression. The gene for cox-2 carries a common single nucleotide polymorphism, T8473C, located within a potential functional region in the 3'-UTR of cox-2 gene was identified. We have investigated the frequencies of cox-2 genotypes in Tunisian population to determine whether that polymorphism was associated with the risk of nasopharyngeal carcinoma (NPC) in Tunisian population. One hundred and eighty-nine NPC patients were compared to 237 healthy controls. The cox-2 T8473C polymorphism was significantly associated with NPC (P=0.031). The CC-genotype and C allele were more frequent in control compared to patients group [CC: OR=0.37; P=0.013; 95% CI: 0.17-0.81; C: OR=0.72; P=0.032; 95% CI: 0.53-0.97]. Multivariate logistic regression analyses revealed that the CC-genotype was associated with a significantly decreased risk of NPC (P=0.013). Tumor sizes, histologic grade, presence of primary lymph node metastases, age or sex were not associated with cox-2 genotypes.

We conclude that the CC-genotype and C allele of cox-2 T8473C gene polymorphism are associated with decreased risk of nasopharyngeal carcinoma in a Tunisian population.

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Does a shoe insole delivering subsensory vibratory noise improve balance and gait in healthy elderly people?

To test whether subsensory vibratory noise applied to the sole of the foot using a novel piezoelectric vibratory insole can significantly improve sensation, enhance balance, and reduce gait variability in elderly people, as well as to determine the optimal level of vibratory noise and whether the therapeutic effect would endure and the user's sensory threshold would remain constant during the course of a day. A randomized, single-blind, crossover study of 3 subsensory noise stimulation levels on 3 days. Balance and gait laboratory. Healthy community-dwelling elderly volunteers (N=12; age, 65-90y) who could feel the maximum insole vibration. A urethane foam insole with the piezoelectric actuators delivering subsensory vibratory noise stimulation to the soles of the feet. Balance, gait, and timed Up and Go (TUG) test. The vibratory insoles significantly improved performance on the TUG test, reduced the area of postural sway, and reduced the temporal variability of walking at both 70% and 85% of the sensory threshold and during the course of a day. Vibratory sensation thresholds remained relatively stable within and across study days.

This study provides proof of concept that the application of the principle of stochastic resonance to the foot sole sensory system using a new low-voltage piezoelectric technology can improve measures of balance and gait that are associated with falls. Effective vibratory noise amplitudes range from 70% to 85% of the sensory threshold and can be set once daily.

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Do sleep spindle and slow wave frequency reflect motor skill performance in primary school-age children?

The role of sleep in the enhancement of motor skills has been studied extensively in adults. We aimed to determine involvement of sleep and characteristics of spindles and slow waves in a motor skill in children. We hypothesized sleep-dependence of skill enhancement and an association of interindividual differences in skill and sleep characteristics. 30 children (19 females, 10.7 ± 0.8 years of age; mean ± SD) performed finger sequence tapping tasks in a repeated-measures design spanning 4 days including 1 polysomnography (PSG) night. Initial and delayed performance were assessed over 12 h of wake; 12 h with sleep; and 24 h with wake and sleep. For the 12 h with sleep, children were assigned to one of three conditions: modulation of slow waves and spindles was attempted using acoustic perturbation, and compared to yoked and no-sound control conditions. Mixed effect regression models evaluated the association of sleep, its macrostructure and spindles and slow wave parameters with initial and delayed speed and accuracy.

Children enhance their accuracy only over an interval with sleep. Unlike previously reported in adults, children enhance their speed independent of sleep, a capacity that may to be lost in adulthood. Individual differences in the dominant frequency of spindles and slow waves were predictive for performance: children performed better if they had less slow spindles, more fast spindles and faster slow waves. On the other hand, overnight enhancement of accuracy was most pronounced in children with more slow spindles and slower slow waves, i.e., the ones with an initial lower performance. Associations of spindle and slow wave characteristics with initial performance may confound interpretation of their involvement in overnight enhancement. Slower frequencies of characteristic sleep events may mark slower learning and immaturity of networks involved in motor skills.

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Does the dual CCR5 and CCR2 inhibitor cenicriviroc redistribute HIV into extracellular space : implications for plasma viral load and intracellular DNA decline?

Cenicriviroc is a potent antagonist of the chemokine coreceptors 5 and 2 (CCR5/CCR2) and blocks HIV-1 entry. The CCR5 inhibitor maraviroc has been shown in tissue culture to be able to repel cell-free virions from the cell surface into extracellular space. We hypothesized that cenicriviroc might exhibit a similar effect, and tested this using clinical samples from the Phase IIb study 652-2-202, by measuring rates of intracellular DNA decline. We also monitored viral RNA levels in culture fluids. We infected PM-1 cells with CCR5-tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of cenicriviroc (20 nM) or maraviroc (50 nM) or controls. Viral load levels and p24 were measured by ELISA, quantitative PCR and quantitative real-time reverse transcription PCR at 4 h post-infection. Frozen PBMC DNA samples from 30 patients with virological success in the Phase IIb study were studied, as were early and late reverse transcript levels. Docking studies compared binding between cenicriviroc/CCR5 and maraviroc/CCR5. Unlike maraviroc, cenicriviroc did not cause an increase in the amount of virus present in culture fluids at 4 h compared with baseline. The use of cenicriviroc did, however, result in lower levels of intracellular viral DNA after 4 h. Structural modelling indicates that cenicriviroc binds more deeply than maraviroc to the hydrophobic pocket of CCR5, providing an explanation for the absence of viral rebound with cenicriviroc.

In contrast to maraviroc, cenicriviroc does not repel virus back into extracellular space. Differences in results may be due to superior binding of cenicriviroc to CCR5 compared with maraviroc.

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Do our experiences on the reconstruction of lateral scalp burn alopecia with tissue expanders?

Cicatricial alopecia is a form of hair loss that causes both cosmetic and psychological concerns. Although tissue expanders are the common approach to reconstruction, no algorithm exists in the literature for this process. In this study, it was aimed to create an algorithm for the reconstruction of lateral scalp alopecias with the goal to achieve better and standardized results. Lateral scalp alopecias were divided into three groups: total lateral alopecia (type I), temporal and sideburn alopecia (type II), and sideburn alopecia (type III). Tissue expanders were placed at the parieto-occipital area in type I defects, parietal area in type II defects, and the temporal region in type III defects. Tissue expanders were used to create flaps that were advanced with 60° rotation, 90° rotation, and no rotation for type I, II, and III defects, respectively. Fifteen patients were treated with this algorithm. Using this simple approach, we achieved natural, standardized aesthetic results for each patient, all of whom were satisfied with the final results.

Although the number of case were limited, the ideal and standardized cosmetic results could be obtained by this approach.

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Is prostate-specific antigen doubling time subsequent to radical prostatectomy a predictor of outcome following salvage external beam radiation therapy : a single-centre experience?

The aim of this study was to review the impact of salvage external beam radiotherapy (EBRT) of postprostatectomy patients with long-term follow-up on biochemical-free recurrence (BFR) and metastatic-free survival, and to describe pathological and clinical predictors of outcome. In the period 1987-2010, 76 postprostatectomy patients with biochemical and clinical recurrence received salvage EBRT. Patients were treated with conformal EBRT and 68 (90%) received a dose of 70 Gy; eight patients (10%) received a dose of 60-64 Gy. No patients received adjuvant or neoadjuvant androgen deprivation therapy in conjunction with salvage EBRT. The median follow-up time after salvage EBRT was 82 months (range 5-192 months). Seventeen patients (22%) developed biochemical recurrence subsequent to postprostatectomy salvage EBRT during the observation time, and the overall 50 and 75 month actuarial BFR rates after salvage EBRT were 84% and 79%, respectively. Seven patients (9%) developed metastatic disease and two patients died of prostate cancer. Independent predictors of biochemical recurrence were seminal vesicle invasion (SVI) in the prostatectomy specimen (p < 0.05) and prostate-specific antigen doubling time (PSADT) of 6 months or less (p = 0.041) before salvage EBRT.

Salvage EBRT provides effective long-term BFR and metastatic-free survival in a selected group of patients with detectable, rising prostate-specific antigen values following radical prostatectomy. SVI and PSADT are prognostic variables for a non-durable response to salvage EBRT and thus predictors of high-risk prostate cancer in patients in whom neoadjuvant and adjuvant androgen deprivation therapy should be considered.

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Is head-shaft angle a risk factor for hip displacement in children with cerebral palsy?

Hip dislocation in children with cerebral palsy (CP) is a common and severe problem. The Swedish follow-up program for CP (CPUP) includes standardized monitoring of the hips. Migration percentage (MP) is a widely accepted measure of hip displacement. Coxa valga and valgus of the femoral head in relation to the femoral neck can be measured as the head-shaft angle (HSA). We assessed HSA as a risk factor for hip displacement in CP. We analyzed radiographs of children within CPUP from selected regions of Sweden. Inclusion criteria were children with Gross Motor Function Classification System (GMFCS) levels III-V, MP of < 40% in both hips at the first radiograph, and a follow-up period of 5 years or until development of MP > 40% of either hip within 5 years. Risk ratio between children who differed in HSA by 1 degree was calculated and corrected for age, MP, and GMFCS level using multiple Poisson regression. 145 children (73 boys) with a mean age of 3.5 (0.6-9.7) years at the initial radiograph were included. 51 children developed hip displacement whereas 94 children maintained a MP of < 40%. The risk ratio for hip displacement was 1.05 (p < 0.001; 95% CI 1.02-1.08). When comparing 2 children of the same age, GMFCS level, and MP, a 10-degree difference in HSA results in a 1.6-times higher risk of hip displacement in the child with the higher HSA.

A high HSA appears to be a risk factor for hip displacement in children with CP.

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Is implementation of a surgical intensive care unit service associated with improved outcomes for trauma patients?

Our trauma service recently transitioned from a pulmonary intensive care unit (ICU) service to a surgical ICU (SICU) service. We hypothesized that a newly formed SICU service could provide comparable outcomes to the existing pulmonary ICU service. A specific aim of this study was to compare outcomes of trauma patients admitted to the ICU before and after implementation of a SICU service. We performed a retrospective study of trauma patients admitted to the ICU of our urban, American College of Surgeons- verified, Level 1 trauma center during a 4-year period (2009-2012). Patients managed by the pulmonary ICU service (2009-2010) were compared with patients managed by a SICU service (2011-2012). The primary outcome was mortality, while secondary outcomes included complications (pulmonary, infectious, cardiac, and thromboembolic), hospital and ICU length of stay, ventilator days, and need for reintubation. There were 2,253 trauma patients admitted to the ICU during the study period, 1,124 and 1,129 managed by the pulmonary ICU and SICU services, respectively. When comparing outcomes for SICU and pulmonary ICU patients, there was no difference in mortality (11% vs. 13%, p = 0.41), but patients managed by the SICU service had fewer pulmonary complications (3% vs. 6%, p < 0.001), fewer days on the ventilator (3 vs. 4, p = 0.002), and less often required reintubation after extubation (4% vs. 9%, p < 0.001).

Transition from a pulmonary ICU service to a SICU service at our institution was associated with no change in mortality but an improvement in pulmonary complications, ventilator days, and reintubation rates. Trauma centers currently staffed with a pulmonary ICU service should feel comfortable converting to SICU service and should expect comparable or improved outcomes for trauma patients admitted to the ICU.

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Does elevated amygdala activity during reappraisal anticipation predict anxiety in avoidant personality disorder?

Avoidant personality disorder is characterized by pervasive anxiety, fear of criticism, disapproval, and rejection, particularly in anticipation of exposure to social situations. An important but underexplored question concerns whether anxiety in avoidant patients is associated with an impaired ability to engage emotion regulatory strategies in anticipation of and during appraisal of negative social stimuli. We examined the use of an adaptive emotion regulation strategy, cognitive reappraisal, in avoidant patients. In addition to assessing individual differences in state and trait anxiety levels, self-reported affect as well as measures of neural activity were compared between 17 avoidant patients and 21 healthy control participants both in anticipation of and during performance of a reappraisal task. Avoidant patients showed greater state and trait-related anxiety relative to healthy participants. In addition, relative to healthy participants, avoidant patients showed pronounced amygdala hyper-reactivity during reappraisal anticipation, and this hyper-reactivity effect was positively associated with increasing self-reported anxiety levels.

Our finding of exaggerated amygdala activity during reappraisal anticipation could reflect anxiety about the impending need to reappraise, anxiety about the certainty of an upcoming negative image, or anxiety relating to anticipated scrutiny of task responses by the experimenters. While we believe that all of these possibilities are consistent with the phenomenology of avoidant personality disorder, future research may clarify this ambiguity.

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Does prenatal marijuana exposure predict marijuana use in young adulthood?

Studies have reported effects of prenatal marijuana exposure (PME) on cognitive and behavioral outcomes. An earlier publication from this study found that PME predicted early onset of marijuana use and frequency of marijuana use at age 14. No study has reported the effects of PME on marijuana use in young adulthood. This is a developmental period when substance use peaks, and by which, initiation of substance use has largely occurred. Subjects were from a longitudinal cohort. Women were interviewed initially in their fourth prenatal month and women and their offspring were followed through 22 years. Significant covariates of offspring marijuana use at 22 years were identified and controlled for using ordinal logistic regression. PME predicted marijuana use in the offspring at 22 years after controlling for significant covariates. Prenatal alcohol exposure, offspring race, gender, and age were also significant predictors, but family history of substance abuse or disorder, and sociodemographic and psychological characteristics of the mother and offspring were not. This association was not moderated by gender or race.

PME is associated with subsequent marijuana use in young adulthood after considering the effects of other significant factors. These findings have important implications for public health given the recent trend toward legitimization of marijuana use.

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Does nAIF1 inhibit gastric cancer cells migration and invasion via the MAPK pathways?

Nuclear apoptosis-inducing factor 1 (NAIF1) could induce apoptosis in gastric cancer cells. Previously, we have reported that the expression of NAIF1 protein is down-regulated in gastric cancer tissues compared with the adjacent normal tissues. However, the role of NAIF1 in gastric cancer cells is not fully understood. The effects of NAIF1 on cell viability were evaluated by MTT and colony formation assays. The ability of cellular migration and invasion were analyzed by transwell assays. The expression levels of targeted proteins were determined by western blot. The relative RNA expression levels were analyzed using quantitative polymerase chain reaction assays. Xenograft experiment was employed to determine the anti-tumor ability of NAIF1 in vivo. The study demonstrates that transient transfection of NAIF1 in gastric cancer cells BGC823 and MKN45 could inhibit the cell proliferation, migration, and invasion of the two gastric cancer cell lines. The tumor size is smaller in NAIF1-overexpressed MKN45 cell xenograft mice than in unexpressed group. Further in-depth analysis reveals that NAIF1 reduces the expression of MMP2 as well as MMP9, and inhibits the activation of FAK, all of which are key molecules involved in regulating cell migration and invasion. In addition, NAIF1 inhibits the expression of c-Jun N-terminal kinase (JNK) by accelerating its degradation through ubiquitin-proteasome pathway. Meanwhile, NAIF1 reduces the mRNA and protein expression of ERK1/2.

Our study revealed that NAIF1 plays a role in regulating cellular migration and invasion through the MAPK pathways. It could be a therapeutic target for gastric cancer.

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Is cMV specific cytokine release assay in whole blood optimized by combining synthetic CMV peptides and toll like receptor agonists?

Interferon gamma release assays (IGRAs) are widely used to detect pathogen specific cellular immunity. Cytomegalovirus (CMV) is the foremost problematic viral infection in immunocompromised patients such as transplant or HIV infected patients. CMV antibody ELISAs are not able to predict CMV specific cellular immunity during immunosuppression. We developed a CMV specific IGRA comparing synthetic CMV peptides, native lysate and recombinant antigen. In addition, TLR agonists were tested to enhance CMV antigen immunogenicity. 397 healthy controls (HC) were stratified according to CMV IgM and IgG serostatus and subsequently tested for IFNγ- and IL2-secretion in whole blood after challenge with synthetic, native or recombinant CMV antigens and TLR agonists by ELISA. The selected TLR agonists were lipopolysaccharide (LPS), lipoteichoic acid (LTA), peptidoglycan (PGN), zymosan (Zym), polyinosinic-polycytidylic acid (Poly(I:C)), flagellin (Fla), R848, loxoribine (Lox) and bropirimine (Bro). Synthetic pp65 peptides elicited strong IFNγ responses in CMV seropositive, but not seronegative HC (6418 vs. 13 pg/ml). Native lysates and recombinant pp65 induced equally high IFNγ responses in seropositive (35,877 and 26,428 pg/ml) and increased background IFNγ expression in seronegative HC (43 and 1148 pg/ml). Diagnostic sensitivity and specificity with regard to anti-CMV serology reached 100% for synthetic pp65 and native CMV lysate, but 57% and 100% for recombinant pp65, respectively. TLR agonists LTA and Poly(I:C) augmented IFNγ responses after challenge with synthetic pp65 peptide, native lysate or recombinant pp65 in seropositive HC. Seronegative HC remained unaffected. IL2 production was negligible compared to IFNγ.

IGRAs using synthetic CMV peptides or native lysate showed the best cytokine signal to noise ratio compared to recombinant antigen and TLR agonists LTA and Poly(I:C) constitute potential costimulating reagents.

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Does light alcohol consumption play a protective role against non-alcoholic fatty liver disease in Japanese men with metabolic syndrome?

Although excess alcohol consumption has been believed to cause liver injury, light alcohol consumption (LAC) has been reported to play a protective role against fatty liver in recent studies. However, the association between non-alcoholic fatty liver disease (NAFLD) and LAC in men with metabolic syndrome (MS) is unclear. The aim of this study was to examine the association between NAFLD and LAC in men with MS. Subjects were 1055 men with MS who underwent a regular health check-up and drank less 20 g/day of alcohol. A distinction was made between non-drinkers and light drinkers and the association between NAFLD and LAC in men with MS was elucidated. NAFLD was referred as fatty liver with alanine aminotransferase (ALT) levels ≧31 IU/L in this study. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the prevalence of NAFLD were significantly lower in light drinkers than in non-drinkers. Logistic regression analysis showed body mass index (BMI), waist circumference (WC), uric acid (UA), haemoglobin A1c (HbA1c), visceral fat type MS and LAC (odds ratios: 0.654; 95% confidence intervals: 0.473-0.906; <0.05) were significant predictors of the prevalence of NAFLD.

The prevalence of NAFLD in light drinkers was significantly lower than in non-drinkers, and supporting previous reports studying the general population, LAC is one of the significant predictors of a decreased prevalence of NAFLD in men with MS.

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Do genomic selection accuracies within and between environments and small breeding groups in white spruce?

Genomic selection (GS) may improve selection response over conventional pedigree-based selection if markers capture more detailed information than pedigrees in recently domesticated tree species and/or make it more cost effective. Genomic prediction accuracies using 1748 trees and 6932 SNPs representative of as many distinct gene loci were determined for growth and wood traits in white spruce, within and between environments and breeding groups (BG), each with an effective size of Ne ≈ 20. Marker subsets were also tested. Model fits and/or cross-validation (CV) prediction accuracies for ridge regression (RR) and the least absolute shrinkage and selection operator models approached those of pedigree-based models. With strong relatedness between CV sets, prediction accuracies for RR within environment and BG were high for wood (r = 0.71-0.79) and moderately high for growth (r = 0.52-0.69) traits, in line with trends in heritabilities. For both classes of traits, these accuracies achieved between 83% and 92% of those obtained with phenotypes and pedigree information. Prediction into untested environments remained moderately high for wood (r ≥ 0.61) but dropped significantly for growth (r ≥ 0.24) traits, emphasizing the need to phenotype in all test environments and model genotype-by-environment interactions for growth traits. Removing relatedness between CV sets sharply decreased prediction accuracies for all traits and subpopulations, falling near zero between BGs with no known shared ancestry. For marker subsets, similar patterns were observed but with lower prediction accuracies.

Given the need for high relatedness between CV sets to obtain good prediction accuracies, we recommend to build GS models for prediction within the same breeding population only. Breeding groups could be merged to build genomic prediction models as long as the total effective population size does not exceed 50 individuals in order to obtain high prediction accuracy such as that obtained in the present study. A number of markers limited to a few hundred would not negatively impact prediction accuracies, but these could decrease more rapidly over generations. The most promising short-term approach for genomic selection would likely be the selection of superior individuals within large full-sib families vegetatively propagated to implement multiclonal forestry.

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Do local and general anaesthesia influence outcome of transfemoral aortic valve implantation?

There is great variability for the type of anaesthesia used during TAVI, with no clear consensus coming from comparative studies or guidelines. We sought to detect regional differences in the anaesthetic management of patients undergoing transcatheter aortic valve implantation (TAVI) in Europe and to evaluate the relationship between type of anaesthesia and in-hospital and 1 year outcome. Between January 2011 and May 2012 the Sentinel European TAVI Pilot Registry enrolled 2807 patients treated via a transfemoral approach using either local (LA-group, 1095 patients, 39%) or general anaesthesia (GA-group, 1712 patients, 61%). A wide variation in LA use was evident amongst the 10 participating countries. The use of LA has increased over time (from a mean of 37.5% of procedures in the first year, to 57% in last 6 months, p<0.01). MI, major stroke as well as in-hospital death rate (7.0% LA vs 5.3% GA, p=0.053) had a similar incidence between groups, confirmed in multivariate regression analysis after adjusting for confounders. Dividing our population in tertiles according to the Log-EuroSCORE we found similar mortality under LA, whilst mortality was higher in the highest risk tertile under GA. Survival at 1 year, compared by Kaplan-Meier analysis, was similar between groups (log-rank: p=0.1505).

Selection of anaesthesia appears to be more influenced by national practice and operator preference than patient characteristics. In the absence of an observed difference in outcomes for either approach, there is no compelling argument to suggest that operators and centres should change their anaesthetic practice.

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Does multidrug resistant bacteriuria before percutaneous nephrolithotomy predict for postoperative infectious complications?

Multidrug resistant (MDR) uropathogens are increasing in prevalence and may contribute to significant morbidity after percutaneous nephrolithotomy (PCNL). We investigate the presence of MDR bacteriuria and occurrence of postoperative infectious complications in patients who underwent PCNL at our institution. Retrospective review was performed of 81 patients undergoing PCNL by a single surgeon (RLS) between 2009 and 2013. Patient demographics, comorbidities, stone parameters on imaging, and microbial data were compiled. MDR organisms were defined as resistant to three or more of the American Urological Association Best Practice Statement antimicrobial classes for PCNL. Postoperative complications were graded by Clavien score and European Association of Urology infection grade. Univariate comparisons were analyzed between patients with and without a postoperative infectious complication. Multivariate logistic regression was performed to determine significant predictor variables for postoperative infectious complications. Of the 81 patients undergoing PCNL, 41/81 (51%) had positive preoperative urine culture, 24/81 (30%) had positive MDR urine culture, and 16/81 (19%) had a postoperative infectious complication. Multivariate analysis revealed a positive preoperative MDR urine culture significantly increased the risk of postoperative infectious complication (odds ratio [OR]=4.89, 95% confidence interval [CI] 1.134-17.8, P=0.016). The presence of more than one access tract during PCNL also predicted for infectious complications (OR=7.5, 95% CI 2.13-26.4, P=0.003) Of the 16 patients with a postoperative infection 3 (18%) had postoperative urine cultures discordant with the preoperative urine cultures.

Our institution demonstrated a relatively high prevalence of MDR bacteriuria in patients undergoing PCNL and that MDR is a significant risk factor for postoperative infectious complications despite appropriate preoperative antibiotics. Further investigations regarding prophylaxis modalities and infection prevention strategies are needed.

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Is higher fibrinogen level independently linked with the presence and severity of new-onset coronary atherosclerosis among Han Chinese population?

Fibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. However, no data is currently available regarding the association of fibrinogen level with the presence and severity of new-onset coronary atherosclerosis assessed by Gensini score (GS), particularly in Han Chinese with a large sample size. We studied 2288 consecutive, new-onset subjects undergoing coronary angiography with angina-like chest pain. Clinical and laboratory data were collected. Coronary stenotic lesions were considered to be the incidence of coronary atherosclerosis. The severity of coronary stenosis was determined by the GS system. Data indicated that patients with high GS had significantly elevated fibrinogen level (p<0.001). The prevalence and severity of coronary atherosclerosis were dramatically increased according to fibrinogen tertiles. Spearman correlation analysis revealed a positive association between fibrinogen level and GS (r = 0.138, p<0.001). Multivariate logistic regression analysis demonstrated that plasma fibrinogen level was independently associated with high GS (OR = 1.275, 95% CI 1.082-1.502, p = 0.004) after adjusting for potential confounders. Moreover, fibrinogen level was also independently related to the presence of coronary atherosclerosis (fibrinogen tertile 2: OR = 1.192, 95% CI 0.889-1.598, p = 0.241; tertile 3: OR = 2.003, 95% CI 1.383-2.903, p <0.001) and high GS (fibrinogen tertile 2: OR = 1.079, 95% CI 0.833-1.397, p = 0.565; tertile 3: OR = 1.524, 95% CI 1.155-2.011, p = 0.003) in a dose-dependent manner. Receiver-operating characteristic curve analysis showed that the best fibrinogen cut-off value for predicting the severity of coronary stenosis was 3.21 g/L.

Higher fibrinogen level is independently linked with the presence and severity of new-onset coronary atherosclerosis in Han Chinese population.

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Is the combination of pill count and self-reported adherence a strong predictor of first-line ART failure for adults in South Africa?

Suboptimal adherence to antiretroviral therapy (ART) is a strong predictor of virologic failure (VF) among people with HIV. Various methods such as patient self-report, pill counts and pharmacy refills have been utilized to monitor adherence. However, there are limited data on the accuracy of combining methods to better predict VF in routine clinical settings. We examined various methods to assess adherence including pill count, medication possession ratio (MPR), and self-reported adherence in order to determine which was most highly associated with VF after > 6 months on ART. We conducted a secondary analysis of data from a case-control study. At enrollment, pharmacy refill data were collected retrospectively from the medical chart, pill counts were completed to derive a pill count adherence ratio (PCAR) and a self-report questionnaire was administered to all participants. Parametric smooth splines and receiver operator characteristic (ROC) analyses were carried out to assess the accuracy of the adherence methods. 458 patients were enrolled from October 2010 to June 2012. Of these, 158 (34.50%) experienced VF (cases) and 300 (65.50%) were controls. The median (IQR) PCAR was 1.10 (0.99-1.14) for cases and 1.13 (1.08-1.18) for controls (p < 0.0001). The median MPR was 1.00 (0.97-1.07) for cases and 1.03 (0.96-1.07) for controls (p = 0.83). Combination of PCAR and self-reported questions was highly associated with VF.

In this setting, a combination of pill count adherence and self-report adherence questions had the highest diagnostic accuracy for VF. Further validation of this simple, low-cost combination is warranted in large prospective studies.

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Does microRNA-19a enhance proliferation of bronchial epithelial cells by targeting TGFβR2 gene in severe asthma?

Allergic asthma is characterized by inflammation and airway remodeling. Bronchial epithelium is considered a key player in coordinating airway wall remodeling. In mild asthma, the epithelium is damaged and fails to proliferate and to repair, whereas in severe asthma, the epithelium is highly proliferative and thicker. This may be due to different regulatory mechanisms. The purpose of our study was to determine the role of miRNAs in regulating proliferation of bronchial epithelial cells obtained from severe asthmatic subjects in comparison with cells obtained from mild asthmatics and healthy controls. Human bronchial epithelial cells (BEC) were isolated by bronchoscopy from bronchial biopsies of healthy donors and patients with mild and severe asthma. MiRNA expression was evaluated using the TaqMan low-density arrays and qRT-PCR. Transfection studies of bronchial epithelial cells were performed to determine the target genes. Cell proliferation was evaluated by BrdU incorporation test. MiR-19a was upregulated in epithelia of severe asthmatic subjects compared with cells from mild asthmatics and healthy controls. Functional studies based on luciferase reporter and Western blot assays suggest that miR-19a enhances cell proliferation of BEC in severe asthma through targeting TGF-β receptor 2 mRNA. Moreover, repressed expression of miR-19a increased SMAD3 phosphorylation through TGF-β receptor 2 signaling and abrogated BEC proliferation.

Our study uncovers a new regulatory pathway involving miR-19a that is critical to the severe phenotype of asthma and indicates that downregulating miR-19a expression could be explored as a potential new therapy to modulate epithelium repair in asthma.

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Are serum triglycerides , but not cholesterol or leptin , decreased in suicide attempters with mood disorders?

Many peripheral biomarkers, including low cholesterol and its fractions, have been examined to identify suicidal behavior. Herein, we assessed serum lipid profile and some proteins putatively associated with suicidal behavior in subjects with mood disorder (bipolar disorder or major depressive disorder) with a recent suicide attempt and with no lifetime history of suicide attempts. Fifty subjects had presented an episode of attempted suicide during the last 15 days, and 36 subjects had no history of any suicide attempt. We measured total cholesterol, HDL, LDL and triglycerides as well as serum leptin, brain-derived neurotrophic factor (BDNF), S100B and C-reactive protein (CRP). Individuals that had attempted suicide presented decreased body mass index (BMI) and waist circumference. After adjusting for these confounders, we found that triglycerides were decreased in attempted suicide subjects. We found no differences among total cholesterol, LDL, and HDL or leptin, S100B, CRP and BDNF.

This is a cross-sectional study, and we cannot therefore assess whether a decrease in triglycerides caused a mood episode with suicidal ideation that led to a suicide attempt or if the presence of a mood episode originated a loss of appetite and consequent loss of weight, therefore decreasing triglyceride levels.

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Is soft drink consumption associated with depressive symptoms among adults in China?

Research evidence supports a positive link between soft drinks and depressive symptoms. However, data thus far are only from Caucasian populations. We investigated whether high levels of consumption of soft drinks were associated with the depressive symptoms among adults in China. A cross-sectional survey was conducted with 3667 adults in Tianjin, China. Dietary intake was assessed using a valid self-administered food frequency questionnaire, and depressive symptoms were assessed with the Zung Self-Rating Depression Scale (SDS), cut-off point of 40, 45 or 50 indicating elevated depressive symptoms. The prevalence of elevated depressive symptoms was 7.6% (SDS ≥50). After adjustments for potentially confounding factors, the odds ratios (95% confidence interval) of having elevated depressive symptoms by increasing levels of soft drink consumption were 1.00, 1.43 (1.01, 2.01) and 2.00 (1.15, 3.37) (p for trend <0.01). Similar relations were observed when SDS ≥40 or 45 were used as a definition of depressive symptoms.

This is a cross-sectional study, causal relation remains unknown.

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Is blood alcohol concentration negatively associated with gambling money won on the Iowa gambling task in naturalistic settings after controlling for trait impulsivity and alcohol tolerance?

Acute alcohol intoxication has been found to increase perseverative errors on the Wisconsin Card Sorting Test, a well known neuropsychological index of prefrontal cortical functioning, in both laboratory and naturalistic settings. The present study examined the relationship between levels of alcohol consumption at campus drinking venues and performance of the Iowa Gambling Task (IGT), another neuropsychological test designed to assess prefrontal cortex dysfunction, after controlling for potential confounding variables including habitual alcohol intake (as a proxy for alcohol tolerance), trait impulsivity, and everyday executive functioning. The 49 participants of both genders aged 18 to 30years were recruited at the relevant venues and showed a broad range of blood alcohol concentrations (BACs) from virtually zero (.002%) to .19%. After controlling for demographic variables, habitual use of alcohol and illicit drugs, and frontal lobe related behavioural traits including impulsivity and disinhibition, BAC negatively predicted gambling money won on the last two trial blocks of the IGT.

Trait impulsivity and habitual alcohol use were also significant predictors. Results are discussed in terms of acute effects of alcohol on brain systems and the behavioural consequences of such effects on decision making.

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Does sexual activity predispose to reflux episodes in patients with gastroesophageal reflux disease?

The role of sexual activity on gastroesophageal reflux disease (GERD) is an under-recognized concern of patients, and one rarely assessed by physicians. The objective of this article is to determine the influence of sexual activity on the intraesophageal acid exposure and acid reflux events in GERD patients. Twenty-one patients with the diagnosis of GERD were prospectively enrolled. Intraesophageal pH monitoring was recorded for 48 hours with a Bravo capsule. All patients were instructed to have sexual intercourse or abstain in a random order two hours after the same refluxogenic dinner within two consecutive nights. Patients were requested to have sex in the standard "missionary position" and women were warned to avoid abdominal compression. The patients completed a diary reporting the time of the sexual intercourse and GERD symptoms. The percentage of reflux time and acid reflux events were compared in two ways: within 30 and 60 minutes prior to and after sexual intercourse on the day of sexual intercourse and in the same time frame of the day without sexual intercourse. Fifteen of 21 GERD patients were analyzed. The percentage of reflux time and number of acid reflux events did not show a significant difference within the 30- and 60-minute periods prior to and after sexual intercourse on the day of sexual intercourse and on the day without sexual intercourse, as well.

Sexual activity does not predispose to increased intraesophageal acid exposure and acid reflux events. Larger studies are needed to confirm our findings in patients who define reflux symptoms during sexual intercourse.

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Is vascular injury associated with increased mortality in winter sports trauma?

Trauma is the leading cause of injury and death for individuals aged 1-44 years. Up to 8% of the US population participates in winter sports, and although vascular injuries are uncommon in these activities, little is published in this area. We sought to identify the incidence, injury patterns, and outcomes of vascular injuries resulting from winter sports trauma. Patients with winter sports trauma and the subset with vascular injuries were identified by accessing the National Trauma Data Bank querying years 2007-2010. Patients with and without vascular injuries were then compared. Admission variables included transport time, emergency department hypotension (systolic blood pressure < 90), Glasgow Coma Scale ≤ 8, Injury Severity Score ≥ 25, fractures, solid organ injury, and vascular injury. Outcomes were analyzed and associations with vascular injuries were determined. A total of 2,298 patients were identified with winter sports-related trauma and 28 (1.2%) had associated vascular injuries. Overall, the top 3 injuries were head trauma (16.7%), thoracic vertebral fractures (5.5%), and lumbar vertebral fractures (5.1%). The most common associated vascular injures were to the popliteal artery (17.7%), splenic artery (14.7%), and brachial blood vessels (14.7%). In the entire cohort, 1 patient (0.04%) suffered an amputation and 15 patients (0.7%) died. There were no amputations in the vascular injury group. Mortality was 0.6% in patients without a vascular injury compared with 7.1% of those with a vascular injury (P = 0.01).

Although vascular injury is an uncommon associated finding in winter sports trauma, it is associated with a significant increase in mortality. These findings highlight the need for rapid identification of traumatic vascular injuries, which predicts worse overall outcomes in this patient population.

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Is a common variant in RAB27A gene associated with fractional exhaled nitric oxide levels in adults?

Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values.

This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.

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Does a dietary phytochemical blend prevent liver damage associated with adipose tissue mobilization in ovariectomized rats?

Menopausal reduction in estrogen causes increased adipose accumulation, leading many to turn to dietary supplements to prevent and treat such changes. Enhanced adipose mobilization stimulated by some supplements can increase the risk of non-alcoholic fatty liver disease (NAFLD). Cytoprotective and anti-obesity compounds may prevent the lipotoxicity associated with mobilization. A phytochemical blend was tested in aged, ovariectomized rats. Rats were given the AIN-93M basal diet or a diet containing varying doses of phytochemicals with 2.4 IU/g vitamin D [diet 1: 1000 mg/kg genistein (G); diet 2: 500 mg/kg (G), 200 mg/kg resveratrol (R), and 1000 mg/kg quercetin (Q); diet 3: 1000 mg/kg (G), 400 mg/kg (R), and 2000 mg/kg (Q)]. Serum free fatty acids and hepatic triglycerides were elevated with diets 2 and 3. Despite this increase, the phytochemical blends did not increase apoptotic, cell repair, or remodeling gene expression. The highest phytochemical dose prevented increases in serum alanine aminotransferase.

Adverse hepatic effects secondary to ovariectomy were mitigated through the inclusion of a dietary phytochemical blend in aged ovariectomized rats. The use of such compounds may not only help with weight management and disease risk in menopausal women, but may also prevent the lipotoxicity in NAFLD.

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Is real-time three-dimensional transesophageal echocardiography useful for percutaneous closure of multiple secundum atrial septal defects?

The purpose of this study was to investigate the clinical value of real-time three-dimensional transesophageal echocardiography (RT-3D-TEE) for percutaneous transcatheter closure of multiple secundum atrial septal defects (ASDs) using a Chinese domestic occluder device. From July 2008 to September 2011, 37 patients (mean age 28.4 ± 9.7 years; 24 females) with multiple secundum ASDs underwent percutaneous transcatheter closure in our institution with custom-made occluder devices. RT-3D-TEE was used to clarify the diagnosis and to help determine the operation scheme before the procedure, for real-time monitoring and guiding the operation during the procedure, and for evaluating the result shortly after the procedure. The custom-made atrial septal occluders were successfully implanted in 36 patients under RT-3DTEE guidance. Twenty-seven patients were implanted with two devices and 9 patients with a single device. In two patients where the distance between the two defects was less than 7 mm (5.5 mm and 6 mm), double occluder devices were also successfully implanted. One patient underwent surgery for the complication of unstable occluder and increased residual shunt after closure. No other severe complications were observed.

RT-3D-TEE provides reliable diagnostic evidence of multiple ASDs and can help the clinician to select an appropriate operation scheme according to the number and morphology of multiple defects prior to percutaneous transcatheter closure. It also allows for proper positioning of the devices during the procedure and provides an effective means of evaluating the success of the procedure. For two devices to be implanted simultaneously in multiple ASDs, the usual requirement for the distance between the two defects may differ between our domestically made devices and the Amplatzer occluder.

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Do longitudinal patterns of cortisol regulation differ in maltreated and nonmaltreated children?

Child maltreatment is associated with dysregulation of stress-mediating systems and an increased risk of mental and physical health problems. Specifically, disruptions in hypothalamic-pituitary-adrenal (HPA) axis regulation have been reported in maltreated children. The current study investigates whether increased cortisol variability is responsible for inconsistent patterns in the literature. This study modeled cortisol activity over 20 weeks in 187 maltreated and 154 nonmaltreated children (mean = 8.4 years, SD = 1.8 years) in order to capture week-to-week cortisol patterns. Maltreatment was assessed through coding of Department of Human Services records. Children attended an after-school program 1 day per week for 20 weeks, where saliva was collected at the same time each day and subsequently assayed for cortisol. Multiple-group growth curves indicated that maltreated and non-maltreated children differ in longitudinal cortisol patterns. Maltreated children showed higher variance in the initial cortisol levels and slope over time compared to nonmaltreated children, indicating greater between-person variability in the maltreated group. Maltreated children with higher cortisol at the first assessment showed cortisol suppression over time, indicating potential HPA blunting after chronic high cortisol levels. The severity, timing, and number of subtypes of maltreatment predicted individuals' cortisol variability, and both maltreatment status and greater cortisol variability predicted more behavior problems.

Interventions for maltreated children may benefit from pre- and post-intervention HPA assessments to determine a component of treatment efficacy. As maltreatment dimensions predicted differential cortisol regulation, assessment of maltreatment experiences is necessary to understand alterations in behavior and HPA regulation post-intervention.

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Does substance Use and Related harm Among Adolescents With and Without Traumatic Brain Injury?

The relationship between self-reported lifetime traumatic brain injury (TBI) and drug and alcohol use and associated harms was examined using an epidemiological sample of Canadian adolescents. Data were derived from a 2011 population-based cross-sectional school survey, which included 6383 Ontario 9th-12th graders who self-completed anonymous self-administered questionnaires in classrooms. Traumatic brain injury was defined as loss of consciousness for at least 5 minutes or a minimum 1-night hospital stay due to symptoms. Relative to high schoolers without a history of TBI, those who acknowledged having a TBI in their lifetime had odds 2 times greater for binge drinking (5+ drinks per occasion in the past 4 weeks), 2.5 times greater for daily cigarette smoking, 2.9 times greater for nonmedical use of prescription drugs, and 2.7 times greater for consuming illegal drug in the past 12 months. Adolescents with a history of TBI had greater odds for experiencing hazardous/harmful drinking (adjusted odds ratio [aOR] = 2.3), cannabis problems (aOR = 2.4), and drug problems (aOR = 2.1), compared with adolescents who were never injured.

There are strong and demographically stable associations between TBI and substance use. These associations may not only increase the odds of injury but impair the quality of postinjury recovery.

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Is eGFR-TKI effective regardless of treatment timing in pulmonary adenocarcinoma with EGFR mutation?

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become key therapeutic agents for non-small cell lung cancer (NSCLC) patients with EGFR mutation, little is known about the efficacy of EGFR-TKIs according to different treatment timings. A total of 1,250 patients with NSCLC were screened for EGFR mutations at a single institution between March 2006 and May 2010. The efficacy of EGFR-TKIs in terms of response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared according to the treatment timing. Among the 437 patients (36.1 %) with EGFR mutation, we analyzed 222 patients who received EGFR-TKI treatment. With a median follow-up duration of 27.5 months (range 8.3-69.2), EGFR-TKI was given to 97 (43.7 %), 109 (49.1 %), and 16 (7.2 %) patients as first-line, second-line, and third-line therapy, respectively. All three groups showed similar RR (71.1, 72.5, and 75.0 %, respectively) to EGFR-TKI (p = 0.802). No significant difference was observed according to treatment timing of EGFR-TKI in terms of PFS (median 10.6, 13.0, and 10.4 months; p = 0.670) and OS (median 20.5, 26.2, and 17.1 months; p = 0.142). The treatment timing of EGFR-TKI still showed no association with PFS or OS after adjusting significant prognostic factors including performance, disease status, and EGFR mutation types.

EGFR-TKIs showed similar efficacy in patients with EGFR mutation-positive adenocarcinoma in terms of RR, PFS, and OS irrespective of treatment timing. Although EGFR-TKIs are currently the treatment of choice of first-line treatment in patients with EGFR-positive tumors, the sequential treatment with EGFR-TKI could be a reasonable option when EGFR mutation status cannot be obtained in a short time.

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Is diabetes associated with increased risk of venous thromboembolism : a systematic review and meta-analysis?

Increasing evidence suggests an association between diabetes and risk of venous thromboembolism (VTE); however, the results are inconsistent. We conducted a systematic review and meta-analysis of all epidemiological evidence to clarify association of diabetes with risk of VTE. We searched MEDLINE and EMBASE to retrieve all relevant articles. Pooled effect estimates were calculated through a random-effects model. Sixteen articles involving 803,627,121 participants and 10,429,227 VTE patients were included. Pooled analysis of all evidence suggested that diabetes was associated with increased risk of VTE (HR, 1.35; 95%CI, 1.17-1.55; p=2.92*10(-5)), with evidence of small-study effect (p=0.024) and heterogeneity (I(2)=87.1%, p<0.001). However, when analysis was restricted to high quality cohort studies, the association remained significantly (HR, 1.36; 95%CI 1.11-1.68; p=0.004), with no evidence of publication bias (p=0.192) and heterogeneity (I(2)=23.2%, p=0.245).

Diabetes is associated with increased risk of VTE, which may have implications for the primary and secondary prevention of VTE.

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Is invasion of uterine cervical squamous cell carcinoma cells facilitated by locoregional interaction with cancer-associated fibroblasts via activating transforming growth factor-beta?

Local invasion is a common pattern of spread in uterine cervical squamous cell carcinoma (CSCC). Although transforming growth factor-beta (TGF-β) facilitates invasion of various types of cancer cells, the role of the TGF-β pathway in CSCC is unclear. In this study, we analyzed the role of TGF-β signaling in the progression of CSCC. Immunohistochemistry was used to examine the expression of TGF-β pathway molecules in 67 CSCC samples with clinicopathological data. Activation of the TGF-β pathway was investigated following co-culture of CSCC cells and cervical cancer-associated fibroblasts (CCAFs). Clinicopathological analysis of CSCC samples revealed that prominent expression of TGF-β receptor-2 was more frequent in CSCC with lymphovascular space invasion (LVSI) than without LVSI (p < 0.01). Lymph node metastasis was more frequent in cases in which phosphorylated SMAD3 (pSMAD3) was localized exclusively at the boundary of tumor clusters (n = 9, p < 0.05). Recombinant TGF-β1 increased pSMAD3 expression and enhanced cellular invasion (p < 0.005) in CSCC cells, which was attenuated by an inhibitor of the TGF-β receptor (p < 0.005). Enhanced pSMAD3 expression and invasion was also observed when conditioned media from CSCC cells co-cultured with CCAFs were administered. Luciferase assays showed that this medium contained a large amount of active TGF-β. Along with TGF-β activation, thrombospondin-1 was upregulated in both CSCC cells and CCAFs, while thrombospondin-1 silencing in either CSCC cells or CCAFs repressed the activity of TGF-β. Thrombospondin-1 was prominently expressed in cases with pSMAD3 boundary staining (p < 0.05).

These results suggest that interaction between CSCC cells and surrounding CCAFs activates TGF-β via thrombospondin-1 secretion to facilitate CSCC invasion.

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Is increased serum cancer antigen-125 a marker for severity of deep endometriosis?

To determine whether cancer antigen-125 (CA-125) levels are increased in women with endometriosis, especially in those with endometriomas (OMAs), deep infiltrating lesions (DIE), and superficial endometriosis (SUP) compared with controls without endometriosis in a large cohort of operated women. Cross-sectional study (Canadian Task Force classification II-2). Tertiary-care university hospital. Four hundred six women with histologically proven endometriosis and 279 women without endometriosis. Surgical examination of the abdomino-pelvic cavity. Preoperative serum CA-125 antigen levels were evaluated by electrochemoluminescence immunoassay in women with endometriosis and controls. Correlations between serum CA-125 levels and clinical and anatomical characteristics of disease severity were examined. Women with endometriosis displayed higher mean serum CA-125 levels compared with disease-free controls (50.1 ± 62.4 U/mL vs 22.5 ± 25.2 U/mL; p ≤ .001). CA-125 levels were significantly increased in women with OMA (60.8 ± 63.5 U/mL) and DIE (55.2 ± 68.7 U/mL) compared with women with SUP (23.2 ± 24.5 U/mL) and controls (22.5 ± 25.2 U/mL). There was no difference in CA-125 levels between patients with SUP and controls and between patients with OMA and DIE. CA-125 serum levels were correlated with DIE severity: the mean number of DIE lesions and worst DIE lesion.

Serum CA-125 levels were significantly increased in women with severe forms of endometriosis, OMA, and DIE lesions. In addition, elevated serum Ca-125 levels were associated with more severe and extended DIE lesions. In women with superficial peritoneal lesions, CA-125 levels were not different from women without endometriosis.

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Do detailed characterization of tumor infiltrating lymphocytes in two distinct human solid malignancies show phenotypic similarities?

We examined the phenotype and function of lymphocytes collected from the peripheral blood (PBL) and tumor (TIL) of patients with two different solid malignancies: colorectal cancer liver metastases (CRLM) and ovarian cancer (OVC). Tumor and corresponding peripheral blood were collected from 16 CRLM and 22 OVC patients; immediately following resection they were processed and analyzed using a multi-color flow cytometry panel. Cytokine mRNA from purified PBL and TIL CD4(+) T cells were also analyzed by qPCR. Overall, we found similar changes in the phenotypic and cytokine profiles when the TIL were compared to PBL from patients with two different malignancies. The percentage of Treg (CD4(+)/CD25(+)/FoxP3(+)) in PBL and TIL was similar: 8.1% versus 10.2%, respectively in CRLM patients. However, the frequency of Treg in primary OVC TIL was higher than PBL: 19.2% versus 4.5% (p <0.0001). A subpopulation of Treg expressing HLA-DR was markedly increased in TIL compared to PBL in both tumor types, CRLM: 69.0% versus 31.7% (p = 0.0002) and OVC 74.6% versus 37.0% (p <0.0001), which suggested preferential Treg activation within the tumor. The cytokine mRNA profile showed that IL-6, a cytokine known for its immunosuppressive properties through STAT3 upregulation, was increased in TIL samples in patients with OVC and CRLM. Both TIL populations also contained a significantly higher proportion of activated CD8(+) T cells (HLA-DR(+)/CD38(+)) compared to PBL (CRLM: 30.2% vs 7.7%, (p = 0.0012), OVC: 57.1% vs 12.0%, (p <0.0001)).

This study demonstrates that multi-color flow cytometry of freshly digested tumor samples reveals phenotypic differences in TIL vs PBL T cell sub-populations. The TIL composition in primary and metastatic tumors from two distinct histologies were remarkably similar, showing a greater proportion of activated/suppressive Treg (HLA-DR(+), CD39(+), CTLA-4(+) and Helios(+)) and activated cytotoxic T cells (CD8(+)/HLA-DR(+)/CD38(+)) when compared to PBL and an increase in IL-6 mRNA from CD4 TIL.

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Do long-term lung cancer survivors have permanently decreased quality of life after surgery?

Retrospective evaluation of the long-term health-related quality of life (HRQoL) among survivors after non-small-cell lung cancer (NSCLC) surgery. A total of 586 patients underwent surgery for NSCLC in Helsinki University Central Hospital between January 2000 and June 2009. Two validated quality-of-life questionnaires, the 15D and the EORTC QLQ-C30 with its lung cancer-specific module, QLQ-LC13, were sent to the 276 patients alive in June 2011. Response rate was 83.3%. Results of the 15D were compared with those of an age- and gender-standardized general population. Median follow-up was 5 years. Compared with a general population, our patients had a significantly lower 15D total score, representing their total HRQoL and scores for dimensions of mobility, breathing, usual activities, depression, distress, and vitality. The patients, however, scored significantly higher on vision, hearing, and mental function.

NSCLC survivors may suffer postoperatively from permanently reduced long-term HRQoL compared to an age- and gender-matched general population. This is essential patient information as more patients are surviving longer.

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Does pregestational maternal obesity impair endocrine pancreas in male F1 and F2 progeny?

The aim of this study was to evaluate the effects of maternal obesity on pancreas structure and carbohydrate metabolism in early adult life, focusing on the F1 and F2 generations after F0 maternal pregestational, gestation, and lactation high-fat diet (HF). C57 BL/6 female mice (F0) were fed standard chow (SC) or an HF diet for 8 wk before mating and during the gestation and lactation periods to provide the F1 generation (F1-SC and F1-HF). At 3 mo old, F1 females were mated to produce the F2 generation (F2-SC and F2-HF). The male offspring from all groups were evaluated at 3 mo old. F0-HF and F1-HF dams were overweight before gestation and had a higher body mass gain and energy intake during gestation, although only F0-HF dams presented pregestational hyperglycemia. The F1-HF offspring had higher body mass, energy intake, fasting glucose levels, and were glucose intolerant compared with F1-SC offspring. These parameters were not significantly altered in F2-HF offspring. Both F1-HF and F2-HF offspring showed hyperinsulinemia, hyperleptinemia, decreased adiponectin levels, increased pancreatic mass, and islet volume density with elevated α- and β-cell mass, hypertrophied islet characterized by an altered distribution of α- and β-cells and weak pancreatic-duodenal homeobox (Pdx)1 immunoreactivity.

Maternal HF diet consumed during the preconception period and throughout the gestation and lactation periods in mice promotes metabolism and pancreatic programming in F1 and F2 male offspring, implying intergenerational effects.

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Does chloroquine enhance temozolomide cytotoxicity in malignant gliomas by blocking autophagy?

In a recent clinical trial, patients with newly diagnosed glioblastoma multiforme benefited from chloroquine (CQ) in combination with conventional therapy (resection, temozolomide [TMZ], and radiation therapy). In the present study, the authors report the mechanism by which CQ enhances the therapeutic efficacy of TMZ to aid future studies aimed at improving this therapeutic regimen. Using in vitro and in vivo experiments, the authors determined the mechanism by which CQ enhances TMZ cytotoxicity. They focused on the inhibition-of-autophagy mechanism of CQ by knockdown of the autophagy-associated proteins or treatment with autophagy inhibitors. This mechanism was tested using an in vivo model with subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ. Knockdown of the autophagy-associated proteins (GRP78 and Beclin) or treatment with the autophagy inhibitor, 3-methyl adenine (3-MA), blocked autophagosome formation and reduced CQ cytotoxicity, suggesting that autophagosome accumulation precedes CQ-induced cell death. In contrast, blocking autophagosome formation with knockdown of GRP78 or treatment with 3-MA enhanced TMZ cytotoxicity, suggesting that the autophagy pathway protects from TMZ-induced cytotoxicity. CQ in combination with TMZ significantly increased the amounts of LC3B-II (a marker for autophagosome levels), CHOP/GADD-153, and cleaved PARP (a marker for apoptosis) over those with untreated or individual drug-treated glioma cells. These molecular mechanisms seemed to take place in vivo as well. Subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ displayed higher levels of CHOP/GADD-153 than did untreated or individual drug-treated tumors.

Taken together, these results demonstrate that CQ blocks autophagy and triggers endoplasmic reticulum stress, thereby increasing the chemosensitivity of glioma cells to TMZ.

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Is long-term therapy with temozolomide a feasible option for newly diagnosed glioblastoma : a single-institution experience with as many as 101 temozolomide cycles?

The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m(2) starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30-72 years (mean 56.1 years), received 150 mg/m(2) for 5 days every 28 days for more than 6 cycles (range 7-101 cycles). The 18 patients in Group B, aged 46-82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. All patients but 1 in Group A survived at least 18 months (range 18-101 months), and patients in Group B survived no more than 17 months (range 2-17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group.

This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

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Is thiazide-induced hyponatraemia associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin-2?

Hyponatraemia is a common, potentially life-threatening, complication of thiazide diuretics. The mechanism of thiazide-induced hyponatraemia is incompletely understood. Previous experiments have suggested a direct effect of thiazide diuretics on the plasma membrane expression of aquaporin (AQP)2. We examined the effects of a single re-exposure to hydrochlorothiazide (HCTZ) 50 mg on water balance, renal sodium handling and osmoregulation in 15 elderly hypertensive patients with a history of thiazide-induced hyponatraemia and 15 matched hypertensive controls using thiazide diuretics without previous hyponatraemia. Patients with thiazide-induced hyponatraemia had significantly lower body weight and lower plasma sodium and osmolality at baseline. After HCTZ administration, plasma sodium and osmolality significantly decreased and remained lower in patients compared with controls (P < 0.001). Plasma antidiuretic hormone (ADH) and urine AQP2 were low or suppressed in patients, whereas solute and electrolyte-free water clearance was significantly increased compared with controls. Ad libitum water intake was significantly higher in patients (2543 ± 925 ml) than in controls (1828 ± 624 ml, P < 0.05), whereas urinary sodium excretion did not differ. In contrast, urea excretion remained significantly lower in patients (263 ± 69 mmol per 24 h) compared with controls (333 ± 97 mmol per 24 h, P < 0.05) and predicted the decrease in plasma sodium following HCTZ administration.

Thiazide diuretics are associated with markedly impaired free water excretion at low ADH and AQP2 in elderly patients. The higher water intake and lower urea excretion in patients points to an important role for polydipsia and urea-mediated water excretion in the pathogenesis of thiazide-induced hyponatraemia.

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Is weight based heparin dosing for thromboembolic disease associated with earlier anticoagulation in surgical patients?

Achievement of early therapeutic anticoagulation with unfractionated heparin (UFH) is associated with improved outcomes in thromboembolic disease. Weight based UFH expedites time to therapeutic anticoagulation. Treatment with UFH is challenging in surgical patients due to their high propensity for bleeding. We sought to test the hypothesis that an initial weight based UFH infusion in surgical patients increases the percentage of patients who achieve early therapeutic anticoagulation without increasing the risk of hemorrhagic events. Using a non-concurrent retrospective cohort study design, adult surgical patients receiving UFH for venous thromboembolism (VTE) at a tertiary care center were included. Two groups were identified: the weight based (WB) and the under-dosed (UD) heparin groups. For our primary outcome, we compared percentage of patients in each group that achieved a therapeutic PTT within 24 h. Secondary outcomes included the incidence of supratherapeutic PTT levels, hemorrhagic events, and complications associated with VTE. 73 subjects met study criteria, which included 8 subjects in the WB group and 65 in the UD group. The demographic, baseline laboratory, admitting service and type of VTE were similar between the 2 groups. The percentages of WB and UD subjects who achieved a therapeutic PTT within 24 h were 75% and 28%, respectively (p < 0.01). There was no difference in the incidence of supratherapeutic PTT or hemorrhagic events.

Surgical patients who received an initial weight based UFH infusion achieved earlier therapeutic anticoagulation compared to under-dosed UFH without increasing the occurrence of supratherapeutic PTT levels or hemorrhagic events.

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Does prospective international cohort study demonstrate inability of interim PET to predict treatment failure in diffuse large B-cell lymphoma?

The International Atomic Energy Agency sponsored a large, multinational, prospective study to further define PET for risk stratification of diffuse large B-cell lymphoma and to test the hypothesis that international biological diversity or diversity of healthcare systems may influence the kinetics of treatment response as assessed by interim PET (I-PET). Cancer centers in Brazil, Chile, Hungary, India, Italy, the Philippines, South Korea, and Thailand followed a common protocol based on treatment with R-CHOP (cyclophosphamide, hydroxyadriamycin, vincristine, prednisolone with rituximab), with I-PET after 2-3 cycles of chemotherapy and at the end of chemotherapy scored visually. Two-year survivals for all 327 patients (median follow-up, 35 mo) were 79% (95% confidence interval [CI], 74%-83%) for event-free survival (EFS) and 86% (95% CI, 81%-89%) for overall survival (OS). Two hundred ten patients (64%) were I-PET-negative, and 117 (36%) were I-PET-positive. Two-year EFS was 90% (95% CI, 85%-93%) for I-PET-negative and 58% (95% CI, 48%-66%) for I-PET-positive, with a hazard ratio of 5.31 (95% CI, 3.29-8.56). Two-year OS was 93% (95% CI, 88%-96%) for I-PET-negative and 72% (95% CI, 63%-80%) for I-PET-positive, with a hazard ratio of 3.86 (95% CI, 2.12-7.03). On sequential monitoring, 192 of 312 (62%) patients had complete response at both I-PET and end-of-chemotherapy PET, with an EFS of 97% (95% CI, 92%-98%); 110 of these with favorable clinical indicators had an EFS of 98% (95% CI, 92%-100%). In contrast, the 107 I-PET-positive cases segregated into 2 groups: 58 (54%) achieved PET-negative complete remission at the end of chemotherapy (EFS, 86%; 95% CI, 73%-93%); 46% remained PET-positive (EFS, 35%; 95% CI, 22%-48%). Heterogeneity analysis found no significant difference between countries for outcomes stratified by I-PET.

This large international cohort delivers 3 novel findings: treatment response assessed by I-PET is comparable across disparate healthcare systems, secondly a negative I-PET findings together with good clinical status identifies a group with an EFS of 98%, and thirdly a single I-PET scan does not differentiate chemoresistant lymphoma from complete response and cannot be used to guide risk-adapted therapy.

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Does fungal metabolite myriocin promote human herpes simplex virus-2 infection?

Myriocin is a fungal metabolite with antiviral activity, including influenza, hepatitis B, and hepatitis C viruses. We investigated whether myriocin has activity against human HSV-2, one of the most prevalent pathogens of sexually transmitted disease. Cell culture systems were used to evaluate myriocin effect on HSV-2 infection. Plaque forming assay and immunoblotting studies were used to determine virus production and viral protein expression, respectively. Myriocin showed no cytotoxic effect at up to 5 μM. Myriocin treatment did not inhibit HSV-2 infection. Instead, the treatment resulted in accelerated replication of HSV-2 and increased titers of infectious virion. The effect was detected at concentrations as low as 3 nM and plateaued at approximately 30 nM. Myriocin at 30 nM increased HSV-2 production by approximately 1.7 logs. Myriocin also promoted HSV-1 infection but required higher concentrations. A time course study revealed that myriocin promoted HSV-2 infection by acceleration of virus replication. Unlike trichostatin A that promotes HSV-2 infection and histone modifications, myriocin treatment did not alter histone modifications. Myriocin is a well characterized inhibitor of sphingolipid biosynthesis pathway. Structurally different inhibitors of the pathway showed no effect on HSV-2 infection. Exogenous sphingolipids did not reverse the effect of myriocin on HSV-2 infection either.

We found that myriocin promotes HSV-2 replication at nanomolar concentrations with yet unknown mechanisms. Further studies may uncover novel mechanisms regulating HSV replication and targets of myriocin action. This may have potential application in enhancing efficacy of oncolytic HSV for cancer therapy and other diseases.

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Does prenatal zinc reduce stress response in adult rat offspring exposed to lipopolysaccharide during gestation?

Previous investigations by our group have shown that prenatal treatment with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneally) on gestation day (GD) 9.5 in rats, which mimics infections by Gram-negative bacteria, induces short- and long-term behavioral and neuroimmune changes in the offspring. Because LPS induces hypozincemia, dams were treated with zinc after LPS in an attempt to prevent or ameliorate the impairments induced by prenatal LPS exposure. LPS can also interfere with hypothalamic-pituitary-adrenal (HPA) axis development; thus, behavioral and neuroendocrine parameters linked to HPA axis were evaluated in adult offspring after a restraint stress session. We prenatally exposed Wistar rats to LPS (100 μg/kg, intraperitoneally, on GD 9.5). One hour later they received zinc (ZnSO4, 2 mg/kg, subcutaneously). Adult female offspring that were in metestrus/diestrus were submitted to a 2 h restraint stress session. Immediately after the stressor, 22 kHz ultrasonic vocalizations, open field behavior, serum corticosterone and brain-derived neurotrophic factor (BDNF) levels, and striatal and hypothalamic neurotransmitter and metabolite levels were assessed. Offspring that received prenatal zinc after LPS presented longer periods in silence, increased locomotion, and reduced serum corticosterone and striatal norepinephrine turnover compared with rats treated with LPS and saline. Prenatal zinc reduced acute restraint stress response in adult rats prenatally exposed to LPS.

Our findings suggest a potential beneficial effect of prenatal zinc, in which the stress response was reduced in offspring that were stricken with infectious/inflammatory processes during gestation.

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Are global histone H3 lysine 27 triple methylation levels reduced in vessels with advanced atherosclerotic plaques?

Alterations in epigenetic processes are frequently noted in human disease. These epigenetic processes involve methylation of DNA and post-translational modifications of histones. It is well established that in particular histone methylation plays a key role in gene transcription. In this study, we have investigated the relationship between triple methylation of lysine 27 in histone H3 (H3K27Me3) modifications and atherosclerotic plaque stage. 28 peri-renal aortic tissue patches covering the entire spectrum of atherosclerotic plaque development were evaluated by immunohistochemistry for the levels of H3K27Me3, EZH2, JMJD3 and BMI1. The results of our studies are in support of a reduction in global levels of the H3K27Me3 modification in vessels with advanced atherosclerotic plaques. This reduction in H3K27Me3 levels is not accompanied by alterations in global levels of the corresponding histone methyltransferase EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2). Likewise no alterations in global levels of BMI1, a component of the PRC1 complex, which binds to H3K27Me3-modified histones or the global expression levels of the histone demethylase JMJD3, which removes the methyl marks on H3K27, were observed.

Together, our data show that in atherosclerosis development alterations in global levels of H3K27Me3 occur. The reduction in the number of nuclei in the tunica media that display the repressive H3K27Me3 mark in vessels with advanced atherosclerosis plaques therefore could be a reflection of the dynamic pattern of smooth muscle cell differentiation and proliferation associated with atherosclerotic disease.

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Does corn silk maysin induce apoptotic cell death in PC-3 prostate cancer cells via mitochondria-dependent pathway?

Despite recent advances in prostate cancer diagnostics and therapeutics, the overall survival rate still remains low. This study was aimed to assess potential anti-cancer activity of maysin, a major flavonoid of corn silk (CS, Zea mays L.), in androgen-independent human prostate cancer cells (PC-3). Maysin was isolated from CS of Kwangpyeongok, a Korean hybrid corn, via methanol extraction and preparative C18 reverse phase column chromatography. Maysin cytotoxicity was determined by either monitoring cell viability in various cancer cell lines by MTT assay or morphological changes. Apoptotic cell death was assessed by annexin V-FITC/PI double staining, depolarization of mitochondrial membrane potential (MMP), expression levels of Bcl-2 and pro-caspase-3 and by terminal transferase mediated dUTP-fluorescein nick end labeling (TUNEL) staining. Underlying mechanism in maysin-induced apoptosis of PC-3 cells was explored by evaluating its effects on Akt and ERK pathway. Maysin dose-dependently reduced the PC-3 cell viability, with an 87% reduction at 200 μg/ml. Maysin treatment significantly induced apoptotic cell death, DNA fragmentation, depolarization of MMP, and reduction in Bcl-2 and pro-caspase-3 expression levels. Maysin also significantly attenuated phosphorylation of Akt and ERK. A combined treatment with maysin and other known anti-cancer agents, including 5-FU, etoposide, cisplatin, or camptothecin, synergistically enhanced PC-3 cell death.

These results suggested for the first time that maysin inhibits the PC-3 cancer cell growth via stimulation of mitochondria-dependent apoptotic cell death and may have a strong therapeutic potential for the treatment of either chemo-resistant or androgen-independent human prostate cancer.

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Do some Strychnos spinosa ( Loganiaceae ) leaf extracts and fractions have good antimicrobial activities and low cytotoxicities?

Strychnos spinosa Lam. is a deciduous tree used in traditional medicine to treat infectious diseases. This study is designed to determine the antimicrobial, antioxidant and cytotoxic activities of extracts and fractions from leaves of S. spinosa. Extracts were obtained by maceration with acetone, methanol and dichloromethane/methanol (1/1) while fractions were prepared by liquid-liquid fractionation of the acetone extract. A broth serial microdilution method with tetrazolium violet as growth indicator was used to determine the minimum inhibitory concentration (MIC) against fungi, Gram-positive and Gram-negative bacteria. The antioxidant activity was determined using free-radical-scavenging assays, and the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide reduction assay was used to determine cytotoxicity. Four extracts and five fractions had good to weak antimicrobial activity with MICs ranging from 0.04 to >1.25 mg/ml against both fungi and bacteria. The chloroform and ethyl acetate fractions had an MIC of 0.08 mg/ml against Aspergillus fumigatus. The n-butanol fraction had an MIC of 0.04 mg/ml against Cryptococcus neoformans. The hexane and chloroform fractions had an MIC of 0.08 mg/ml against Staphylococcus aureus. The antioxidant activities were much lower than that of the positive controls. Except for the alkaloid extract, all the extracts and fractions had free-radical-scavenging activity (IC50 ranging from 33.66 to 314.30 μg/ml). The cytotoxicity on Vero cells was reasonable to low with LC50 values ranging between 30.56 and 689.39 μg/ml.

The acetone extract and the chloroform fraction had the highest antibacterial activity. By solvent-solvent fractionation it was possible to increase the activity against A. fumigatus and to decrease the cytotoxicity leading to a potentially useful product to protect animals against aspergillosis. Our results therefore support the use of S. spinosa leaves in traditional medicine to treat infectious diseases.

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Does maternal immune activation in nonhuman primates alter social attention in juvenile offspring?

Sickness during pregnancy is associated with an increased risk of offspring neurodevelopmental disorders. Rodent models have played a critical role in establishing causal relationships and identifying mechanisms of altered brain and behavior development in pups prenatally exposed to maternal immune activation (MIA). We recently developed a novel nonhuman primate model to bridge the gap between human epidemiological studies and rodent models of prenatal immune challenge. Our initial results demonstrated that rhesus monkeys given the viral mimic synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-l-lysine) during pregnancy produce offspring with abnormal repetitive behaviors, altered communication, and atypical social interactions. We utilized noninvasive infrared eye tracking to further evaluate social processing capabilities in a subset of the first trimester MIA-exposed offspring (n = 4) and control animals (n = 4) from our previous study. As juveniles, the MIA offspring differed from control animals on several measures of social attention, particularly when viewing macaque faces depicting the fear grimace facial expression. Compared with control animals, MIA offspring had a longer latency before fixating on the eyes, had fewer fixations directed at the eyes, and spent less total time fixating on the eyes of the fear grimace images.

In the rhesus monkey model, exposure to MIA at the end of the first trimester results in abnormal gaze patterns to salient social information. The use of noninvasive eye tracking extends the findings from rodent MIA models to more human-like behaviors resembling those in both autism spectrum disorder and schizophrenia.

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Does atractylodes macrocephala Koidz stimulate intestinal epithelial cell migration through a polyamine dependent mechanism?

Atractylodes macrocephala Koidz (AMK), a valuable traditional Chinese herbal medicine, has been widely used in clinical practice for treating patients with disorders of the digestive system. AMK has shown noteworthy promoting effect on improving gastrointestinal function and immunity, which might represent a promising candidate for the treatment of intestinal mucosa injury. The aim of this study was to investigate the efficacy of AMK on intestinal mucosal restitution and the underlying mechanisms via intestinal epithelial (IEC-6) cell migration model. A cell migration model of IEC-6 cells was induced by a single-edge razor blade along the diameter of the cell layers in six-well polystyrene plates. After wounding, the cells were grown in control cultures and in cultures containing spermidine (5μM, SPD, reference drug), alpha-difluoromethylornithine (2.5mM, DFMO, polyamine inhibitor), AMK (50, 100, and 200mg/L), DFMO plus SPD and DFMO plus AMK for 12h. The polyamines content was detected by high-performance liquid chromatography (HPLC) with pre-column derivatization. The Rho mRNAs expression levels were assessed by Q-RT-PCR. The Rho and non-muscle myosin II proteins expression levels were analyzed by Western blot. The formation and distribution of non-muscle myosin II stress fibers were monitored with immunostaining techniques using specific antibodies and observed by confocal microscopy. Cell migration assay was carried out using inverted microscope and the Image-Pro Plus software. All of these indexes were used to evaluate the effectiveness of AMK. (1) Treatment with AMK caused significant increases in cellular polyamines content and Rho mRNAs and proteins expression levels, as compared to control group. Furthermore, AMK exposure increased non-muscle myosin II protein expression levels and formation of non-muscle myosin II stress fibers, and resulted in an acceleration of cell migration in IEC-6 cells. (2) Depletion of cellular polyamines by DFMO resulted in a decrease of cellular polyamines levels, Rho mRNAs and proteins expression, non-muscle myosin II protein formation and distribution, thereby inhibiting IEC-6 cell migration. AMK not only reversed the inhibitory effects of DFMO on the polyamines content, Rho mRNAs and proteins expression, non-muscle myosin II protein formation and distribution, but also restored cell migration to control levels.

The results obtained from this study revealed that AMK significantly stimulates the migration of IEC-6 cells through a polyamine dependent mechanism, which could accelerate the healing of intestinal injury. These findings suggest the potential value of AMK in curing intestinal diseases characterized by injury and ineffective repair of the intestinal mucosa in clinical practice.

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Does chronic exercise normalize changes in Cav 1.2 and KCa 1.1 channels in mesenteric arteries from spontaneously hypertensive rats?

Regular physical activity is an effective non-pharmacological therapy for prevention and control of hypertension. However, the underlying mechanisms are not fully understood. Accumulating evidence shows that the elevated vascular tone in hypertension is a consequence of the 'ion channel remodelling' that occurs during sustained high BP. The present study investigated the effects of aerobic exercise on the electrical remodelling of L-type Ca(2+) (Cav 1.2) and large-conductance Ca(2+) -activated K(+) (KCa 1.1) channels in mesenteric arteries (MAs) from spontaneously hypertensive rats (SHRs). SHRs and normotensive (Wistar-Kyoto) rats were subjected to aerobic training or kept sedentary, and vascular mechanical and functional properties were evaluated. Exercise did not affect the heart weight, but reduced the heart rate and body weight in SHR. In mesenteric arterial myocytes, exercise normalized the increased Cav 1.2 and KCa 1.1 current density in SHRs. Exercise also ameliorated the increased open probability and mean open time of the single KCa 1.1 channel in hypertension. The isometric contraction study revealed that both nifedipine (Cav 1.2 channel blocker) and NS11021 (KCa 1.1 channel activator) induced concentration-dependent vasorelaxation in MAs precontracted with noradrenaline. Exercise normalized the increased sensitivity of tissues to nifedipine and NS11021 in SHR. Furthermore, protein expression of the Cav 1.2 α1C -subunit together with the KCa 1.1 α- and β1-subunit was significantly increased in SHRs; and exercise ameliorated these molecular alterations in hypertension.

Chronic exercise reduces BP and restores vascular function in MAs from SHR, which might be related to the correction of the Cav 1.2 and KCa 1.1 channel remodelling during hypertension.

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Does cXCR3 antagonist VUF10085 bound to an intrahelical site distinct from that of the broad spectrum antagonist TAK-779?

The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5. Molecular modelling of CXCR3, followed by virtual ligand docking, highlighted several CXCR3 residues likely to contact either antagonist, notably a conserved aspartate in helix 2 (Asp-112(2:63) ), which was postulated to interact with the quaternary nitrogen of TAK-779. Validation of modelling was carried out by site-directed mutagenesis of CXCR3, followed by assays of cell surface expression, ligand binding and receptor activation. Mutation of Asn-132(3.33) , Phe-207 and Tyr-271(6.51) within CXCR3 severely impaired both ligand binding and chemotactic responses, suggesting that these residues are critical for maintenance of a functional CXCR3 conformation. Contrary to our hypothesis, mutation of Asp-112(2:63) had no observable effects on TAK-779 activity, but clearly decreased the antagonist potency of VUF 10085. Likewise, mutations of Phe-131(3.32) , Ile-279(6.59) and Tyr-308(7.43) were well tolerated and were critical for the antagonist activity of VUF 10085 but not for that of TAK-779.

This more detailed definition of a binding pocket within CXCR3 for low MW antagonists should facilitate the rational design of newer CXCR3 antagonists, with obvious clinical potential.

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