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Does prolonged P wave duration predict stroke mortality among type 2 diabetic patients with prevalent non-major macrovascular disease?

Prolonged P wave duration is a marker of delayed inter-atrial conduction which may predict cardiovascular disease (CVD). Type 2 diabetes is a risk factor for all atherosclerotic manifestations including stroke. We evaluated the prognostic significance of prolonged P wave duration among middle-aged Finnish type 2 diabetes patients with and without prevalent non-major macrovascular disease (PNMMVD) with respect to total and stroke mortality. We followed up for 18 years 739 type 2 diabetic patients without previous major CVD event at baseline. Participants were stratified according to P wave duration (<114 or ≥ 114 ms) and PNMMVD (i.e. coronary heart disease defined as ischaemic ECG changes and typical symptoms of angina pectoris, or claudication; yes or no). The Cox proportional hazards model was used to estimate the joint association between P wave duration, PNMMVD and the mortality risk. During the follow-up, 509 patients died, and 59 of them died from stroke. Those who had prolonged P wave duration had 2.45 (95% confidence interval: 1.11-5.37) increased stroke mortality among PNMMVD patients. In patients without PNMMVD, there was no relationship between P wave duration and stroke mortality.

As an easily measurable factor P wave duration merits further studies with higher number of patients to evaluate its importance in the estimation of stroke risk in type 2 diabetic patients with PNMMVD.

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Do central adenosine A1 and A2A receptors mediate the antinociceptive effects of neuropeptide S in the mouse formalin test?

The present study aimed to investigate the intraplantar (ipl) and central (icv) effects of neuropeptide S (NPS) in the formalin test and to evaluate the role of adenosine receptors, mainly A1 and A2A, in mediating such effects. The ipl injection of formalin was used to assess the nociceptive activity. Moreover, by pretreating mice with non-selective and selective antagonists of adenosine receptors, the effects of icv NPS on formalin-induced ongoing nociception were assessed. Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was active only at the later nociceptive phase. The ipl injection of NPS (alone or combined with formalin) did not modify the nociceptive response. However, icv NPS significantly reduced formalin-induced nociception during both phases. Caffeine (3 mg/kg, ip), a non-selective adenosine receptor antagonist, prevented NPS-induced antinociceptive effects. Similar to caffeine, icv ZM241385 (0.01 nmol), an A2A receptor antagonist, prevented the antinociceptive effects of NPS. Moreover, icv DPCPX (0.001 nmol), an A1 receptor antagonist, blocked the effects of NPS only during phase 1.

The above findings suggest that: (i) NPS evokes central antinociceptive effects by activating both A1 and A2A receptors during phase 1, but (ii) only the adenosine A2A receptor during phase 2 of the formalin test.

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Does experimental diabetes mellitus type 1 increase hippocampal content of kynurenic acid in rats?

Diabetes mellitus (DM) is frequently associated with peripheral and central complications and has recently emerged as a risk factor for cognitive impairment and dementia. Kynurenic acid (KYNA), a unique tryptophan derivative, displays pleiotropic effects including blockade of ionotropic glutamate and α7 nicotinic receptors. Here, the influence of experimental diabetes on KYNA synthesis was studied in rat brain. DM was induced by i.p. administration of streptozotocin (STZ). Five weeks later, KYNA content and the activity of semi-purified kynurenine aminotransferases (KATs) were measured in frontal cortex, hippocampus and striatum of diabetic and insulin-treated rats, using HPLC-based methods. Hippocampal but not cortical or striatal KYNA concentration was considerably increased during DM, either untreated or treated with insulin (220% and 170% of CTR, respectively). The activity of kynurenine aminotransferase I (KAT I) was not affected by DM in all of the studied structures. KAT II activity was moderately increased in cortex (145% of CTR) and hippocampus (126% of CTR), but not in striatum of diabetic animals. Insulin treatment normalized cortical but not hippocampal KAT II activity.

A novel factor potentially implicated in diabetic hippocampal dysfunction has been identified. Observed increase of KYNA level may stem from the activation of endogenous neuroprotection, however, it may also have negative impact on cognition.

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Does blockade of p38 mitogen-activated protein kinase pathway ameliorate delayed gastric emptying in streptozotocin-induced diabetic rats?

Gastrointestinal dysfunction is one of the major complications of diabetes. The roles of inflammation in diabetes and its associated complications are increasingly recognized. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of pro-inflammatory mediators. The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on delayed gastric emptying in diabetic rats and to elucidate its possible mechanism. SB203580 was administered in diabetic rats induced by intraperitoneal injection of streptozotocin. The gastric emptying rate of rats was measured by using phenol red solution, and blood glucose levels and body weights were observed. p38 MAPK activity and iNOS expression were assessed by Western blot analysis. The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were determined by enzyme-linked immunosorbent assay. Gastric emptying was delayed significantly in diabetic rats and improved significantly with SB203580; high glucose significantly activated p38 MAPK and increased the expression of iNOS, TNF-α and IL-1β. The administration of SB203580 led to a significant decrease in the activation of p38 MAPK and the expression of iNOS, TNF-α and IL-1β.

Inflammation was associated with the development of delayed gastric emptying, and blockade of p38 MAPK pathway with SB203580 ameliorates delayed gastric emptying in diabetic rats, at least in part, by inhibiting the expression of iNOS, TNF-a and IL-1β. Therefore, p38MAPK may serve as a novel target for the therapy of diabetes-related gastrointestinal dysmotility.

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Is high level of plasma matrix metalloproteinase-11 associated with clinicopathological characteristics in patients with oral squamous cell carcinoma?

Matrix metalloproteinase-11 (MMP-11) is reported to be overexpressed in several cancers and may contribute to tumorigenesis. The current study investigated the association between the clinicopathological characteristics and plasma level of MMP-11 in oral squamous cell carcinoma (OSCC) patients. The plasma MMP-11 concentration was determined by ELISA on 330 male OSCC patients. In addition, the metastatic effects of the MMP-11 knockdown on the oral cancer cells were investigated by cell migration assay. Our results showed that the plasma MMP-11 levels were significantly higher in patients with advanced T status (p = 0.001), lymph node metastasis (p = 0.006) and higher TNM stages (p<0.001). Moreover, treatment with the MMP-11 shRNA exerted an inhibitory effect on migration in SCC9 oral cancer cells.

Our study showed that plasma level of MMP-11 may be useful for assessment of the disease progression, especially lymph node metastasis, in patients with OSCC.

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Is interferon lambda-3 associated with clinical outcome in patients with HCV-induced compensated cirrhosis : a long-term cohort study?

Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear. We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome. IFN-λ3 was determined in 264 patients (52% males, mean age 57±8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression.

IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease.

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Does dorsomedial Prefrontal Cortex mediate the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions?

Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states. The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals' anticipatory responses to potential threat. Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2).

The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology.

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Does intensity-modulated whole pelvic radiotherapy provide effective dosimetric outcomes for cervical cancer treatment with lower toxicities?

To compare the efficacy of intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, and conventional radiotherapy for cervical cancer treatment. Whole pelvis intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, and conventional radiotherapy plans were designed for 16 patients with stage IIB cervical cancer, each using the prescribed dose of 50.4 Gy/28 fractions. Dose-volume histograms of the target volume and organs at risk were evaluated. Compared to the 3D conformal and conventional radiotherapy plans, the intensity-modulated radiotherapy plan demonstrated superior conformal treatment. The mean planning target volume dose of all three plans reached the target effective therapeutic dose. The planning target volume dose of the intensity-modulated radiotherapy plan was significantly higher than that of either the three-dimensional conformal radiotherapy or conventional radiotherapy plan (P<0.05). When more than 30 Gy was administered in intensity-modulated radiotherapy, organs at risk including the small intestine, rectum, bladder, and bone marrow received a significantly reduced volume of radiation. In comparison of the average planning target volume doses, significant volume reductions in irradiation of organs at risk were obtained with full bladders.

An intensity-modulated radiotherapy plan with appropriate margins encompassing the primary tumour and potential microscopic pelvic disease reduces the dose to organs at risk without compromising target coverage. Intensity-modulated radiotherapy is an appropriate definitive treatment for patients with cervical cancer.

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Does treatment with anti-C5a antibody improve the outcome of H7N9 virus infection in African green monkeys?

Patients infected with influenza A(H7N9) virus present with acute lung injury (ALI) that is due to severe pneumonia and systemic inflammation. It is often fatal because there are few effective treatment options. Complement activation has been implicated in the pathogenesis of virus-induced lung injury; therefore, we investigated the effect of targeted complement inhibition on ALI induced by H7N9 virus infection. A novel neutralizing specific antihuman C5a antibody (IFX-1) was used. This antibody blocked the ability of C5a to induce granulocytes to express CD11b while not affecting the ability of C5b to form the membrane attack complex. African green monkeys were inoculated with H7N9 virus and treated intravenously with IFX-1. The virus infection led to intense ALI and systemic inflammatory response syndrome (SIRS) in association with excessive complement activation. Anti-C5a treatment in H7N9-infected monkeys substantially attenuated ALI: It markedly reduced the lung histopathological injury and decreased the lung infiltration of macrophages and neutrophils. Moreover, the treatment decreased the intensity of SIRS; the body temperature changes were minimal and the plasma levels of inflammatory mediators were markedly reduced. The treatments also significantly decreased the virus titers in the infected lungs.

Antihuman C5a antibody treatment remarkably reduced the ALI and systemic inflammation induced by H7N9 virus infection. Complement inhibition may be a promising adjunctive therapy for severe viral pneumonia.

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Are socioeconomic inequalities still a barrier to full child vaccine coverage in the Brazilian Amazon : a cross-sectional study in Assis Brasil , Acre , Brazil?

Vaccines are very important to reduce morbidity and mortality by preventable infectious diseases, especially during childhood. Optimal coverage is not always achieved, for several reasons. Here we assessed vaccine coverage for the first 12 months of age in children between 12 and 59 months old, residing in the urban area of a small Amazonian city, and factors associated with incomplete vaccination. A census was performed in the urban area of Assis Brasil, in the Brazilian Amazon, in January 2010, with mothers of 282 children aged 12 to 59 months old, using structured interviews and data from vaccination cards. Mixed logistic regression was used to determine factors associated with incomplete vaccination schemes. Only 82.6% of all children had a completed the basic vaccine scheme for the first year of life. Vaccine coverage ranged from 52.7% coverage (oral rotavirus vaccine) to 99.7% coverage (for Bacille Calmette-Guérin). The major deficiencies occurred in doses administered after the first six months of life. Incomplete vaccination was associated with not having enough income to buy a house (aOR = 2.12, 95% CI 1.06-4.21), low maternal schooling (aOR = 2.60, 95% CI 1.28 - 5.29) , and time of residence of the child in the urban area of the city (aOR = 0.73, 95% CI 0.55 - 0.95).

This study showed that vaccine coverage in the first twelve months of life in Assis Brasil is similar to other areas in the Amazon and it is below the coverage postulated by the Brazilian Ministry of Health. Low vaccine coverage was associated with socioeconomic inequities that still prevail in the Brazilian Amazon. Short and long-term strategies must be taken to update child vaccines and increase vaccine coverage in the Amazon.

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Does mental fatigue affect maximal anaerobic exercise performance?

Mental fatigue can negatively impact on submaximal endurance exercise and has been attributed to changes in perceived exertion rather than changes in physiological variables. The impact of mental fatigue on maximal anaerobic performance is, however, unclear. Therefore, the aim of the present study was to induce a state of mental fatigue to examine the effects on performance, physiological and perceptual variables from subsequent tests of power, strength and anaerobic capacity. Twelve participants took part in the single-blind, randomised, crossover design study. Mental fatigue was induced by 90 min of the computer-based Continuous Performance Task AX version. Control treatment consisted of 90 min of watching emotionally neutral documentaries. Participants consequently completed countermovement jump, isometric leg extension and a 3-min all-out cycling tests. Results of repeated measures analysis of variance and paired t tests revealed no difference in any performance or physiological variable. Rating of perceived exertion tended to be greater when mentally fatigued (mental fatigue = 19 ± 1 vs control = 18 ± 1, p = 0.096, [Formula: see text] = .232) and intrinsic motivation reduced (mental fatigue = 11 ± 4 vs control = 13 ± 6, p = 0.063, d = 0.597) in the mental fatigue condition.

Near identical responses in performance and physiological parameters between mental fatigue and control conditions suggest that peripheral mechanisms primarily regulate maximal anaerobic exercise. Whereas mental fatigue can negatively impact submaximal endurance exercise, it appears that explosive power, voluntary maximal strength and anaerobic work capacity are unaffected.

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Is tP53 Pro72 allele enriched in oral tongue cancer and frequently mutated in esophageal cancer in India?

The tumor suppressor p53 is known to be inactivated frequently in various cancers. In addition, germline polymorphisms in TP53 are known to affect protein function and influence risk of developing different types of cancers. In this study, we analyzed the association of TP53 Pro72Arg polymorphism with squamous cell carcinoma of oral tongue (SCCOT) and esophagus (ESCC) in India. We assessed the distribution of TP53 Pro72Arg polymorphism in one hundred and fifteen and eighty two SCCOT and ESCC patients, respectively, with respect to one hundred and ten healthy controls from the same population. In addition, we analyzed association of the polymorphism with several clinico-pathological and molecular parameters. Pro72 allele was significantly enriched in SCCOT patients compared to the healthy control group but neither allele was enriched in ESCC. Interestingly, Pro72 allele was preferentially mutated in ESCC which was confirmed by analysis of samples heterozygous for Pro72Arg.

Our study revealed the association of Pro72 allele with SCCOT suggesting the effect of this polymorphism on SCCOT risk. Preferential mutation of Pro72 allele exclusively in ESCC indicates the need for further studies to understand the tissue specific effect of p53 polymorphism.

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Does α-Enolase play a catalytically independent role in doxorubicin-induced cardiomyocyte apoptosis and mitochondrial dysfunction?

α-Enolase is a glycolytic enzyme with "second jobs" beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. The expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain- and loss-of-function approaches to regulate α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied. The mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase.

Our findings provided the evidence that α-enolase has a catalytically independent role in inducing cardiomyocyte apoptosis and mitochondrial dysfunction, which could be at least partially contributed to the inhibition of AMPK phosphorylation.

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Do a qualitative study of the background and in-hospital medicolegal response to female burn injuries in India?

Most burns happen in low- and middle-income countries. In India, deaths related to burns are more common in women than in men and occur against a complex background in which the cause - accidental or non-accidental, suicidal or homicidal - is often unclear. Our study aimed to understand the antecedents to burns and the problem of ascribing cause, the sequence of medicolegal events after a woman was admitted to hospital, and potential opportunities for improvement. We conducted semi-structured interviews with 33 women admitted to two major burns units, their families, and 26 key informant doctors, nurses, and police officers. We used framework analysis to examine the context in which burns occurred and the sequence of medicolegal action after admission to hospital. Interviewees described accidents, attempted suicide, and attempted homicide. Distinguishing between these was difficult because the underlying combination of poverty and cultural precedent was common to all and action was contingent on potentially conflicting narratives. Space constraint, problems with cooking equipment, and inflammable clothing increased the risk of accidental burns, but coexisted with household conflict, gender-based violence, and alcohol use. Most burns were initially ascribed to accidents. Clinicians adhered to medicolegal procedures, the police carried out their investigative requirements relatively rapidly, but both groups felt vulnerable in the face of the legal process. Women's understandable reticence to describe burns as non-accidental, the contested nature of statements, their perceived history of changeability, the limited quality and validity of forensic evidence, and the requirement for resilience on the part of clients underlay a general pessimism.

The similarities between accident and intention cluster so tightly as to make them challenging to distinguish, especially given women's understandable reticence to describe burns as non-accidental. The contested status of forensic evidence and a reliance on testimony means that only a minority of cases lead to conviction. The emphasis should be on improving documentation, communication between service providers, and public understanding of the risks of burns.

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Is african-american race a predictor of seminal vesicle invasion after radical prostatectomy?

The purpose of the study was to determine whether racial differences exist in the pattern of local disease progression among men treated with radical prostatectomy (RP) for localized prostate cancer (PCa), which is currently unknown. In this study we evaluated the pattern of adverse pathologic features in an identical cohort of African-American (AA) and Caucasian (CS) men with PCa. The overall cohort consisted of 1104 men (224 AA, and 880 CS) who underwent RP between 1990 and 2012. We compared preoperative factors and pathologic outcomes after RP across race groups. Multivariate analysis was used to identify factors predictive of adverse pathologic outcomes. The effect of race on adverse pathologic outcomes and biochemical control rate (BCR) was evaluated using multivariate regression model and Kaplan-Meier analysis. The 10-year BCR was 59% versus 82% in AA and CS men, respectively (P = .003). There was no significant difference in extraprostatic spread (P = .14), positive surgical margin (P = .81), lymph node involvement (P = .71), or adverse pathologic features (P = .16) across race groups. However, among patients with ≥ 1 adverse pathologic features, AA men had higher rate of seminal vesicle invasion (SVI) compared with CS men (51% vs. 30%; P = .01). After adjusting for known predictors of adverse pathologic features AA race remained a predictor of SVI.

AA men have an increased risk of SVI after RP, particularly among men with Gleason ≤ 6 disease. This might represent racial differences in the biology of PCa disease progression, which contribute to poorer outcomes in AA men.

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Is self-rated health associated with the length of stay at the intensive care unit and hospital following cardiac surgery?

Recently, a considerable amount of evidence suggested that anxiety, depression and other psychosocial variables might influence the outcomes of cardiac surgery. This study investigated the relationship between length of stay at the intensive care unit (ICU) and hospital after surgery and different psychosocial variables (e.g. depression, anxiety, self rated health, happiness, satisfaction). We enrolled prospective patients who were waiting for elective cardiac surgery (N = 267) and consented to take part in the study. We collected data of sociodemographic, medical and perioperative factors as well as psychosocial questionnaires completed 1.56 days (standard deviation [SD] = 0.7) before surgery. The primary clinical endpoint was an ICU stay of at least 3 days and the secondary was hospital stay of at least 10 days. Two hundred sixty-seven patients participated in this study. Four patients (1.5%) died in the hospital and 38 patients (14.5%) spent more than 3 days in the ICU and 62 patients (23.2%) spent more than 10 days in the hospital. After controlling for medical and sociodemographic factors, lower self rated health (Adjusted Odds Ratio [AOR]: 0.51, 95% confidence interval [CI]: 0.28-0.95; p = 0.03), lower rate of happiness (AOR: 0.76, 95% CI: 0.59-0.97, p = 0.03), postoperative cardiac failure (AOR: 7.09, 95% CI:1.21-41.54; p = 0.03) and postoperative complications (AOR: 9.52, 95% CI: 3.76-24.11; p < 0.001) were associated with longer ICU stay. More than 10 days of hospital stay was associated with higher occurrence of COPD (AOR 4.56, CI: 1.95-10.67, p < 0.001), NYHA stage (AOR 6.76, CI: 2.57-17.79, p < 0.001), operation time (AOR 1.45, CI: 1.19-1.76, p < 0.001), female gender (AOR 2.16, CI: 1.06-4.40, p = 0.034) and lower self-rated health (AOR 0.63, CI: 0.41-0.99, p = 0.044).

Lower happiness and self-rated health may influence the outcome of cardiac surgery. Therefore, these variables should be assessed in patients.

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Is integrin-based meningioma cell migration promoted by photon but not by carbon-ion irradiation?

Sublethal doses of photon irradiation (IR) are suspected to increase tumor cell migration and support locoregional recurrence of disease, which has already been shown in other cell lines. This manuscript describes the effect of photon and carbon-ion IR on WHO class I meningioma cell migration and provides an approach to the underlying cellular mechanisms. Meningioma cells were gained operatively at the university hospital in Homburg/Saar, Germany. For migration, membranes (8-µm pore sizes) were coated with collagen I, with collagen IV, and with fibronectin. Cells were analyzed in migration experiments with or without serum stimulation, with or without photon and carbon IR 24 h prior to experiments, and with or without integrin antibodies. Fluorescence-activated cell sorting (FACS) analyses of the integrins ανβ1, ανβ3, and ανβ5 were performed without IR and 6, 12 and 24 h after IR. Enzyme-linked immunosorbent assay (ELISA) analyses of matrix metalloproteinases (MMP)-2 and MMP-9 were realized with and without IR after cells were cultured on collagen I, collagen IV, or fibronectin for 24 h. Cells and supernatants for FACS and ELISA were stored at - 18 °C. The significance level was set at 5 % using both Student's t test and two-way ANOVA. Migration of meningioma cells was serum-inducible (p < 0.001). It could be increased by photon IR (p < 0.02). The integrins ανβ1 and ανβ5 showed a 21 and 11 % higher expression after serum stimulation (not significant), respectively, and ανβ1 expression was raised by 14 % (p = 0.0057) after photon IR. Antibody blockage of the integrins ανβ1 and ανβ5 inhibited serum- and photon-induced migration. Expression of MMP-2 and MMP-9 remained unchanged after both IR and fetal bovine serum (FBS). Carbon-ion IR left both integrin expression and meningioma cell migration unaffected.

Photon but not carbon-ion IR promotes serum-based meningioma cell migration. Fibronectin receptor integrin ανβ1 signaling can be identified as an important mechanism for serum- and photon-induced migration of WHO class I meningioma cells.

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Does early-life stress selectively affect gastrointestinal but not behavioral responses in a genetic model of brain-gut axis dysfunction?

Early-life stress and a genetic predisposition to display an anxiety- and depressive-like phenotype are associated with behavioral and gastrointestinal (GI) dysfunction. Animals exposed to early-life stress, and those genetically predisposed to display anxiety or depressive behaviors, have proven useful tools in which to study stress-related GI disorders, such as irritable bowel syndrome (IBS). IBS is a heterogeneous disorder, and likely a consequence of both genetic and environmental factors. However, the combined effects of early-life stress and a genetic predisposition to display anxiety- and depression-like behaviors on GI function have not been investigated. We assessed the effect of maternal separation (MS) on behavioral and GI responses in WKY animals relative to a normo-anxious reference strain. Both non-separated (NS) WKY and WKY-MS animals displayed anxiety-like responses in the open-field test and depressive-like behaviors in the forced swim test relative to Sprague-Dawley rats. However, MS had no further influence on anxiety- and depressive-like behaviors exhibited by this stress-prone rat strain. Similarly, corticosterone levels measured after the OFT were insensitive to MS in WKY animals. However, WKY-MS displayed significantly increased colonic visceral hypersensitivity, fecal output, and altered colonic cholinergic sensitivity.

Our data suggest that early-life stress, on the background of a genetic predisposition to display an anxiety- and depressive-like phenotype, selectively influences GI function rather than stress-related behaviors. Thus, our findings highlight the importance of genetic predisposition on the outcome of early-life adversity on GI function.

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Are historic and current hepatitis B viral DNA and quantitative HBsAg level associated with cirrhosis in non-Asian women with chronic hepatitis B?

Some studies done in Asian patients have shown that serum levels of hepatitis B virus (HBV) DNA predict the development of cirrhosis. However, it is unclear whether this also applies for non-Asian patients. This study investigated historic and current HBV DNA and quantitative hepatitis B surface antigen (HBsAg) levels as predictors of cirrhosis in non-Asian women with chronic HBV. A retrospective cohort study of non-Asian women with chronic HBV was performed. Among other variables, HBV DNA and quantitative HBsAg levels were measured in stored historic serum samples obtained during pregnancy (period 1990-2004) and current serum samples (period 2011-2012) to determine any association with liver cirrhosis by liver stiffness measurement (LSM). One hundred and nineteen asymptomatic, treatment-naïve non-Asian women were included; the median number of years between the historic sample and the current sample was 17 (interquartile range (IQR) 13-20). The median historic log HBV DNA and quantitative log HBsAg levels were 2.5 (IQR 1.9-3.4) IU/ml and 4.2 (IQR 3.6-4.5) IU/ml, respectively. LSM diagnosed 14 patients (12%) with F3-F4 fibrosis, i.e. stiffness >8.1kPa. No association of cirrhosis was found with historic HBV DNA (relative risk (RR) 0.34, 95% confidence interval (CI) 0.05-2.44) or with the quantitative HBsAg level (HBsAg level >1000 IU/ml, RR 0.35, 95% CI 0.11-1.11). Multivariable analysis identified alcohol consumption (odds ratio (OR) 6.4, 95% CI 1.3-30.1), aspartate aminotransferase >0.5 times the upper limit of normal (OR 15.4, 95% CI 1.9-122.6), and prothrombin time (OR 12.0, 95% CI 1.2-120.4), but not HBV DNA or quantitative HBsAg level, to be independent predictors of the presence of cirrhosis.

Neither historic nor current HBV DNA or the quantitative HBsAg level is associated with the development of HBV-related cirrhosis in non-Asian women.

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Does patatin-related phospholipase pPLAIIIδ influence auxin-responsive cell morphology and organ size in Arabidopsis and Brassica napus?

The members of the patatin-related phospholipase subfamily III (pPLAIIIs) have been implicated in the auxin response. However, it is not clear whether and how these genes affect plant and cell morphogenesis. Here, we studied the roles of the patatin-related phospholipase pPLAIIIδ in auxin-responsive cell morphology and organ size in Arabidopsis and Brassica napus. We show that overexpression of pPLAIIIδ inhibited longitudinal growth but promoted transverse growth in most organs of Arabidopsis and Brassica napus. Compared to wild-type plants, pPLAIIIδ-KO plants exhibited enhanced cell elongation in hypocotyls, and pPLAIIIδ-OE plants displayed broadened radial cell growth of hypocotyl and reduced leaf pavement cell polarity. For the hypocotyl phenotype in pPLAIIIδ mutants, which resembles the "triple response" to ethylene, we examined the expression of the ACS and ACO genes involved in ethylene biosynthesis and found that ACS4 and ACS5 were up-regulated by 2.5-fold on average in two OE lines compared with WT plants. The endogenous auxin distribution was disturbed in plants with altered pPLAIIIδ expression. pPLAIIIδ-OE and KO plants exhibited different sensitivities to indole-3-acetic acid-promoted hypocotyl elongation in both light and dark conditions. Gene expression analysis of auxin-induced genes in the dark showed that OE plants maintained a higher auxin response compared with WT and KO plants after treatment with 1 μM IAA for 12 h. Following treatment with 10 μM IAA for 30 min in the light, early auxin-induced genes were significantly up-regulated in two OE plant lines.

These data suggest that the PLAIIIδ gene plays an important role in cell morphology and organ size through its involvement in the regulation of auxin distribution in plants.

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Does histoscanning have low sensitivity and specificity for seminal vesicle invasion?

To examine the accuracy of HistoScanning (HS) in detecting seminal vesicle (SV) invasion (SVI) within prostate cancer (PCa) patients. We relied on our prospective institutional database. Patients who received HS before radical prostatectomy were included in the study cohort. An experienced HS examiner retrospectively reanalyzed the HS data blinded to patient characteristics and pathologic results. The HS results for every single SV were compared with the corresponding findings from the final pathologic report after radical prostatectomy. An area under the receiver operating characteristic curve for the prediction of SVI by HS was calculated. Depending on HS signal volume cut-offs (>0, >0.2, and >0.5 mL), the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of SVI were assessed. Overall, 131 patients and 262 SVs were assessable. Of those, 23 (17.5%) men had SVI, and 39 (14.9%) single SVs were infiltrated by tumor overall. The area under the receiver operating characteristic curve for predicting SVI by HS was 0.54. Depending on the HS signal volume cut-offs (>0, >0.2, and >0.5 mL), the sensitivity, specificity, positive predictive value, and negative predictive value for predicting SVI were 76.9%, 10.8%, 13.1%, and 72.7%; 61.5%, 24.2%, 12.4%, and 78.3%; and 46.2%, 50.2%, 14.0%, and 84.2%, respectively.

HS results did not allow a reliable prediction of SVI within PCa patients. Despite, the application of HS signal volume cut-offs (>0.2 and >0.5 mL), the prediction of SVI within PCa patients remained insufficient.

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Is low percentage of free prostate-specific antigen ( PSA ) a strong predictor of later detection of prostate cancer among Japanese men with serum levels of total PSA of 4.0 ng/mL or less?

To investigate the effect of the percentage of free prostate-specific antigen (%fPSA) on future prostate cancer risk. We examined serum total PSA (tPSA) and %fPSA annually in a prostate cancer-screening cohort between July 2001 and June 2011. Men with tPSA >4.0 ng/mL or tPSA of 2.0-4.0 ng/mL with %fPSA ≤12% were screened as positive and were recommended to undergo a biopsy. The study population consisted of 6368 men, aged 40-79 years, who had tPSA ≤4.0 ng/mL at initial screening and who subsequently underwent 1 or more screenings. We calculated the cumulative risk and hazard ratio of prostate cancer stratified by the initial %fPSA groups as quartiles of prostate cancer patients. During a median follow-up of 36 months, 119 men were diagnosed with prostate cancer. The lowest quartile of %fPSA (<13.3%) was associated with a 21.2-fold higher risk of having prostate cancer compared with the highest quartile (>22.2%). For the subset with an initial tPSA ≤1.0 ng/mL, all men diagnosed with cancer had an initial %fPSA ≤33.3% (median). For the subset with tPSA >1.0 ng/mL, men with %fPSA ≤23.0% (median) had significantly higher risk for cancer than those with %fPSA >23.0% (P <.0001). Of the 114 men with prostate cancer in whom pathologic findings were available, 79 (69.3%) had a Gleason score ≥3 + 4 = 7.

A low %fPSA is a strong predictor of a subsequent diagnosis of prostate cancer among men with tPSA levels ≤4.0 ng/mL. Measurement of %fPSA might enhance the detection of high-grade cancer that warrants aggressive treatment.

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Is permanent His-bundle pacing feasible , safe , and superior to right ventricular pacing in routine clinical practice?

Right ventricular pacing (RVP) has been associated with heart failure and increased mortality. His-bundle pacing (HBP) is more physiological but requires a mapping catheter or a backup right ventricular lead and is technically challenging. We sought to assess the feasibility, safety, and clinical outcomes of permanent HBP in an unselected population as compared to RVP. All patients requiring pacemaker implantation routinely underwent attempt at permanent HBP using the Select Secure (model 3830) pacing lead in the year 2011 delivered through a fixed-shaped catheter (C315 HIS) at one hospital and RVP at the second hospital. Patients were followed from implantation, 2 weeks, 2 months, 1 year, and 2 years. Fluoroscopy time (FT), pacing threshold (PTh), complications, heart failure hospitalization, and mortality were compared. HBP was attempted in 94 consecutive patients, while 98 patients underwent RVP. HBP was successful in 75 patients (80%). FT was similar (12.7 ± 8 minutes vs 10 ± 14 minutes; median 9.1 vs 6.4 minutes; P = .14) and PTh was higher in the HBP group than in the RVP group (1.35 ± 0.9 V vs 0.6 ± 0.5 V at 0.5 ms; P < .001) and remained stable over a 2-year follow-up period. In patients with >40% ventricular pacing (>60% of patients), heart failure hospitalization was significantly reduced in the HBP group than in the RVP group (2% vs 15%; P = .02). There was no difference in mortality between the 2 groups (13% in the HBP group vs 18% in the RVP group; P = .45).

Permanent HBP without a mapping catheter or a backup right ventricular lead was successfully achieved in 80% of patients. PTh was higher and FT was comparable to those of the RVP group. Clinical outcomes were better in the HBP group than in the RVP group.

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Are clinical and serum-based markers associated with death within 1 year of de novo implant in primary prevention ICD recipients?

Implantable cardioverter-defibrillator (ICD) implantation is contraindicated in those with <1-year life expectancy. The aim of this study was to develop a risk prediction score for 1-year mortality in patients with primary prevention ICDs and to determine the incremental improvement in discrimination when serum-based biomarkers are added to traditional clinical variables. We analyzed data from the Prospective Observational Study of Implantable Cardioverter-Defibrillators, a large prospective observational study of patients undergoing primary prevention ICD implantation who were extensively phenotyped for clinical and serum-based biomarkers. We identified variables predicting 1-year mortality and synthesized them into a comprehensive risk scoring construct using backward selection. Of 1189 patients deemed by their treating physicians as having a reasonable 1-year life expectancy, 62 (5.2%) patients died within 1 year of ICD implantation. The risk score, composed of 6 clinical factors (age ≥75 years, New York Heart Association class III/IV, atrial fibrillation, estimated glomerular filtration rate <30 mL/min/1.73 m(2), diabetes, and use of diuretics), had good discrimination (area under the curve 0.77) for 1-year mortality. Addition of 3 biomarkers (tumor necrosis factor α receptor II, pro-brain natriuretic peptide, and cardiac troponin T) further improved model discrimination to 0.82. Patients with 0-1, 2-3, 4-6, or 7-9 risk factors had 1-year mortality rates of 0.8%, 2.7%, 16.1%, and 46.2%, respectively.

Individuals with more comorbidities and elevation of specific serum biomarkers were at increased risk of all-cause mortality despite being deemed as having a reasonable 1-year life expectancy. A simple risk score composed of readily available clinical data and serum biomarkers may better identify patients at high risk of early mortality and improve patient selection and counseling for primary prevention ICD therapy.

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Does astaxanthin prevent TGFβ1-induced pro-fibrogenic gene expression by inhibiting Smad3 activation in hepatic stellate cells?

Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease, the most common chronic liver disease in the U.S. Fibrosis, a common feature of NASH, results from the dysregulation of fibrogenesis in hepatic stellate cells (HSCs). In this study, we investigated whether astaxanthin (ASTX), a xanthophyll carotenoid, can inhibit fibrogenic effects of transforming growth factor β1 (TGFβ1), a key fibrogenic cytokine, in HSCs. Reactive oxygen species (ROS) accumulation was measured in LX-2, an immortalized human HSC cell line. Quantitative realtime PCR, Western blot, immunocytochemical analysis, and in-cell Western blot were performed to determine mRNA and protein of fibrogenic genes, and the activation of Smad3 in TGFβ1-activated LX-2 cells and primary mouse HSCs. In LX-2 cells, ROS accumulation induced by tert-butyl hydrogen peroxide and TGFβ1 was abolished by ASTX. ASTX significantly decreased TGFβ1-induced α-smooth muscle actin (α-SMA) and procollagen type 1, alpha 1 (Col1A1) mRNA as well as α-SMA protein levels. Knockdown of Smad3 showed the significant role of Smad3 in the expression of α-SMA and Col1A1, but not TGFβ1, in LX-2 cells. ASTX attenuated TGFβ1-induced Smad3 phosphorylation and nuclear translocation with a concomitant inhibition of Smad3, Smad7, TGFβ receptor I (TβRI), and TβRII expression. The inhibitory effect of ASTX on HSC activation was confirmed in primary mouse HSCs as evidenced by decreased mRNA and protein levels of α-SMA during activation.

Taken together, ASTX exerted anti-fibrogenic effects by blocking TGFβ1-signaling, consequently inhibiting the activation of Smad3 pathway in HSCs.

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Is vitamin D deficiency in mycosis fungoides and Sézary syndrome patients similar to other cancer patients?

The purpose of this study was to determine the prevalence of vitamin D deficiency in CTCL patients and whether supplementation corrects vitamin D deficiency or treatment outcome. Three hundred eleven CTCL patients including 27/311 (8.7%) with Sézary syndrome (SS), 169 cancer controls, and 69 normal controls from the M.D. Anderson clinics had 25(OH)D3 levels determined and categorized as deficient (< 20 ng/mL),insufficient (20-29 ng/mL), or sufficient (≥ 30 ng/mL). Clinical response was determined according to a change in percent body surface area involvement. Low 25(OH)D3 (< 30 ng/mL) levels were present in 76.9% of mycosis fungoides/SS patients, 75.2% of cancer controls, and 66.7% of healthy controls (P ¼ .05, .07) and in 30% to 39% of historical normal controls. Correction of deficiency was successful in 35% or 55 of 156 patients who were given dealer's choice of either vitamin D2 at 50,000 IU orally (p.o.) biweekly or D3 1000 IU p.o. daily. Correction of vitamin D levels was noted in 27 of 100 (27%) patients given D3 and 28 of 56 (50%) given D2. Responses to standard CTCL therapy was similar among patients with corrected and persistently low levels (P ¼ .51).

To our knowledge,this is the first study of vitamin D status in CTCL patients. Vitamin D deficiency was present in CTCL and other cancer patients compared with normal and historical controls. Correction of vitamin D deficiency and type of vitamin D supplementation used did not affect the overall clinical disease response.

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Does genome wide association study identify variants in NBEA associated with migraine in bipolar disorder?

Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine. We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS). We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases.

Our study is based on self-reported migraine.

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Is nASH resolution associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels?

Nonalcoholic steatohepatitis (NASH) is associated with dyslipidemia and cardiovascular disease (CVD). To determine the relationship between resolution of NASH and dyslipidemia. Individuals in the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial with paired liver biopsies and fasting lipid levels were included (N = 222). In the PIVENS trial individuals were randomised to pioglitazone 30 mg, vitamin E 800 IU or placebo for 96 weeks. Change in lipid levels at 96 weeks was compared between those with and without NASH resolution. Dyslipidemia at baseline was frequent, with low high-density lipoprotein (HDL) (<40 mg/dL in men or <50 mg/dL in women) in 63%, hypertriglyceridaemia (≥150 mg/dL) in 46%, hypercholesterolaemia (≥200 mg/dL) in 47% and triglycerides (TG)/HDL >5.0 in 25%. Low-density lipoprotein (LD) ≥160 mg/dL was found in 16% and elevated non-HDL cholesterol (non-HDL-C) (≥130 mg/dL) in 73%. HDL increased with NASH resolution but decreased in those without resolution (2.9 mg/dL vs. -2.5 mg/dL, P < 0.001). NASH resolution was associated with significant decreases in TG and TG/HDL ratio compared to those without resolution (TG: -21.1 vs. -2.3 mg/dL, P = 0.03 and TG/HDL: -0.7 vs. 0.1, P = 0.003). Non-HDL-C, LDL and cholesterol decreased over 96 weeks in both groups, but there was no significant difference between groups. Treatment group did not impact lipids.

NASH resolution is associated with improvements in TG and HDL but not in other cardiovascular disease risk factors including LDL and non-HDL-C levels. Individuals with resolution of NASH may still be at increased risk of cardiovascular disease. ClinicalTrials.gov identifier: NCT00063622.

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Is aberrant P-cadherin expression associated to aggressive feline mammary carcinomas?

Cadherins are calcium-dependent cell-to-cell adhesion glycoproteins playing a critical role in the formation and maintenance of normal tissue architecture. In normal mammary gland, E-cadherin is expressed by luminal epithelial cells, while P-cadherin is restricted to myoepithelial cells. Changes in the expression of classical E- and P-cadherins have been observed in mammary lesions and related to mammary carcinogenesis. P-cadherin and E-cadherin expressions were studied in a series of feline normal mammary glands, hyperplastic/dysplastic lesions, benign and malignant tumours by immunohistochemistry and double-label immunofluorescence. In normal tissue and in the majority of hyperplastic/dysplastic lesions and benign tumours, P-cadherin was restricted to myoepithelial cells, while 80% of the malignant tumours expressed P-cadherin in luminal epithelial cells. P-cadherin expression was significantly related to high histological grade of carcinomas (p <0.0001), tumour necrosis (p = 0.001), infiltrative growth (p = 0.0051), and presence of neoplastic emboli (p = 0.0401). Moreover, P-cadherin positive carcinomas had an eightfold likelihood of developing neoplastic emboli than negative tumours. Cadherins expression profile in high grade and in infiltrative tumours was similar, the majority expressing P-cadherin, regardless of E-cadherin expression status. The two cadherins were found to be co-expressed in carcinomas with aberrant P-cadherin expression and preserved E-cadherin.

The results demonstrate a relationship between P-cadherin expression and aggressive biological behaviour of feline mammary carcinomas, suggesting that P-cadherin may be considered an indicator of poor prognosis in this animal species. Moreover, it indicates that, in queens, the aberrant expression of P-cadherin is a better marker of mammary carcinomas aggressive behaviour than the reduction of E-cadherin expression. Further investigation with follow-up studies in feline species should be conducted in order to evaluate the prognostic value of P-cadherin expression in E-cadherin positive carcinomas.

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Does casticin inhibit COX-2 and iNOS expression via suppression of NF-κB and MAPK signaling in lipopolysaccharide-stimulated mouse macrophages?

The fruits of Vitex rotundifolia L. are widely used to treat inflammation of the airway in Traditional Chinese medicine. Previous studies found that casticin, isolated from Vitex rotundifolia, could induce apoptosis of tumor cells. In this study, we evaluated the anti-inflammatory effects of casticin and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated macrophages. RAW264.7 cells were pretreated with various concentrations of casticin (0.3-10μM), and then treated with LPS to induce inflammation. We assayed the levels of proinflammatory cytokines and prostaglandin E2 (PGE2) using ELISA, and examined the protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and heme oxygenase (HO)-1 by Western blot. We also investigated the anti-inflammatory molecular mechanism by analyzing inflammatory-associated signaling pathways, including the nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. We found casticin inhibited the levels of nitric oxide and PGE2, and decreased the production of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α). In addition, iNOS and COX-2 expression levels were suppressed and casticin increased HO-1 and Nrf2 production in a concentration-dependent manner. Furthermore, casticin significantly inhibited NF-κB subunit p65 proteins in the nucleus and decreased Akt and MAPK activation.

These results suggest that the anti-inflammatory effect of casticin is due to inhibition of proinflammatory cytokines and mediators by blocking the NF-κB, Akt, and MAPK signaling pathways.

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Do transcriptome sequencing and comparative analysis reveal long-term flowing mechanisms in Hevea brasiliensis latex?

The rubber tree, Hevea brasiliensis, is a major commercial source of natural rubber. Increasing the rubber yield of rubber trees is a very serious problem since the demands for high quality rubber materials are great. Establishment of a tapping system is based on an estimate of tapping intensity from the rubber tree. Latex flowing time is one of the most critical factors that determine the rubber yield. Long-term flow is a type of phenomenon of the rubber tree latex with longer flowing time than normal latex flow, and is always caused by intensive tapping. Thus, transcriptome and expression profiling data for long-term flowing latex (LFL) are needed as an important resource to identify genes and to better understand the biological mechanisms of latex flow in rubber trees. The transcripts were sequenced using the Illumina sequencing platform. After cleaning, quality checks and sequencing, 98,697 transcripts and 38,584 unigenes were assembled with the mean size of 1437.31bp and 923.86bp, respectively. In BLAST searches of our database against public databases, 65.17% (25,147) of the unigenes were annotated with gene descriptions, conserved protein domains, or gene ontology terms. Functional categorization further revealed 853 individual unigenes related to long-term flow. According to KEGG classification, the clusters for "cysteine and methionine metabolism", "energy", "oxidative phosphorylation", "terpenoid backbone biosynthesis", "plant hormone signal transduction" and "copper, potassium transporter" were significantly enriched metabolic pathways.

We conducted high-resolution transcriptome profiling related to LFL in H. brasiliensis. The research facilitates further studies on gene discovery and on the molecular mechanisms related to the estimation of tapping intensity and prolonging latex flowing time. We concluded that it was necessary to improve energy supplies for intensive tapping and the copper ion content of rubber tree latex could be considered as a standard to estimate tapping intensity.

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Does cannabidiol fail to reverse hypothermia or locomotor suppression induced by Δ ( 9 ) -tetrahydrocannabinol in Sprague-Dawley rats?

Growing evidence shows cannabidiol (CBD) modulates some of the effects of Δ(9) -tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats. Male Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10-30 mg·kg(-1) , i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant). CBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model.

There is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats.

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Does miR-1228 promote the proliferation and metastasis of hepatoma cells through a p53 forward feedback loop?

The effective mechanisms of microRNAs (miRNAs) functions as oncogenes or tumour suppressors in human hepatocellular carcinoma (HCC) are still obscure. Here, we investigated the function and expression of miR-1228 in HCC. The role of miR-1228 in HCC was determined by colony formation, transwell, and nude mice xenograft experiments. miR-1228 target gene were identified by EGFP reporter assays, real-time PCR, and western blot analysis. Dual-luciferase reporter assay and real-time PCR analysis are used to examine the regulation of p53. miR-1228 promoted proliferation and metastasis, and facilitated the transition of cell cycle in hepatoma cells. miR-1228 downregulated p53 expression by binding to its 3'UTR. The ectopic expression of p53 abrogated the phenotypes induced by miR-1228. An inverse correlation existed between miR-1228 and p53 expression in hepatoma tissues compared with the adjacent tissues and three hepatoma cell lines. Moreover, we found that p53 suppressed the expression and promoter activity of miR-1228.

miR-1228 functions as an oncogene by promoting cell cycle progression and cell mobility and negatively regulates the expression of p53. p53 downregulation in turn leads to an increase in miR-1228 expression, thereby forming a positive feedback loop that contributes to cancerogenesis in HCC.

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Does over-expression of small ubiquitin-like modifier proteases 1 predict chemo-sensitivity and poor survival in non-small cell lung cancer?

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors. Despite the advances in therapy over the years, its mortality remains high. The aim of this study was to evaluate the expression of small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) in NSCLC tissues and its role in the regulation of vascular endothelial growth factor (VEGF) expression. We also investigated the association between the expression level of SENP1 and the clinicopathological features and survival of the patients. A SENP1 small interfering RNA (siRNA) was constructed and transfected into the NSCLC cells. VEGF gene expression was analyzed by real-time polymerase chain reaction (RT-PCR). Immunohistochemistry staining was used to assess the expression of SENP1 in 100 NSCLC patients and its association with the clinicopathological features and survival was analyzed. VEGF expression was significantly higher in NSCLC tissues than in normal lung tissues. Inhibition of SENP1 by siRNA was associated with decreased VEGF expression. SENP1 was over-expressed in 55 of the 100 NSCLC samples (55%) and was associated with a moderate and low histological tumor grade (3.6%, 38.2%, and 58.2% in high, moderate and low differentiated tumors, respectively, P = 0.046), higher T stage (10.9% in T1, and 89.1% in T2 and T3 tumor samples, P < 0.001) and TNM stage (10.9% in stage I, and 89.1% in stages II and III tumor samples, P < 0.001). The rate of lymph node metastasis was significantly higher in the SENP1 over-expression group (76.4%) than that in the SENP1 low expression group (33.3%, P < 0.001). Sixty three patients received postoperative chemotherapy, including 34 with SENP1 over-expression and 29 with SENP1 low expression. Among the 34 patients with SENP1 over-expression, 22 (64.7%) patients developed recurrence or metastasis, significantly higher than those in the low expression group 27.6% (8/29) (P = 0.005). Multivariate Cox regression analysis showed that lymph node metastasis (P = 0.015), TNM stage (P = 0.001), and SENP1 expression level (P = 0.002) were independent prognostic factors for the survival of NSCLC patients.

SENP1 may be a promising predictor of survival, a predictive factor of chemo-sensitivity for NSCLC patients, and potentially a desirable drug target for lung carcinoma target therapy.

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Is wnt signaling involved in 6-benzylthioinosine-induced AML cell differentiation?

We previously demonstrated that 6-benzylthioinosine (6-BT) could induce the differentiation of a subset of acute myeloid leukemia (AML) cell lines and primary AML cells regardless of their cytogenetics. In this study we investigated whether Wnt signaling pathways played roles in 6-BT-induced differentiation of AML cells. We induced differentiation of HL-60 leukemic cells and primary AML cells in vitro using 6-BT. Real-time PCR (qPCR), western blot, and luciferase assays were used to examine the molecules' expression and biological activity in canonical and noncanonical Wnt signaling pathways. AML cell differentiation was measured by the Nitroblue tetrozolium (NBT) reduction assay. 6-BT regulated the expression of both canonical and non-canonical Wnt signaling molecules in HL-60 cells. Both 6-BT and all-trans-retinoic-acid (ATRA) reduced canonical Wnt signaling and activated noncanonical Wnt/Ca2+ signaling in HL-60 cells. Pre-treatment of HL-60 cells with an inhibitor of glycogen synthase kinase-3β (GSK-3β), which activated canonical Wnt signaling, partly abolished the differentiation of HL-60 cells induced by 6-BT. Pre-treatment of HL-60 cells with an inhibitor of protein kinase C (PKC), resulting in inactivation of non-canonical Wnt/Ca2+ signaling, abolished 6-BT-induced differentiation of HL-60 cells. Several molecules in the non-canonical Wnt/Ca2+ pathway were detected in bone marrow samples from AML patients, and the expression of FZD4, FZD5, Wnt5a and RHOU were significantly reduced in newly diagnosed AML samples compared with normal controls.

Both canonical and non-canonical Wnt signaling were involved in 6-BT-induced differentiation of HL-60 cells, and played opposite roles in this process. Wnt signaling could be involved in the pathogenesis of AML not only by regulating self-renewal of hematopoietic stem cells, but also by playing a role in the differentiation of AML cells.

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Does ginsenoside Rg3 improve erectile function in streptozotocin-induced diabetic rats?

Ginsenoside Rg3 is one of the active ingredients isolated from Panax ginseng C.A. Meyer. Previous studies demonstrated that Rg3 has antioxidant and neuroprotective abilities. The purpose of this study was to evaluate the protective effect of Rg3 on erectile function in streptozotocin (STZ)-induced diabetic rats. Two-month-old Sprague-Dawley male rats received a one-time intraperitoneal (IP) STZ (60 mg/kg) or vehicle injection after a 16-hour fast. Three days later, rats were randomly divided into four groups and were treated with daily gavage feedings of a mix of distilled saline water and 0.5% carboxymethylcellulose or Rg3 dissolved in the mix at doses of 10 mg/kg and 100 mg/kg for 3 months. A sham group underwent IP injection of saline followed by daily gavage of the above mix for 3 months. Erectile function was assessed by cavernosal nerve electrostimulation at 3 months. The penis was then harvested and deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed. Western blot was performed to examine cleaved caspase-3, platelet endothelial cell adhesion molecule (PECAM)-1, and smooth muscle actin (SMA). Neural regeneration was measured by nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. In the negative control group, the functional evaluation showed a lower mean intracavernosal pressure (ICP) with cavernosal nerve stimulation than in the sham group; there was a significant change in the expression of cleaved caspase-3, bcl-2, bcl-xl, PECAM-1, and SMA, as well as in the SOD and MDA production in the corpus cavernosum. Histological analysis of specimens stained for NADPH showed a significant change in the staining quality of the neurons in the dorsal nerves; TUNEL showed a greater apoptotic index in corpus cavernosum cells. With daily oral gavage with 100 mg/kg Rg3, the ICP/mean arterial pressure value was significantly higher than in the controls. The level of cleaved caspase-3, bcl-2, bcl-xl, PECAM-1, and SMA and the number of positively stained nerve fibers tended to revert to normal after Rg3 treatment. The apoptotic index in corpus cavernosum cells was lowered.

Oral gavage with Rg3 appears to both prevent degeneration of neurons in the dorsal nerves and exert an antioxidant effect in the corpus cavernosum of rats.

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Does serum alanine aminotransferase predict the histological course of non-alcoholic steatohepatitis in Japanese patients?

Some cases with non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic steatohepatitis (NASH), can ultimately progress to liver cirrhosis. However, studies to clarify factors predictive of histological change in patients with NASH remain scarce. Our aim is to determine predictors of histological progression in Japanese patients with biopsy-proven NASH. This retrospective cohort study enrolled 52 patients with NASH who underwent serial liver biopsies. Histological evaluation included NAFLD activity score (NAS) and liver fibrosis. The median interval between initial and second liver biopsies was 968 days. An alanine aminotransferase (ALT) response was defined as a decrease of 30% or more from baseline. Of 52 patients, NAS was ameliorated in 30.8%, deteriorated in 30.8% and remained unchanged in 38.4%. Liver fibrosis was improved in 25.0% of patients, progressed in 25.0% and remained stable in 50.0%. Multivariate analysis identified ALT non-response as a predictor of deterioration of NAS (hazard ratio [HR], 5.85; P = 0.031) and progression of liver fibrosis (HR, 4.50; P = 0.029). The mean annual rate of fibrosis was 0.002 stages/year overall, increasing to 0.15 stages/year in ALT non-responders.

A lack of reduction in serum ALT level by at least 30% from baseline was a predictor for histological progression in patients with NASH. Serum ALT level is a better predictor of histological change than insulin resistance or bodyweight and can be a valid index in treatment. Serum ALT should be strictly controlled to prevent liver histological progression in patients with NASH.

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Does hepatic Notch2 deficiency lead to bile duct agenesis perinatally and secondary bile duct formation after weaning?

Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp-Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-) ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos-biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile-duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2-cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1β, Cebpα and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation.

Cholangiocyte differentiation becomes progressively less dependent on NOTCH2 signaling with age, suggesting that ductal-plate formation is dependent on NOTCH2, but subsequent cholangiocyte differentiation is not.

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Does recipient T cell TIM-3 and hepatocyte galectin-9 signalling protect mouse liver transplants against ischemia-reperfusion injury?

By binding to T cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation. We used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT). Orthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro. Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells.

Harnessing TIM-3/Gal-9 signalling at the T cell-hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients.

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Does contrast enhancement pattern on multidetector CT predict malignancy in pancreatic endocrine tumours?

Preoperative suspicion of malignancy in pancreatic neuroendocrine tumours (pNETs) is mostly based on tumour size. We retrospectively reviewed the contrast enhancement pattern (CEP) of a series of pNETs on multiphasic multidetector computed tomography (MDCT), to identify further imaging features predictive of lesion aggressiveness. Sixty pNETs, diagnosed in 52 patients, were classified based on CEP as: type A showing early contrast enhancement and rapid wash-out; type B presenting even (B1) or only (B2) late enhancement. All tumours were resected allowing pathologic correlations. Nineteen pNETs showed type A CEP (5-20 mm), 29 type B1 CEP (5-80 mm) and 12 type B2 (15-100 mm). All tumours were classified as well differentiated tumours, 19 were benign (WDt-b), 15 with uncertain behaviour (WDt-u) and 26 carcinomas (WDC). None of A lesions were malignant (12 WDt-b; 7 WDt-u), all B2 lesions were WDC, 7 B1 lesions were WDt-b, 8 WDt-u and 14 WDC; 4/34 (12 %) lesions ≤2cm were WDC. CEP showed correlation with all histological prognostic indicators.

Correlating with the lesion grading and other histological prognostic predictors, CEP may preoperatively suggest the behaviour of pNETs, assisting decisions about treatment. Moreover CEP allows recognition of malignant small tumours, incorrectly classified on the basis of their dimension.

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Does ketamine inhibit proliferation of neural stem cell from neonatal rat hippocampus in vitro?

Ketamine is a widely used anesthetic in obstetric and pediatric anesthesia. In the developing brain, the widespread neuron apoptosis triggered by ketamine has been demonstrated. However, little is known about its effect on neural stem cells (NSCs) function. This study aimed to investigate the effect of ketamine on proliferation of NSCs from neonatal rat hippocampus. Neural stem cells were isolated from the hippocampus of Sprague-Dawley rats on postnatal day 3. In dose-response experiments, cultured neural stem cells (NSCs) were exposed to different concentrations of ketamine (0-1000 µM) for 24 hrs. The proliferative activity of NSCs was evaluated by 5-Bromo-2'-deoxyuridine (BrdU) incorporation assay. Apoptosis of neural stem cells were assessed using caspase-3 by western blot. The intracellular Ca(2+) concentration ([Ca(2+)]i) in NSCs was analyzed by flow cytometry. The activation of protein kinase C-α (PKCα) and the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) were measured by western blot analysis. Clinical relevant concentration of ketamine (10, 20 and 50 µM) did not markedly alter the proliferation of NSCs from neonatal rat hippocampus in vitro. However, ketamine (200, 500, 800 and 1000μM) significantly inhibited the proliferation of NSCs and did not affect the expression of caspase-3. Meanwhile, ketamine (200, 500, 800 and 1000μM) also markedly decreased [Ca(2+)]i as well as suppressed PKCα activation and ERK1/2 phosphorylation in NSCs. A combination of subthreshold concentrations of ketamine (100 μM) and Ca(2+) channel blocker verapamil (2.5 μM), PKCα inhibitor chelerythrine (2.5 μM) or ERK1/2 kinase inhibitor PD98059 (5 μM) significantly produced suprathreshold effects on PKCα activation, ERK1/2 phosphorylation and NSC proliferation.

Ketamine inhibited proliferation of NSCs from neonatal rat hippocampus in vitro. Suppressing Ca(2+)-PKCα-ERK1/2 signaling pathway may be involved in this inhibitory effect of ketamine on NSCs proliferation.

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Does iTRAQ-based quantitative proteome and phosphoprotein characterization reveal the central metabolism changes involved in wheat grain development?

Wheat (Triticum aestivum L.) is an economically important grain crop. Two-dimensional gel-based approaches are limited by the low identification rate of proteins and lack of accurate protein quantitation. The recently developed isobaric tag for relative and absolute quantitation (iTRAQ) method allows sensitive and accurate protein quantification. Here, we performed the first iTRAQ-based quantitative proteome and phosphorylated proteins analyses during wheat grain development. The proteome profiles and phosphoprotein characterization of the metabolic proteins during grain development of the elite Chinese bread wheat cultivar Yanyou 361 were studied using the iTRAQ-based quantitative proteome approach, TiO2 microcolumns, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among 1,146 non-redundant proteins identified, 421 showed at least 2-fold differences in abundance, and they were identified as differentially expressed proteins (DEPs), including 256 upregulated and 165 downregulated proteins. Of the 421 DEPs, six protein expression patterns were identified, most of which were up, down, and up-down expression patterns. The 421 DEPs were classified into nine functional categories mainly involved in different metabolic processes and located in the membrane and cytoplasm. Hierarchical clustering analysis indicated that the DEPs involved in starch biosynthesis, storage proteins, and defense/stress-related proteins significantly accumulated at the late grain development stages, while those related to protein synthesis/assembly/degradation and photosynthesis showed an opposite expression model during grain development. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of 12 representative genes encoding different metabolic proteins showed certain transcriptional and translational expression differences during grain development. Phosphorylated proteins analyses demonstrated that 23 DEPs such as AGPase, sucrose synthase, Hsp90, and serpins were phosphorylated in the developing grains and were mainly involved in starch biosynthesis and stress/defense.

Our results revealed a complex quantitative proteome and phosphorylation profile during wheat grain development. Numerous DEPs are involved in grain starch and protein syntheses as well as adverse defense, which set an important basis for wheat yield and quality. Particularly, some key DEPs involved in starch biosynthesis and stress/defense were phosphorylated, suggesting their roles in wheat grain development.

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Are low serum 25-hydroxyvitamin d concentrations associated with increased risk for melanoma and unfavourable prognosis?

Low vitamin D status (serum 25(OH)D concentration) is associated with increased incidence and unfavourable outcome of various types of cancer. However, there are limited data on influence of serum 25(OH)D on risk and prognosis of malignant melanoma. Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients (n = 324) and healthy controls (n = 141). We tested the hypothesis that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS). Median serum 25(OH)D concentrations were significantly lower (p = 0.004) in melanoma patients (median = 13.6 ng/ml) as compared to controls (median = 15.6 ng/ml). Primary tumors of patients with low serum 25(OH)D concentrations (<10 ng/ml) had significantly (p = 0.006) greater Breslow thickness (median: 1.9 mm) as compared to patients with higher levels (>20 ng/ml; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049).

Our data support the concept that serum 25(OH)D concentrations are associated with risk and prognosis of melanoma. Whether normalizing serum 25(OH)D concentrations in these patients improves outcomes will require testing in future clinical trials.

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Does [ Descriptive study of healthcare professionals ' management of tick bite ]?

Rural primary health centers frequently treat patients with tick bites. This study compares everyday clinical practice at our primary healthcare center to practices recommended by current scientific evidence. To describe the everyday management of tick bites by different healthcare professionals and to compare this management to evidence-based therapy guidelines. Cross-sectional, descriptive observational study. Data was collected through an anonymous self-completed questionnaire. The form was filled out by a consecutive sample of nurses, physicians and pediatricians of the clinical management unit of Medina-Sidonia (Cádiz). Most nurses in the sample group use some type of product to facilitate the extraction of the tick (10 of the 11 surveyed nurses, 90.9%). The most frequently used products were chloroethyl and local anesthetic. In addition, nine nurses use gentle traction with tweezers (81.82%) to remove the tick. In the physician sample group, 3 out of 12 respondents (25%) prescribe antibiotics in all cases and nine stated that they knew which antibiotic should be used as first choice. In both cases, a high number of healthcare providers confirm giving post-extraction advice to patients: 11 in the medical community (91.66%) and nine nurses (81.82%).

We conclude that the performance of the healthcare providers that integrate this study does not closely follow general recommendations for extraction, treatment and follow-up care in patients with tick bites. Therefore, there is a need to improve the level of knowledge to ensure quality care in these instances.

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Do left ventricular end-diastolic pressure and ejection fraction correlate independently with high-sensitivity cardiac troponin-T concentrations in stable heart failure?

Cardiac troponin is widely accepted as a biomarker of myocyte injury in patients with myocardial ischemia. Patients with congestive heart failure are also associated with elevated cardiac troponin and it is a very sensitive prognostic marker. However, the mechanisms of troponin elevation in patients with heart failure are not fully understood. Decompensated state itself is suggested as a factor contributing to elevated cardiac troponin-T. However comparison between invasive hemodynamic parameters and cardiac troponin-T is insufficient. Data were collected from 167 patients in stable, chronic HF, without acute coronary syndrome, recent revascularization, mitral stenoses, hemodialysis, or clinically significant right HF. We evaluated the correlations and 95% confidence intervals (CI) between invasive hemodynamic measurements and serum high-sensitivity (hs) concentrations of cTnT. The serum cTnT concentration was equal to or more than the detection threshold (0.003ng/ml) in all patients. The serum cTnT concentration was equal to or more than the cut-off value of 0.014ng/ml in 46% of patients. By multiple variable analysis, left ventricular (LV) end-diastolic pressure (EDP; adjusted coefficient=0.014; 95% CI 0.0003-0.029; P=0.046) was positively correlated, while hemoglobin (adjusted coefficient=-0.079; 95% CI -0.140 to -0.018; P=0.012), estimated glomerular filtration rate (adjusted coefficient=-0.008; 95% CI -0.013 to -0.003; P=0.004), and LV ejection fraction (EF; adjusted coefficient=-0.011; 95% CI -0.018 to -0.003; P=0.004) were negatively correlated with hs-cTnT concentrations.

In patients with stable chronic HF, LVEDP and LVEF correlate with the serum concentrations of hs-cTnT, independently of other correlates of elevated plasma concentrations of hs-cTnT.

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Does image-guided placement of long-term central venous catheters reduce complications and cost?

The goals of this study were to evaluate the complication rate for intraoperative placement of a long-term central venous catheter (CVC) using intraoperative ultrasound (US) and fluoroscopy and to examine the feasibility for eliminating routine postprocedure chest X-ray. Retrospective data pertaining to operative insertion of long-term CVC were collected and the rate of procedural complications was determined. From January 2008 to August 2013, 351 CVCs were placed via the internal jugular vein using US. Of these, 93% had a single, successful internal jugular vein insertion. The complications included 4 arterial sticks (1.14%). Starting in October 2012, postprocedure chest radiography (CXR) was eliminated in 170 cases, with no complications. A total of $29,750 in charges were deferred by CXR elimination.

This review supports the use of US for CVC placement with fluoroscopy in reducing the rate of procedural complications. Additionally, with fluoroscopic imaging, postprocedural CXR can be eliminated with associated healthcare savings.

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Does exosome-mediated transfer of miR-10b promote cell invasion in breast cancer?

Exosomes are 30-100 nm membrane vesicles of endocytic origin, mediating diverse biological functions including tumor cell invasion, cell-cell communication and antigen presentation through transfer of proteins, mRNAs and microRNAs. Recent evidence suggests that microRNAs can be released through ceramide-dependent secretory machinery regulated by neutral sphingomyelinase 2 (nSMase2) enzyme encoded by the smpd3 gene that triggers exosome secretion. However, whether exosome-mediated microRNA transfer plays any role in cell invasion remains poorly understood. Thus, the aim of this study was to identify the exosomal microRNAs involved in breast cancer invasion. The expression level of endogenous and exosomal miRNAs were examined by real time PCR and the expression level of target proteins were detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study its uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-10b was estimated by invasion assay. In this study, we demonstrate that microRNA carrying exosomes can be transferred among different cell lines through direct uptake. miR-10b is highly expressed in metastatic breast cancer MDA-MB-231 cells as compared to non-metastatic breast cancer cells or non-malignant breast cells; it is actively secreted into medium via exosomes. In particular, nSMase2 or ceramide promotes the exosome-mediated miR-10b secretion whereas ceramide inhibitor suppresses this secretion. Moreover, upon uptake, miR-10b can suppress the protein level of its target genes such as HOXD10 and KLF4, indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could induce the invasion ability of non-malignant HMLE cells.

Together, our results suggest that a set of specific microRNAs may play an important role in modulating tumor microenvironment through exosomes. Thus, a better understanding of this process may aid in the development of novel therapeutic agents.

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Does biolimus-eluting stent with biodegradable polymer improve clinical outcomes in patients with acute myocardial infarction?

To investigate clinical outcomes of coronary intervention using a biolimus-eluting stent (BES) compared with a sirolimus-eluting stent (SES) in patients with acute myocardial infarction (AMI) in the Limus Eluted from A Durable versus ERodable Stent (LEADERS) coating trial at the final 5-year follow-up. The LEADERS trial is a multicentre all-comer study, where patients (n=1707) were randomised to percutaneous intervention with either BES containing biodegradable polymer or SES containing durable polymer. Out of 1707 patients enrolled in this trial, 573 patients had percutaneous coronary intervention for AMI (BES=280, SES=293) and were included in the current analysis. Patient-oriented composite endpoint (POCE, including all death, all myocardial infarction (MI) and all revascularisations), major adverse cardiac events (MACE, including cardiac death, MI and clinically indicated target vessel revascularisation) and stent thrombosis were assessed at 5-year follow-up. The baseline clinical, angiographic and procedural characteristics were well matched between BES and SES groups. In all patients with AMI, coronary intervention with a BES, compared with SES, significantly reduced POCE (28.9% vs 42.3%; relative risk (RR) 0.61, 95% CI 0.47 to 0.82, p=0.001) at 5-year follow-up. There was also a reduction in MACE rate in the BES group (18.2% vs 25.9%; RR 0.67, 95% CI 0.47 to 0.95, p=0.025); however, there was no difference in cardiac death and stent thrombosis. In patients with ST-elevation MI (STEMI), coronary intervention with BES significantly reduced POCE (24.4% vs 39.3%; RR 0.55, 95% CI 0.36 to 0.85, p=0.006), MACE (12.6% vs 25.0%; RR 0.47, 95% CI 0.26 to 0.83, p=0.008) and cardiac death (3.0% vs 11.4%; RR 0.25, 95% CI 0.08 to 0.75, p=0.007), along with a trend towards reduction in definite stent thrombosis (3.7% vs 8.6%; RR 0.41, 95% CI 0.15 to 1.18, p=0.088), compared with SES.

BES, compared with SES, significantly improved safety and efficacy outcomes in patients with AMI, especially those with STEMI, at 5-year follow-up.

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Does triptolide inhibit TGF-β1-induced cell proliferation in rat airway smooth muscle cells by suppressing Smad signaling?

We have reported that triptolide can inhibit airway remodeling in a murine model of asthma via TGF-β1/Smad signaling. In the present study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation and the possible mechanism. Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentration of triptolide before stimulated by TGF-β1. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Signal proteins (Smad2, Smad3 and Smad7) were detected by western blotting analysis. Triptolide significantly inhibited TGF-β1-induced ASMC proliferation (P<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. No pro-apoptotic effects were detected under the concentration of triptolide we used. Western blotting analysis showed TGF-β1 induced Smad2 and Smad3 phosphorylation was inhibited by triptolide pretreatment, and the level of Smad7 was increased by triptolide pretreatment.

Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via negative regulation of Smad signaling pathway.

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Are aerobic capacity and upper limb strength reduced in women diagnosed with breast cancer : a systematic review?

What are typical values of physical function for women diagnosed with breast cancer and how do these compare to normative data? Systematic review with meta-analysis. Women diagnosed with breast cancer who were before, during or after treatment. Physical function was divided into three categories: aerobic capacity, upper and lower extremity muscular fitness, and mobility. Measures of aerobic capacity included field tests (6-minute walk test, 12-minute walk tests, Rockport 1-mile test, and 2-km walk time) and submaximal/maximal exercise tests on a treadmill or cycle ergometer. Measures of upper and lower extremity muscular fitness included grip strength, one repetition maximum (bench, chest or leg press), muscle endurance tests, and chair stands. The only measure of mobility was the Timed Up and Go test. Of the 1978 studies identified, 85 were eligible for inclusion. Wide ranges of values were reported, reflecting the range of ages, disease severity, treatment type and time since treatment of participants. Aerobic fitness values were generally below average, although 6-minute walk time was closer to population norms. Upper and lower extremity strength was lower than population norms for women who were currently receiving cancer treatment. Lower extremity strength was above population norms for women who had completed treatment.

Aerobic capacity and upper extremity strength in women diagnosed with breast cancer are generally lower than population norms. Assessment of values for lower extremity strength is less conclusive. As more research is published, expected values for sub-groups by age, treatment, and co-morbidities should be developed. [Neil-Sztramko SE, Kirkham AA, Hung SH, Niksirat N, Nishikawa K Campbell KL (2014) Aerobic capacity and upper limb strength are reduced in women diagnosed with breast cancer: a systematic review.Journal of Physiotherapy60: 189-200].

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Is same-day intrauterine device placement rarely complicated by pelvic infection?

To compare rates of pelvic inflammatory disease (PID) among women who did and did not receive an intrauterine device (IUD) the day they sought emergency contraception (EC) or pregnancy testing. Women, 15 to 45 years of age, who sought EC or pregnancy testing from an urban family planning clinic completed surveys at the time of their clinic visit (August 22, 2011, to May 30, 2013) and 3 months after their clinic visit. The surveys assessed contraceptive use and symptoms, testing, and treatment for sexually transmitted infections (STI) and PID. We reviewed the medical records of participants who reported IUD placement within 3 months of enrollment and abstracted de-identified electronic medical record (EMR) data on all women who sought EC or pregnancy testing from the study clinic during the study period. During the study period, 1,060 women visited the study clinic; 272 completed both enrollment and follow-up surveys. Among survey completers with same-day IUD placement, PID in the 3 months after enrollment was not more common (1/28 [3.6%]; 95% CI, 0%-10.4%) than among women who did not have a same-day IUD placed (11/225 [4.9%]; 95% CI, 2.7%-8.6%; p = .71). Chart review and EMR data similarly showed that rates of PID within 3 months of seeking EC or pregnancy testing were low whether women opted for same-day or delayed IUD placement.

Same-day IUD placement was not associated with higher rates of PID. Concern for asymptomatic STI should not delay IUD placement, and efforts to increase the uptake of this highly effective reversible contraception should not be limited to populations at low risk of STI.

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Do obese first-degree relatives of patients with type 2 diabetes with elevated triglyceride levels exhibit increased β-cell function?

Type 2 diabetes mellitus (T2DM) is characterized as a disease continuum that is marked by metabolic changes that are present for several years, sometimes well before frank diagnosis of T2DM. Genetic predisposition, ethnicity, geography, alterations in BMI, and lipid profile are considered important markers for the pathogenesis of T2DM through mechanisms that remain unresolved and controversial. The aim of this study was to investigate the relationship between triglycerides (TGs) and β-cell function, insulin resistance (IR), and insulin sensitivity (IS) in obese first-degree relatives of patients with T2DM (FDR-T2DM) among subjects from central Mexico with normal glucose tolerance (NGT). We studied 372 FDR-T2DM subjects (ages,18-65) and determined body mass index (BMI), fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), insulin, and TGs levels. Subjects were categorized based on glycemic control [NGT, prediabetes (PT2DM), or T2DM]. NGT subjects were further categorized by BMI [normal weight (Ob-) or obese (Ob+)] and TGs levels (TG-, <150 mg/dL, or TG+, ≥150 mg/dL). β-cell function, IR, and IS were determined by the homeostasis model assessment of β-cell function (HOMA2-β), homeostasis model assessment of insulin resistance (HOMA2-IR), and Quantitative Insulin Sensitivity Check Index (QUICKI) indices, respectively. The obese subjects with elevated TGs levels had 21%-60% increased β-cell function when compared to all groups (P<0.05). In addition, this group had insulin levels, IS, and IR similar to PT2DM. Furthermore, only in obese subjects did TGs correlate with β-cell function (ρ=0.502, P<0.001).

We characterized FDR-T2DM subjects from central Mexico with NGT and revealed a class of obese subjects with elevated TGs and β-cell function, which may precede PT2DM.

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Do identification of methicillin-resistant Staphylococcus aureus ( MRSA ) strains isolated from burn patients by multiplex PCR?

Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS) as important human pathogens are causes of nosocomial infections worldwide. Burn patients are at a higher risk of local and systemic infections with these microorganisms. A screening method for MRSA by using a multiplex polymerase chain reaction (PCR) targeting the 16S ribosomal RNA (rRNA), mecA, and nuc genes was developed. The aim of the present study was to investigate the potential of this PCR assay for the detection of MRSA strains in samples from burn patients. During an 11-month period, 230 isolates (53.11%) of Staphylococcus spp. were collected from burn patients. The isolates were identified as S. aureus by using standard culture and biochemical tests. DNA was extracted from bacterial colonies and multiplex PCR was used to detect MRSA and MRCoNS strains. Of the staphylococci isolates, 149 (64.9%) were identified as S. aureus and 81 (35.21%) were described as CoNS. Among the latter, 51 (62.97%) were reported to be MRCoNS. From the total S. aureus isolates, 132 (88.6%) were detected as MRSA and 17 (11.4%) were methicillin-susceptible S. aureus (MSSA). The presence of the mecA gene in all isolates was confirmed by using multiplex PCR as a gold standard method.

This study presented a high MRSA rate in the region under investigation. The 16S rRNA-mecA-nuc multiplex PCR is a good tool for the rapid characterization of MRSA strains. This paper emphasizes the need for preventive measures and choosing effective antimicrobials against MRSA and MRCoNS infections in the burn units.

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Is coexpression of IQ-domain GTPase-activating protein 1 ( IQGAP1 ) and Dishevelled ( Dvl ) correlated with poor prognosis in non-small cell lung cancer?

IQ-domain GTPase-activating protein 1 (IQGAP1) binds to Dishevelled (Dvl) and functions as a modulator of Dvl nuclear localization in Xenopus embryos. However, the relationship between IQGAP1 and Dvl in tumor tissues is unclear. We used immunohistochemistry to assess the expressions of IQGAP1 and Dvl in a cohort of 111 non-small cell lung cancer (NSCLC) patients. Association of their localization expressions with clinicopathological factors was also analyzed. The positive rate of IQGAP1 in primary tumors was 48.6% (54/111) for its cytoplamic expression, 9.0% (10/111) for nuclear expression and 31.5% (35/111) for membranous expression; the positive rate of Dvl was 65.8% (73/111) for cytoplamic expression, 9.9% (11/111) for nuclear expression and 10.8% (12/111) for membranous expression. Coexpression rate of IQGAP1 and Dvl was 77.8% (42/54) in the cytoplasm, 80.0% (8/10) in the nucleus and 8.6% (3/35) in the membrane. Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus were significantly correlated (P<0.05), but not in the membrane (P>0.05). The positive expression rates of cyclin D1 and c-myc were significantly higher in the group of IQGAP1 and Dvl coexpression in the nucleus than that in the cytoplasm. Coexpression rate of IQGAP1 and Dvl in the cytoplasm and nucleus was significantly higher in lymph nodal metastases (63.3%, 19/30) than in primary growths (38.3%, 31/81), correlating with poor prognosis. Five-year survival time after resection in the group with their coexpression in the cytoplasm and nucleus was significantly lower than that with no coexpression (44.705±3.355 vs 58.403±2.543 months, p<0.05).

Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus was correlated with the lymph nodal metastase and poor prognosis of NSCLC, and coexpression in nucleus might play a critical role in the activation of canonical Wnt pathway.

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Do ethnobotanical survey of medicinal plants used for pregnant women׳s health conditions in Menoua division-West Cameroon?

In Cameroon, most women use traditional medicine for the treatment of pregnancy and childbirth complaints. In order to identify some of the medicinal plants locally used to alleviate these complaints, an ethnobotanical survey was undertaken in five villages of Menoua Division (West-Cameroon). Interviews were conducted through structured questionnaires among 24 traditional healers and 179 women living either in the town of Dschang or in 4 neighboring villages. After having recorded the interviewee personal information on issues related to medicinal plants utilization, a literature investigation on their therapeutic or pharmacological effects and phytochemical composition was conducted. A total of 88 medicinal plants species used to treat 24 conditions occurring during or after pregnancy and belonging to 70 genera or 34 families were recorded. Maximum medicinal uses of plants are reported for the treatment of the following ailments: swelling of legs and ankles (23%), facilitation of delivery (22%), cleaning of the baby (12%). Most herbal remedies are prepared with the leaves (30%), leaves+stems (28%) and whole plant (23%) as maceration (76%). The majority of women who used medicinal plants were very satisfied (75 %) and it is reported that most of these plants are used in the treatment of women health conditions.

Many herbal remedies used for the treatment of pregnant women׳s health conditions in Menoua division-West Cameroon have been revealed. It would therefore be judicious for our government and research institution to evaluate the therapeutic and toxicological potentials of these plants in order to valorize their use.

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Does shexiang Tongxin dropping pill attenuate atherosclerotic lesions in ApoE deficient mouse model?

Shexiang Tongxin dropping pill (STDP) is a formulation of Traditional Chinese Medicine mainly used for clinical treatment of stable angina pectoris in China. To investigate the effects and mechanisms of STDP treatment on atherosclerosis. ApoE deficient (ApoE(-/-)) mice were utilized to evaluate the effect of STDP treatment (30 mg/kg/day) on atherosclerotic lesions. Histopathological features of atherosclerotic lesions, serum levels of lipid proteins, parameters of oxidative stress and pro-inflammatory cytokines were measured by H&E staining, Masson's trichrome staining and ELISA, respectively. Real-time PCR analyses were performed to examine the aortic expression of atherosclerosis-associated microRNAs. The STDP treatment resulted in attenuated atherosclerotic lesion manifested by reduced lipid deposition, fibrosis and oxidative stress. It also led to increase in serum levels of GSH and SOD, decrease in MDA, decrease in CHO, TG, LDL, ox-LDL and increase in HDL, respectively. Additionally, the levels of pro-inflammatory cytokines including IL-2, IL-6, TNF-α and γ-IFN were markedly reduced by STDP treatment. Furthermore, STDP treatment was associated with a significant reduction in the aortic expression of miR-21a, miR-132, miR-126a, miR-155 and increased expression of miR-20a.

Our results demonstrated for the first time that STDP attenuated atherosclerotic lesions in ApoE(-/-) mouse model. Moreover, STDP treatment exhibited multi-targeting effects on pathological, biochemical and molecular aspects of atherosclerosis implicating lipid regulation, fibrosis, inflammation and oxidative stress. Findings from the current study warrant further evaluation of the clinical application of STDP in atherosclerosis treatment.

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Do aCTN3 R577X genotypes associate with Class II and deepbite malocclusions?

α-Actinins are myofibril anchor proteins that influence the contractile properties of skeletal muscles. ACTN2 is expressed in slow type I and fast type II fibers, whereas ACTN3 is expressed only in fast fibers. ACTN3 homozygosity for the 577X stop codon (ie, changing 577RR to 577XX, the R577X polymorphism) results in the absence of α-actinin-3 in about 18% of Europeans, diminishes fast contractile ability, enhances endurance performance, and reduces bone mass or bone mineral density. We have examined ACTN3 expression and genetic variation in the masseter muscle of orthognathic surgery patients to determine the genotype associations with malocclusion. Clinical information, masseter muscle biopsies, and saliva samples were obtained from 60 subjects. Genotyping for ACTN3 single nucleotide polymorphisms, real-time polymerase chain reaction quantitation of muscle gene message, and muscle morphometric fiber type properties were compared to determine statistical differences between genotype and phenotype. Muscle mRNA expression level was significantly different for ACTN3 single nucleotide polymorphism genotypes (P <0.01). The frequency of ACTN3 genotypes was significantly different for the sagittal and vertical classifications of malocclusion, with the clearest association being elevated 577XX genotype in skeletal Class II malocclusion (P = 0.003). This genotype also resulted in significantly smaller diameters of fast type II fibers in masseter muscles (P = 0.002).

ACTN3 577XX is overrepresented in subjects with skeletal Class II malocclusion, suggesting a biologic influence during bone growth. ACTN3 577XX is underrepresented in subjects with deepbite malocclusion, suggesting that muscle differences contribute to variations in vertical facial dimensions.

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Is percutaneous intervention of circumflex chronic total occlusions associated with worse procedural outcomes : insights from a Multicentre US Registry?

We sought to determine whether outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) vary according to CTO target vessel: left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). We evaluated the clinical and angiographic characteristics and procedural outcomes of 636 patients who underwent CTO PCI at 6 high-volume centres in the United States between January 2012 and March 2014. The CTO target vessel was the RCA in 387 cases (61%), LAD in 132 (21%), and LCX in 117 (18%). LCX lesions were more tortuous and RCA lesions had greater occlusion length and Japanese Chronic Total Occlusion (J-CTO) score, but were less likely to have a side branch at the proximal cap and had more developed collateral circulation. The rate of procedural success was lower in LCX CTOs (84.6%), followed by RCA (91.7%), and LAD (94.7%) CTOs (P = 0.016). Major complications tended to occur more frequently in LCX PCI (4.3% vs 1.0% for RCA vs 2.3% for LAD; P = 0.07). LCX and RCA CTO PCI required longer fluoroscopy times (45 [interquartile range (IQR), 30-74] minutes vs 45 [IQR, 21-69] minutes for RCA vs 34 [IQR, 20-60] minutes for LAD; P = 0.018) and LCX CTOs required more contrast administration (280 [IQR, 210-370] mL vs 250 [IQR, 184-350] mL for RCA and 280 [IQR, 200-400] mL for LAD).

In a contemporary, multicentre CTO PCI registry, LCX was the least common target vessel. Compared with LAD and RCA, PCI of LCX CTOs was associated with a lower rate of procedural success, less efficiency, and a nonsignificant trend for higher rates of complications.

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Does fiber supplementation lower plasma p-cresol in chronic kidney disease patients?

To determine the effects of supplemental fiber on plasma p-cresol, stool frequency, and quality of life (QoL) in chronic kidney disease (CKD) patients. In a 12-week single-blind study, participants were provided with control muffins and supplements (5.5 g sucrose/day) for 2 weeks, muffins containing 10 g/day pea hull fiber and control supplements for 4 weeks, and muffins with 10 g/day pea hull fiber and 15 g/day inulin as a supplement for 6 weeks. Individuals with CKD (n = 13; 6 males, 7 females; aged 65 ± 3 years; estimated glomerular filtration rate <50 mL/minute/1.73(2)) completed the study. Plasma p-cresol was determined by gas chromatography-mass spectrometry, stool frequency by 5-day journals, and QoL by the KDQOL-36™. Plasma p-cresol decreased from 7.25 ± 1.74 mg/L during week 1 to 5.82 ± 1.72 mg/L during week 12 (P < .05), and in participants with high compliance (>70% inulin intake), from 6.71 ± 1.98 mg/L to 4.22 ± 1.16 mg/L (P < .05). Total fiber intake increased from 16.6 ± 1.7 g/day during control to 26.5 ± 2.4 g/day (P < .0001) with the added pea hull and to 34.5 ± 2.2 g/day with pea hull and inulin (P < .0001). Stool frequency increased from 1.4 ± 0.2 stools/day during control to 1.9 ± 0.3 stools/day during both fiber periods (P < .05). No change in overall QoL was observed.

Supplementing the diet of CKD patients with fiber may be a dietary therapy to reduce p-cresol and improve stool frequency.

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Do antiphospholipid antibodies correlate with stroke severity and outcome in patients with antiphospholipid syndrome?

Our goal was to analyze the association of the level of antiphospholipid antibodies (aPLs) with stroke severity and outcome in patients with antiphospholipid syndrome (APS). Observational study included consecutive patients with ischemic stroke younger than 55 years (2007-2012). We analyzed serum levels of aPLs, including anticardiolipin (aCL) antibodies, anti-β2-glycoprotein I antibodies (anti-β2GPI) and antiprothrombin antibodies (aPS/PT) within the first 48 h after admission, and again, in the case of a positive result, at least 12 weeks after the first measurement. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS), and the three-month stroke outcome by the modified Rankin Scale (mRS). Multiple linear regression models were used to analyze the correlation between the aPLs and stroke severity and outcome. Overall 255 stroke patients were included, 22 (8.6%) with APS. Among them, a positive correlation was found between immunoglobulin M (IgM) aCL levels within 48 h and NIHSS (rho = 0.471; p = 0.027), as well as a tendency toward a positive correlation between immunoglobulin G (IgG) anti-β2GPI levels within 48 h and three-month mRS (rho = 0.364; p = 0.096). Multiple linear regression analyses showed a positive correlation between levels of IgM aCL < 48 h and the NIHSS (β-coefficient [standard error; SE] = 0.127 [0.044]), as well as the levels of IgG anti-β2GPIwithin 48 h and the three-month mRS (β-coefficient [SE] = 0.034 [0.011]).

In young stroke patients with APS, serum levels of IgM aCL within 48 h are correlated with stroke severity and levels of IgG anti-β2GPI within 48 h are correlated with three-month outcomes.

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Are `` There bugs in condoms '' : Tanzanian close-to-community providers ' ability to offer effective adolescent reproductive health services?

Young people in Tanzania are known to access reproductive health services from a range of close-to-community providers outside formal health settings such as drug stores, village AIDS committees, traditional healers and traditional birth attendants (TBAs). However, questions remain about the quality of services such agents provide. This study investigated their capacity to provide adolescent reproductive health (ARH) services and explored their readiness and ability to integrate with the mainstream health sector through community referral interventions. Thirty-five focus group discussions exploring close-to-community provider experiences and attitudes to ARH service provision were carried out in two districts in Northern Tanzania. Discussions were conducted in Kiswahili, digitally recorded, verbatim-transcribed, translated and back-translated from Swahili to English. A thematic analysis was conducted using NVivo 9. The major close-to-community cadres providing reproductive health services were drug stores, traditional healers, TBAs and village health workers. They reported being the first port of call for adolescents seeking reproductive health services, but their knowledge of ARH needs was poor. They had negative attitudes to, and lacked the necessary resources for, the provision of such services for adolescents. Some were particularly unwilling to provide condom services and were prejudiced against adolescents using them. There was poor integration between the close-to-community providers and the formal health sector, further limiting their ability to provide adequate services.

Although close-to-community providers are considered a key resource in the community, most have limited capacity to provide ARH services. Without capacity-building investments such as training and cooperation with the mainstream health sector, their contribution to positive reproductive health outcomes is limited, or could indeed lead to adverse outcomes.

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Does engineered heart tissue transplantation alter electrical-conduction function in rats with myocardial infarction?

To investigate how affects electrical-conduction function following myocardial infarction (MI) in rats. Thirty SD rats of either sex (220-250 g) were anesthetized using chlorine hydrate and were randomly divided into three groups: control group, MI group and transplantation group. The field potential (FP) morphology and activation-conduction duration were recorded with microeletrode array techniques. The MEA recorded clear FP morphology. Activation-conduction duration was (6.5 ± 2.12) ms in the control group, (17.5 ± 3.54) ms in the MI group, and (9.13 ± 1.31) ms in the transplantation group.

EHT transplantation can improve electrical-conduction and function of MI rats.

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Does protein kinase D1 deficiency promote differentiation in epidermal keratinocytes?

Protein kinase D (PKD or PKD1) is a serine/threonine protein kinase that has been shown to play a role in a variety of cellular processes; however, the function of PKD1 in the skin has not been fully investigated. The balance between proliferation and differentiation processes in the predominant cells of the epidermis, the keratinocytes, is essential for normal skin function. To investigate the effect of PKD1 deficiency on proliferation and differentiation of epidermal keratinocytes. We utilized a floxed PKD1 mouse model such that infecting epidermal keratinocytes derived from these mice with an adenovirus expressing Cre-recombinase allowed us to determine the effect of PKD1 gene loss in vitro. Proliferation and differentiation were monitored using qRT-PCR, Western blot, transglutaminase activity assays, [3H]thymidine incorporation into DNA and cell cycle analysis. A significant decrease in PKD1 mRNA and protein levels was achieved in adenoviral Cre-recombinase-infected cells. Deficiency of PKD1 resulted in significant increases in the mRNA and protein expression of various differentiation markers such as loricrin, involucrin, and keratin 10 either basally and/or upon stimulation of differentiation. PKD1-deficient keratinocytes also showed an increase in transglutaminase expression and activity, indicating an anti-differentiative role of PKD1. Furthermore, the PKD1-deficient keratinocytes exhibited decreased proliferation. However, PKD1 loss had no effect on stem cell marker expression.

Cre-recombinase-mediated knockdown represents an additional approach demonstrating that PKD1 is an anti-differentiative, pro-proliferative signal in mouse keratinocytes.

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Is cD133 expression correlated with poor prognosis in colorectal cancer?

Cancer stem cells (CSC) was reported to play an important role in various kinds of cancer. CD133 is one of the cancer stem cell markers in solid cancers. However, the correlation between CD133 expression and the clinicopathological factors in colorectal cancer (CRC) remains unclear. Forty patients with CRC who underwent operations were enrolled. Expression of CD133 was investigated by immunohistochemistry (IHC). The staining was observed in the cytoplasm of cancer cells and the patients who have the staining were defined as CD133-positive cases. The patients were divided into two groups: the CD133-positive group (n = 22) and negative group (n = 18). Clinicopathological factors were compared between the two groups. The prognostic factors were investigated by multivariate analysis. In the CD133-positive group, the incidence of lymph node and liver metastasis, lymphatic and venous invasion, as well as the progression of stage of cancer were higher than that in the CD133-negative group. The 5-year survival rate and the disease-free survival rate in the CD133-positive group were lower than that in the CD133-negative group. The multivariate analysis revealed that CD133 expression tended to be an independent prognostic factor.

CD133 expression is correlated with poor prognosis in CRC.

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Does atomoxetine reduce hyperactive/impulsive behaviours in neurokinin-1 receptor 'knockout ' mice?

Mice with functional ablation of the neurokinin-1 receptor gene (NK1R(-/-)) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10mg/kg; LDEB: 1, 3 or 10mg/kg). Atomoxetine reduced the hyperactivity displayed by NK1R(-/-) mice in the LDEB at a dose (3mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10mg/kg) also reduced impulsivity in NK1R(-/-) mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype.

This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R(-/-) mice consolidates the validity of using NK1R(-/-) mice in research of the aetiology and treatment of ADHD.

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Do pre-treatment serum total bilirubin level as an indicator of optimal CPT-11 dosage?

Irinotecan (CPT-11), a highly effective chemotherapeutic agent, can cause severe neutropenia and diarrhea. The area under the curve of plasma levels over time of SN-38, an active metabolite of CPT-11, was previously reported to correlate with the pre-treatment serum total bilirubin level (PTB). However, there are no established criteria for selecting CPT-11 dose on the basis of PTB. Therefore, we evaluated PTB as an indicator for the optimal CPT-11 dose. Retrospective analyses were conducted in patients administered CPT-11 as a single agent at the Osaka National Hospital from June 2006 to July 2013. Data obtained during the first 28 days following CPT-11 administration were analyzed to compare PTB between patients with and without grade 3-4 neutropenia and grade 3-4 diarrhea. Receiver operating characteristics (ROC) curve analysis was performed to determine the optimal PTB cutoff value for PTB-associated toxicity. Subgroup analysis was performed comparing the incidence of toxicity in patients with PTB values below or above the cutoff value. Although PTB incidence was significantly higher in patients who developed grade 3-4 neutropenia than in those who did not, PTB was not associated with grade 3-4 diarrhea. The PTB cutoff value for association with grade 3-4 neutropenia occurrence was set at 0.8 mg/dL. The incidence of febrile neutropenia (FN) significantly elevated to 21% in patients with PTB ≥0.8 mg/dL, whereas that of patients with PTB <0.8 mg/dL was 4%. In the subgroup analysis, no difference was found in the neutropenia incidence between patients treated with a dose below 80 mg/m(2) and those treated on a weekly schedule.

PTB can be used as a predictive marker of CPT-11-induced severe neutropenia and FN. In patients with PTB ≥0.8 mg/dL, the CPT-11 dose should be reduced to less than 80 mg/m(2) with weekly dosing.

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Does the indole derivative NecroX-7 improve nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS/RNS and inflammation?

Nonalcoholic steatohepatitis (NASH) is associated with cirrhosis and hepatocellular carcinoma. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play key roles in the development of the disease. However, the therapeutic target of NASH has not been fully defined and new treatments are needed. We investigated the protective effects of the antioxidant indole-derived NecroX-7 in a NASH mouse model using leptin-deficient ob/ob and methionine- and choline-deficient (MCD) diet-fed ob/ob mice. Six-week-old male mice were divided into three groups: ob/+ mice, ob/ob mice treated with vehicle and ob/ob mice treated daily with NecroX-7 (20 mg/kg) for 4 weeks. To study the effects of NecroX-7 in a fibrosis model, NASH was induced by feeding ob/ob mice an MCD diet. The effects of NecroX-7 on NASH progression were evaluated using biochemical, histological and molecular markers. NecroX-7-treated ob/ob mice had a marked decrease in serum aspartate aminotransferase and alanine transaminase compared with vehicle-treated controls. Interestingly, hepatic steatosis and lipid peroxidation were significantly improved by NecroX-7 treatment. NecroX-7 inhibited tert-butylhydroperoxide- and H2 O2 -induced mitochondrial ROS/RNS in primary hepatocytes and attenuated mitochondrial dysfunction in vitro and in vivo. Furthermore, NecroX-7-treated mice exhibited fewer infiltrating macrophages and reduced hepatic tumour necrosis factor-alpha expression. Hepatic fibrosis in MCD-fed ob/ob mice was significantly decreased by NecroX-7 treatment.

NecroX-7 treatment improved hepatic steatosis and fibrosis in murine NASH models. These effects occurred through the suppression of whole-cell ROS/RNS and inflammatory responses and suggest that NecroX-7 has a potential therapeutic benefit in steatohepatitis.

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Does fluorescent labelling of intestinal epithelial cells reveal independent long-lived intestinal stem cells in a crypt?

The dynamics of intestinal stem cells are crucial for regulation of intestinal function and maintenance. Although crypt stem cells have been identified in the intestine by genetic marking methods, identification of plural crypt stem cells has not yet been achieved as they are visualised in the same colour. Intestinal organoids were transferred into Matrigel® mixed with lentivirus encoding mCherry. The dynamics of mCherry-positive cells was analysed using time-lapse imaging, and the localisation of mCherry-positive cells was analysed using 3D immunofluorescence. We established an original method for the introduction of a transgene into an organoid generated from mouse small intestine that resulted in continuous fluorescence of the mCherry protein in a portion of organoid cells. Three-dimensional analysis using confocal microscopy showed a single mCherry-positive cell in an organoid crypt that had been cultured for >1year, which suggested the presence of long-lived mCherry-positive and -negative stem cells in the same crypt. Moreover, a single mCherry-positive stem cell in a crypt gave rise to both crypt base columnar cells and transit amplifying cells. Each mCherry-positive and -negative cell contributed to the generation of organoids.

The use of our original lentiviral transgene system to mark individual organoid crypt stem cells showed that long-lived plural crypt stem cells might independently serve as intestinal epithelial cells, resulting in the formation of a completely functional villus.

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Does noble-Collip Drum Trauma induce Disseminated Intravascular Coagulation But Not Acute Coagulopathy of Trauma-Shock?

There are two opposing possibilities for the main pathogenesis of trauma-induced coagulopathy: an acute coagulopathy of trauma shock and disseminated intravascular coagulation with the fibrinolytic phenotype. The objective of this study was to clarify the main pathogenesis of trauma-induced coagulopathy using a rat model of Noble-Collip drum trauma. Eighteen rats were divided into the control, trauma 0, and trauma 30 groups. The trauma 0 and 30 groups were exposed to Noble-Collip drum trauma. Blood samples were drawn without, immediately after, and 30 min after Noble-Collip drum trauma in the control, trauma 0, and trauma 30 groups, respectively. Coagulation and fibrinolysis markers were measured. Thrombin generation was assessed according to a calibrated automated thrombogram. Spontaneous thrombin bursts resulting from circulating procoagulants were observed in the nonstimulated thrombin generation assay immediately after trauma. Soluble fibrin levels (a marker of thrombin generation in the systemic circulation) were 50-fold greater in the trauma groups than in the control group. The resultant coagulation activation consumed platelets, coagulation factors, and antithrombin. Endogenous thrombin potential and factor II ratio were significantly negatively correlated with antithrombin levels, suggesting insufficient control of thrombin generation by antithrombin. High levels of active tissue-type plasminogen activator induced hyperfibrin(ogen)olysis. Soluble thrombomodulin increased significantly. However, activated protein C levels did not change.

The systemic thrombin generation accelerated by insufficient antithrombin control leads to the consumption of platelets and coagulation factors associated with hyperfibrin(ogen)olysis. These changes are collectively termed disseminated intravascular coagulation with the fibrinolytic phenotype.

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Does aminoguanidine inhibit ventricular fibrosis and remodeling process in isoproterenol-induced hypertrophied rat hearts by suppressing ROS and MMPs?

Aminoguanidine (AG), a well known inhibitor of advanced glycation end products, has been reported to attenuate cardiac hypertrophy and fibrosis. However, the underlying mechanism by which AG exerts its anti-fibrotic activity is not well understood. Reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) are implicated as playing a major role in the development of cardiac fibrosis. Hence, the present study was designed to investigate the effect of AG on ROS generation and MMPs during the progress of hypertrophic growth. Isoproterenol (ISO) (7 mg/kg/day, s.c., for 15 days) was used to induce cardiac hypertrophy in experimental adult Wistar rats. ISO-treated rats were co-treated with AG (50 mg/kg/day, i.p., for 15 days). Ventricular collagen deposition, gelatinase activity of MMP-2 and MMP-9, and the level of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were investigated. In addition, in silico docking of MMP-2 and MMP-9 proteins, ROS generation, and nuclear translocation of NF-κB-p65 were also studied. AG co-treatment markedly attenuated the ISO-induced hypertrophic growth and fibrosis. Heart-weight-to-body weight ratio and ventricular collagen levels were normalized upon AG co-treatment. A significantly decreased level of ventricular ROS generation (p < 0.001) and NF-κB-p65 nuclear translocation was observed in the rat hearts co-treated with AG. Furthermore, in silico docking analysis revealed that AG interacts at the active site of MMP-2 and MMP-9.

Anti-fibrotic and anti-hypertrophic activities of AG were mainly attributed to its ROS quenching efficacy and its direct interaction with MMP-2 and MMP-9.

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Is biliary-enteric reconstruction with hepaticoduodenostomy following laparoscopic excision of choledochal cyst associated with better postoperative outcomes : a single-centre experience?

With the advent of laparoscopic surgery, more choledochal cysts are excised laparoscopically. In this study, we compared the outcomes from laparoscopic hepaticojejunostomy (HJ) and hepaticoduodenostomy (HD) for biliary-enteric reconstruction. A retrospective analysis of patients who had undergone laparoscopic choledochal cyst excision between February 2005 and January 2014 in a tertiary referral centre was performed. Demographics data, operative techniques and surgical outcomes were analysed according to the way of biliary-enteric reconstruction. A total of 31 patients were identified, 20 of whom underwent HJ and 11 underwent HD. There were no significant differences in terms of demographics. Median operative time was significantly shorter in HD group (211.0 ± 96.4 vs. 386.0 ± 90.4 min, p = 0.001). Although postoperative enteral feeding was initiated later in HD group (5.0 ± 0.8 vs. 4.0 ± 3.6 days, p = 0.036), postoperative stay in intensive care unit (ICU) (0.7 ± 1.0 vs. 2.4 ± 1.7 days, p = 0.007) and overall hospital stay (9.1 ± 1.0 vs. 14.4 ± 12.2 days, p = 0.157) favoured HD group. There was no perioperative mortality. Median follow-up duration was 24.0 (±11.0) months in HD group and 67.5 (±23.7) months in HJ group. One patient in HJ group had postoperative cholangitis related to anastomotic stricture whereas no cholangitis noted in HD group. In total, five patients in HJ group required second operation for complications and residual diseases whereas none in HD group required reoperation.

Laparoscopic excision of choledochal cyst with hepaticoduodenostomy reconstruction is safe and feasible with shorter operative time, ICU stay and overall hospital stay. It is not inferior to HJ in terms of short-term postoperative outcomes.

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Do international observational study of nutritional support in mechanically ventilated patients following burn injury?

It has been proposed that nutritional therapy in critically ill patients after major burn reduces mortality. However, the actual practice of nutrient delivery, and the effect on outcome, has not been described. To evaluate international practices related to nutritional support and outcomes in mechanically ventilated patients with burn injury. Data from the International Nutrition Surveys (2007-2011) for patients with a primary diagnosis of burn were extracted and analysed. Eighty-eight of 90 patients (aged 16-84 years) received enteral nutrition. The median time for initiation of enteral feeding was 17 h [range 0-65]. Fifty patients (57%) had interruptions to nutrient delivery, most often these interruptions were fasting for operative procedures. There were substantive energy and protein deficits [943 (654) kcal/day and 49 (41) g/day, respectively; mean (SD)]. Nineteen (21%) patients died within 60 days of admission, and the energy and protein deficits were greater in those that died compared with survivors [died vs. survived, energy: 1251 (742) vs. 861 (607) kcal/d; p=0.02; and protein 67(42) vs. 44(39) g/d; p=0.03]. Energy and protein deficits were associated with increased mortality with the greater the deficit, the stronger the association with death (odds ratio for death: energy deficit/100 kcal 1.10 (1.01, 1.19); p=0.028 and protein/10 g 1.16 (1.01, 1.33); p=0.037). Results were similar and remained significant after adjusting for severity of illness.

Mechanically ventilated patients following burn develop substantial energy and protein deficits, with lesser deficits observed in survivors.

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Is rs2070424 of the SOD1 gene associated with risk of Alzheimer 's disease?

Oxidative stress plays an important role in Alzheimer's disease (AD) etiopathogenesis. There were several studies that showed impaired antioxidant defense system (ADS) enzymes expression or activity in AD patients. There are only few studies evaluating the importance of ADS gene single nucleotide polymorphisms (SNPs) as risk factors of AD. We evaluated association between chosen SNPs of the enzymes of the ADS and risk of AD. We included 400 AD patients and 402 healthy controls. We studied rs1041740, rs4998557 and rs2070424 of the SOD1 gene, rs2855116, rs5746136 and rs4880 of the SOD2 gene and rs3448, rs1050450 and rs1800668 of the GPx-1 gene (real time PCR). To determine the APOE gene common polymorphism, two single-nucleotide polymorphisms (SNPs; NCBI SNPs rs429358 and rs7412) were genotyped (TaqMan assays, Applied Biosystems [ABI], Foster City, CA, USA). The genotype and gender frequencies were compared between the studied groups by the χ(2) test and mean age by the t-Student test. Among all studied SNPs only rs2070424 of the SOD1 gene was a protective factor for AD in an additive (OR=0.47; 95% CI=0.30-0.74, p=0.001) and recessive (OR=0.47; 95% CI=0.30-0.75, p=0.002) models including age, gender and APOE gene status.

rs2070424 polymorphism of the SOD1 gene is a risk factor for AD in Polish population. Allel G and genotype AG and GG are protective factors for AD.

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Is structural maintenance of chromosomes 4 a predictor of survival and a novel therapeutic target in colorectal cancer?

Structural maintenance of chromosomes 4 (SMC-4) is a chromosomal ATPase which plays an important role in regulate chromosome assembly and segregation. However, the role of SMC-4 in the incidence of malignancies, especially colorectal cancer is still poorly understood. We here used quantitative PCR and Western blot analysis to examine SMC-4 mRNA and protein levels in primary colorectal cancer and paired normal colonic mucosa. SMC-4 clinicopathological significance was assessed by immunohistochemical staining in a tissue microarray (TMA) in which 118 cases of primary colorectal cancer were paired with noncancerous tissue. The biological function of SMC-4 knockdown was measured by CCK8 and plate colony formation assays. Fluorescence detection has been used to detect cell cycling and apoptosis. SMC-4 expression was significantly higher in colorectal cancer and associated with T stage, N stage, AJCC stage and differentiation. Knockdown of SMC-4 expression significantly suppressed the proliferation of cancer cells and degraded its malignant degree.

Our clinical and experimental data suggest that SMC-4 may contribute to the progression of colorectal carcinogenesis. Our study provides a new therapeutic target for colorectal cancer treatment.

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Is intermediate filament protein nestin expressed in developing meninges?

Nestin is a type VI intermediate filament protein known as a marker for progenitor cells that can be mostly found in tissues during the embryonic and fetal periods. In our study, we aimed to determine the expression of nestin in meninges covering the brain tissue at different developmental stages and in the new born. In this study 10 human fetuses in different development stages between developmental weeks 9-34 and a newborn brain tissue were used. Fetuses in paraffin section were stained with H+E and nestin immunohistochemical staining protocol was performed. In this study, in the human meninges intense nestin expression was detected as early as in the 9th week of development. Intensity of this expression gradually decreased in later stages of development and nestin expression still persisted in a small population of newborn meningeal cells.

In the present study, nestin positive cells gradually diminished in the developing and maturing meninges during the fetal period. This probably depends on initiation of a decrease in nestin expression and replacement with other tissue-specific intermediate filaments while the differentiation process continues. These differences can make significant contributions to the investigation and diagnosis of various pathological disorders (Tab. 1, Fig. 3, Ref. 36).

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Is dorsal plication without degloving safe and effective for correcting ventral penile deformities?

To compare the safety and efficacy of patients undergoing dorsal penile plication with patients undergoing ventral and lateral plication. A retrospective review was performed of all patients who underwent penile plication between 2007 and 2013. Plication was performed through a 2-cm longitudinal incision in the proximal or midpenile shaft without degloving. Plication sutures were placed in parallel opposite the angle of greatest curvature. Dorsal plication was performed with minimal displacement of the neurovascular bundle. Patient demographics, perioperative outcomes, and patient-reported outcomes were analyzed. Of 215 patients who underwent penile plication, complete operative and patient-reported outcomes data were available for 118 (55%). Patients were grouped by location of plication: dorsal (n = 17 [14%]), ventral (n = 65 [55%]), and lateral (n = 36 [31%]). Mean age (52-58 years; P = .51) and preoperative curvature (36-51°; P = .78) were similar among the 3 groups. Each group required a similar number of sutures (8-9; P = .18) to achieve similar correction (37-45°; P = .33). Patients completed a satisfaction survey at a mean of 15 months (range, 1-41 months) after surgery. All groups reported equally high rates of satisfaction for penile curvature (P = .64), penile rigidity (P = .64), strength of erection (P = .98), and overall satisfaction (P = .75). Although each group reported subjective decrease in penile length (P = .10), objective length loss occurred on a small scale (mean length loss for all groups, 0.3-0.8 cm; P = .24).

Penile plication is a safe and effective technique for correcting all directions of curvature. Dorsal plication without degloving produces favorable objective and subjective results comparable to ventral and lateral plication.

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Is work disability related to the presence of arthritis and not to a specific diagnosis . Results from a large early arthritis cohort in Argentina?

The objective of the study was to evaluate work disability and its main associated factors in patients with early arthritis. Argentine Consortium for Early Arthritis (CONAART) is the first early arthritis cohort in Argentina. Patients with one or more swollen joints and less than 2 years of symptoms duration were followed up prospectively in 13 departments of rheumatology. Social, demographic, familiar, clinical, and laboratory data were recollected. At first year and every year, X-rays of hands and feet were performed and working status and pharmaco-economic data were recollected. Work status (employed, unemployed, retired) and type of work were assessed by direct interview using a predesigned questionnaire. Eight hundred forty-eight patients were included, rheumatoid arthritis (RA) = 483 (57 %)and undifferentiated arthritis (UA) = 365 (43 %), 694 (81.8 %) were women, median age was 46 years (interquartile range (IQR) 35-55.7) and median symptoms duration 7 months (IQR 3-12). Patients with RA had significantly higher disease activity, worse functional capacity and quality of life, and more severe radiological damage compared to UA patients. However work disability (unemployed patient) was comparable between groups (RA = 21 % versus UA = 18.6 % p = NS). In both groups, unemployed patients had higher disease activity score of 28 joints (DAS28), worse Health Assessment Questionnaire (HAQ) values, and less years of formal education (p value <0.005 in all comparisons). Radiological damage was greater in unemployed patients but this difference did not reach statistical significance. In multivariate analysis, disease activity was the main variable associated with unemployment in both groups. Joint involvement was the main cause of work disability in this cohort of patients with early arthritis, independently of the final diagnosis.

1. Work disability is higher in patients with inflammatory arthritis as compared to the general population. 2. Prevalence of work disability is comparable among patients with undifferentiated and rheumatoid arthritis. 3. Disease activity is the main disease variable associated with work disability.

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Is the highly prevalent H3F3A mutation in giant cell tumours of bone shared by sporadic central giant cell lesion of the jaws?

Central giant cell lesion (CGCL) and giant cell tumour (GCT) are bone lesions that share similar microscopic features. Recently, it was reported that 90% of bone GCT exhibit either p.Gly34 Trp or p.Gly34 Leu in H3F3A, one of two genes for histone H3.3 located on chromosome 1. We aimed to test whether sporadic CGCL of the jaws share the H3F3A mutations reported in GCT of other bones. Nine samples of CGCL of the jaws were included in the study, and mutations were assessed by direct sequencing. None of the CGCL samples presented the recurrent p.Gly34 Trp or p.Gly34 Leu mutations in the H3F3A gene.

On the basis of our findings, H3F3A p.Gly34 Trp or p.Gly34 Leu mutations are not a frequent event in CGCL. If these alterations are confirmed to be exclusive of GCT, the assessment of H3F3A mutations may help in the differential diagnosis of GCT and CGCL of the jaws.

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Is chronic thromboembolic pulmonary hypertension associated with iron overload?

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized as the incomplete resolution of emboli after pulmonary embolism (PE) and the subsequent fibrotic organization and remodeling of pulmonary vascular bed. It has been reported that abnormal fibrin probably contributes to the incomplete resolution of emboli. And there is evidence that free iron could convert fibrinogen into fibrin which is remarkably resistant to lysis. Thus, we hypothesized that persistent iron overload might participate in the development of CTEPH. A case-control study was conducted. Forty-five CTEPH patients were enrolled as cases, and 36 age and sex frequency-matched chronic PE patients without pulmonary hypertension were selected as controls. Levels of free iron, soluble transferrin receptor (sTfR), ferritin, sTfR/ferritin ratio, hepcidin-25, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and malondialdehyde (MDA) were compared between the two groups. Logistic regression analysis was carried out to estimate odds ratios. There was no difference of the levels of free iron, hepcidin-25, sTfR, ferritin, sTfR/ferritin ratio, TNF-α, and MDA between CTEPH patients and the controls. Levels of sTfR and ferritin in both groups were within the normal limits. Levels of IL-6 in CTEPH patients were significantly higher than that in the controls. A negative correlation was observed between hepcidin-25 and sTfR (Spearman's r=-0.438, P<.001), and a positive correlation was observed between hepcidin-25 and ferritin (Spearman's r=0.503, P<.001). In the univariate logistic regression model, there was no association observed between CTEPH and free iron, hepcidin-25, sTfR, ferritin, sTfR/ferritin ratio, TNF-α, IL-6, and MDA.

CTEPH has no association with iron overload. The iron status evaluated by sTfR and ferritin is within the normal limits in this CTEPH population.

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Does immunological profiling in chronic rhinosinusitis with nasal polyps reveal distinct VEGF and GM-CSF signatures during symptomatic exacerbations?

The mechanisms and immune pathways associated with chronic rhinosinusitis (CRS) are not fully understood. Immunological changes during acute exacerbation of CRS may provide valuable clues to the pathogenesis and perpetuation of the disease. To characterize local and systemic immune responses associated with acute worsening of sinonasal symptoms during exacerbation in CRS with nasal polyps (CRSwNP) compared to controls. This was a non-interventional prospective study of individuals with CRSwNP and normal controls. Subjects underwent a baseline visit with collection of nasal secretions, nasal washes, and serum specimens. Within 3 days of acute worsening of sinonasal symptoms, subjects underwent a study visit, followed by a post-visit 2 weeks later. The sinonasal outcome test-22 (SNOT-22) scores and immunological parameters in the specimens were analysed using a novel, unsupervised learning method and by conventional univariate analysis. Both CRSwNP patients and control subjects showed a significant increase in SNOT-22 scores during acute exacerbation. Increased nasal levels of IL-6, IL-5, and eosinophil major basic protein were observed in CRSwNP patients. A network analysis of serum specimens revealed changes in a set of immunological parameters, which are distinctly associated with CRSwNP but not with controls. In particular, systemic increases in VEGF and GM-CSF levels were notable and were validated by a conventional analysis.

CRSwNP patients demonstrate distinct immunological changes locally and systemically during acute exacerbation. Growth factors VEGF and GM-CSF may be involved in the immunopathogenesis of subjects with CRS and nasal polyps experiencing exacerbation.

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Do adolescents and young adults with type 1 diabetes display a high prevalence of endothelial dysfunction?

Little is known about endothelial function in adolescents with type 1 diabetes, and we evaluated endothelial dysfunction, using reactive hyperaemia peripheral arterial tonometry (RH-PAT). This prospective, observational, 1-year study focused on 73 adolescents with type 1 diabetes, using multiple daily injections or continuous subcutaneous insulin infusion. The subjects were assessed using RH-PAT, body mass index, blood pressure, fasting lipid profile, glycated haemoglobin, insulin requirements and hours of physical exercise per week. Endothelial dysfunction was observed in 56 patients (76.7%), with lower mean RH-PAT scores (1.26 ± 0.22 versus 2.24 ± 0.48, p < 0.0001) and higher glycated haemoglobin values at baseline (8.27 ± 1.24% versus 7.37 ± 0.54%, p = 0.006) and as a mean of the whole period since diagnosis (8.25 ± 1.22% versus 7.72 ± 0.82%, p = 0.034). A higher percentage of patients with endothelial dysfunction showed abnormal cardiac autonomic tests (p = 0.02) and were more sedentary, exercising <4 hours a week, than patients with normal endothelial function. After follow-up in 64/73 patients, we observed endothelial dysfunction in 81.8% of patients, despite a modest improvement in glycated haemoglobin.

Adolescents with type 1 diabetes displayed evidence of endothelial dysfunction. Good metabolic control (glycated haemoglobin ≤7.5%, 58 mmol/mol) and regular physical activity of at least 4 h a week might be protective.

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Do azo pigments and quinacridones induce delayed hypersensitivity in red tattoos?

Induction of delayed hypersensitivity reactions by red tattoos has been occasionally reported. Little is known about the inks used. Azo pigments have been implicated in some instances, but there is only one reported case involving quinacridones. To describe the clinical and pathological features and outcome of skin reactions induced by red tattoo pigments. Six patients with a cutaneous reaction induced by a red tattoo pigment underwent biopsy and prick and patch testing with the inks supplied. We observed seven reactions in the 6 patients. Histology showed various patterns: three lichenoid, two eczematous, and two pseudolymphomatous. Five reactions occurred with azo pigments, and two with quinacridones, in both cases with Violet 19 and Red 122. Four inks were tested. Only one patch test gave a positive result at a late reading (day 7). Prick tests gave negative results. The reactions required various treatments, including laser treatment for 2 patients. Activation of the reaction in 1 case was transient.

Azo pigments and quinacridones both triggered reactions with similar clinical aspects but with varying histological findings. Patch and prick test results were disappointing with both. Reactions occurred following laser use in 1 case.

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Is neoadjuvant treatment response in negative nodes an important prognosticator after esophagectomy?

The current American Joint Committee on Cancer Seventh Edition (AJCC7) pathologic staging for esophageal adenocarcinoma (EAC) is derived from data assessing the outcomes of patients having undergone esophagectomy without neoadjuvant treatment and has unclear significance in patients who have received multimodality therapy. Lymph nodes with evidence of neoadjuvant treatment effect without residual cancer cells may be observed and are not traditionally considered in pathologic reports, but may have prognostic significance. All patients who underwent esophagectomy after completing neoadjuvant therapy for EAC at our institution between 2006 and 2012 were reviewed. Slides of pathologic specimens were reexamined for locoregional treatment-response nodes lacking viable cancer cells but with evidence of acellular mucin pools, central fibrosis, necrosis, or calcifications suggesting prior tumor involvement. Kaplan-Meier survival functions were estimated, and Cox proportional hazards regression models were used to compare staging models. Ninety patients (82 men) underwent esophagectomy after neoadjuvant therapy for EAC (mean age, 61.8 ± 8.9 years). All patients received preoperative chemotherapy, and 50 patients also underwent preoperative radiotherapy. Median Kaplan-Meier survival was 55.6 months, and 5-year survival was 35% (95% confidence interval, 19% to 62%). A total of 100 treatment-response nodes were found in 38 patients. For patients with limited nodal disease (62 ypN0-N1), the presence of treatment-response nodes was associated with significantly worse survival (p = 0.03) compared with patients lacking such nodes. Adjusting for patient age and AJCC7 pathologic stage showed the presence of treatment-response nodes significantly increased the risk of death (hazard ratio, 2.7; 95% confidence interval, 1.1 to 6.9; p = 0.04). When stage-adjusted survival was modeled, counting treatment-response nodes as positive nodes offered a better model fit than ignoring them.

Treatment-response lymph nodes detected from esophagectomy specimens in patients having undergone neoadjuvant chemotherapy or combined chemoradiation for EAC provide valuable prognostic information, particularly in patients with limited nodal disease. The current practice of considering lymph nodes lacking viable cancer cells, but with evidence of tumor necrosis, as pathologically negative likely results in understaging. Future efforts at revising the staging system for EAC should consider incorporating treatment-response lymph nodes in the analysis.

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Do adult aortic valve interstitial cells have greater responses to toll-like receptor 4 stimulation?

Aortic valve interstitial cells (AVICs) have been implicated in the pathogenesis of calcific aortic valve disease. Signal transducer and activator of transcription 3 (Stat3) possesses antiinflammatory effects. Given that calcification occurs in adult valves, we hypothesized that AVICs from adult valves more likely undergo a proosteogenic phenotypic change than those from pediatric valves and that may be related to different Stat3 activation in the response of those two age groups to toll-like receptor 4 (TLR4). AVICs from healthy human aortic valve tissues were treated with TLR4 agonist lipopolysaccharide. Cellular levels of TLR4, intercellular adhesion molecule 1, bone morphogenetic protein 2, and alkaline phosphatase, as well as phosphorylation of p-38 mitogen-activated protein kinase (MAPK), nuclear factor-κβ (NF-κβ), and Stat3, were analyzed. Toll-like receptor 4 protein levels were comparable between adult and pediatric AVICs. Adult cells produce markedly higher levels of the above markers after TLR4 stimulation, which is negatively associated with phosphorylation of Stat3. Inhibition of Stat3 enhanced p-38 MAPK and NF-κβ phosphorylation and exaggerated the expression of the above markers in pediatric AVICs after TLR4 stimulation.

Adult AVICs exhibit greater inflammatory and osteogenic responses to TLR4 stimulation. The enhanced responses in adult AVICs are at least partly due to lower levels of Stat3 activation in response to TLR4 stimulation relative to pediatric cells. Stat3 functions as a negative regulator of the TLR4 responses in human AVICs. The results suggest that Stat3 activation (tyrosine phosphorylation) may be protective and that TLR4 inhibition could be targeted pharmacologically to treat calcific aortic valve disease.

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Do pollen tube cell walls of wild and domesticated tomatoes contain arabinosylated and fucosylated xyloglucan?

In flowering plants, fertilization relies on the delivery of the sperm cells carried by the pollen tube to the ovule. During the tip growth of the pollen tube, proper assembly of the cell wall polymers is required to maintain the mechanical properties of the cell wall. Xyloglucan (XyG) is a cell wall polymer known for maintaining the wall integrity and thus allowing cell expansion. In most angiosperms, the XyG of somatic cells is fucosylated, except in the Asterid clade (including the Solanaceae), where the fucosyl residues are replaced by arabinose, presumably due to an adaptive and/or selective diversification. However, it has been shown recently that XyG of Nicotiana alata pollen tubes is mostly fucosylated. The objective of the present work was to determine whether such structural differences between somatic and gametophytic cells are a common feature of Nicotiana and Solanum (more precisely tomato) genera. XyGs of pollen tubes of domesticated (Solanum lycopersicum var. cerasiforme and var. Saint-Pierre) and wild (S. pimpinellifolium and S. peruvianum) tomatoes and tobacco (Nicotiana tabacum) were analysed by immunolabelling, oligosaccharide mass profiling and GC-MS analyses. Pollen tubes from all the species were labelled with the mAb CCRC-M1, a monoclonal antibody that recognizes epitopes associated with fucosylated XyG motifs. Analyses of the cell wall did not highlight major structural differences between previously studied N. alata and N. tabacum XyG. In contrast, XyG of tomato pollen tubes contained fucosylated and arabinosylated motifs. The highest levels of fucosylated XyG were found in pollen tubes from the wild species.

The results clearly indicate that the male gametophyte (pollen tube) and the sporophyte have structurally different XyG. This suggests that fucosylated XyG may have an important role in the tip growth of pollen tubes, and that they must have a specific set of functional XyG fucosyltransferases, which are yet to be characterized.

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Do clinical events after cessation of lamivudine therapy in patients recovered from hepatitis B flare with hepatic decompensation?

Before guidelines were issued, many patients with hepatitis B flare and hepatic decompensation had discontinued lamivudine therapy instead of indefinite therapy. We investigated their outcomes. We performed a retrospective cohort study of 263 consecutive patients with chronic hepatitis B (94 with cirrhosis) who recovered from a flare of hepatitis with hepatic decompensation and were followed after cessation of lamivudine therapy. Clinical events that occurred during the follow-up period were assessed by chart review and analysis of results from retrospective assays. The mean duration of lamivudine therapy was 12.1 ± 8.6 months; data were collected from patients for 89.1 ± 38.7 months after therapy ended. In the first year off therapy, 29.9% of patients had clinical relapse, 16.2% had hepatitis flares, and 8.2% had hepatic decompensation. There was no significant difference in the incidence of hepatic decompensation between patients with and without cirrhosis. Hepatocellular carcinoma developed in 14 patients 20-109 months after cessation of therapy, with 5-year cumulative incidence of 5.2% in patients with cirrhosis. Three patients with cirrhosis died of hepatic decompensation 38-76 months after cessation of therapy (5-year cumulative mortality, 2.9%). Multivariate analyses showed that men were more likely than women to have recurrence of hepatic decompensation (hazard ratio [HR], 4.339; P = .014). Liver cirrhosis (HR, 2.766; P = .041) and age (HR, 1.054; P = .023) increased risk for hepatocellular carcinoma.

Cessation of lamivudine therapy after recovery from hepatitis B flare with decompensation was safe for most patients. However, 8.2% develop decompensation within 1 year and can be rescued by timely retreatment. With close monitoring, the stopping strategy could be a feasible alternative to indefinite therapy, especially in low resource settings.

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Is miRNA-205 a candidate tumor suppressor that targets ZEB2 in renal cell carcinoma?

This study aims to characterize the function of downregulated MicroRNA miR-205 in renal cell carcinoma (RCC), and show how the downstream zinc finger E-box-binding homeobox 2 (ZEB2) is negatively regulated by miR-205. The expression of miR-205 was detected in RCC and adjacent non-tumor tissues using real-time polymerase chain reaction (PCR). The expression of miR-205 and ZEB2 was detected in RCC cell lines using real-time PCR. The luciferase reporter assay was used to assess ZEB2 as a target of miR-205. Protein levels of ZEB2, E-cadherin, and vimentin were measured by western blot after overexpression of miR-205 in ACHN cells. In vivo functions of miR-205 in ACHN cells were measured by MTT assays, migration and invasion assays, and flow cytometry. MiR-205 was significantly downregulated in RCC samples and cell lines compared with matched non-tumor tissues and HK-2 cells, respectively. No significant difference was found in miR-205 expression between well differentiated and poorly to moderately differentiated groups or between phase I and phase II-III. ZEB2 was upregulated in RCC cell lines compared with expression in HK-2 cells. Upregulation of miR-205 expression caused the downregulation of ZEB2 and vimentin, and the upregulation of E-cadherin in ACHN cells. miR-205 also inhibited proliferation, migration, and invasion, and induced apoptosis of ACHN cells.

miR-205 is a candidate tumor suppressor that targets ZEB2 in RCC.

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Does the functional SNP rs3746804 in C20orf54 modify susceptibility to esophageal squamous cell carcinoma?

The aim of the present study was to explore the association of the functional single-nucleotide polymorphism (SNP) rs3746804 in C20orf54 with the susceptibility to esophageal squamous cell carcinoma (ESCC). SNP rs3746804 in C20orf54 was detected by direct sequencing in 434 ESCC patients and 554 healthy controls from Shanxi and Henan Provinces in China, geographically a high incidence area for ESCC. The frequencies and distribution of TT, CT, and CC genotypes of SNP rs3746804 between those 2 cohorts were compared and its association with ESCC was assessed. For SNP rs3746804 the genotype distribution of CT and CC in ESCC patients both significantly differed from those in healthy controls (p=0.002, 0.001, respectively), while the distribution of TT did not differ significantly between the groups (p=0.757). The ratio of T:C was high in healthy individuals and low in ESCC patients. Compared to genotype CC, both genotypes CT (odds ratio (OR)=0.63, 95% confidence interval (CI) 0.48l-0.826), and CT+TT (OR=0.654, 95% CI 0.507-0.844) were associated with significantly decreased risk for ESCC.

A close association exists between functional SNP rs3746804 in C20orf54 and susceptibility to ESCC.

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Does soluble CD30 predict late acute rejection or safe tapering of immunosuppression in renal transplantation?

Previous reports revealed the potential value of the soluble CD30 level (sCD30) as biomarker for the risk of acute rejection and graft failure after renal transplantation, here we examined its use for the prediction of safe tapering of calcineurin inhibitors as well as late acute rejection. In a cohort of renal transplant patients receiving triple immunosuppressive therapy we examined whether sCD30 can be used as a marker for safe (rejection-free) discontinuation of tacrolimus at six months after transplantation (TDS cohort: 24 rejectors and 44 non-rejecting controls). Also, in a second cohort of patients (n=22, rejectors n=11 and non-rejectors n=11), participating in a clinical trial of rituximab as induction therapy after renal transplantation (RITS cohort), we examined whether sCD30 could predict the occurrence of late (>3months post-transplant) acute rejection episodes. sCD30 was measured by ELISA in serum taken before and at several time points after transplantation. Overall, in the TDS cohort sCD30 decreased after transplantation. No difference in sCD30 was observed between rejectors and non-rejecting controls at any of the time points measured. In addition, in the RITS cohort, sCD30 measured at three months after transplantation were not indicative for the occurrence of late acute rejection.

In two prospectively followed cohorts of renal transplant patients we found no association between sCD30 and the occurrence of either late acute rejection or acute rejection after reduction of immunosuppression.

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Is generalized , severe , chronic periodontitis associated with anemia of chronic disease : a pilot study in urban , Indian males?

Anemia of chronic disease, a cytokine-mediated anemia, is a frequent complication of many chronic inflammatory conditions. The present case-control study was aimed to evaluate levels of systemic hematological markers indicative of anemia in patients with generalized, severe, chronic periodontitis. A convenience quota sample of 30 systemically-healthy, urban, male patients comprised two groups, based on full mouth periodontal examination: group A patients (n=15) were diagnosed with generalized, severe, chronic periodontitis, and group B patients comprised the control group (n=15), which included patients with a clinically-healthy periodontium. Laboratory blood investigations included hemoglobin (g%), total number of erythrocytes (red blood cells), hematocrit/packed cell volume, erythrocyte sedimentation rate, mean corpuscular volume of erythrocytes, and mean corpuscular hemoglobin concentration. An analysis of covariance using age as a covariate was done to compare the mean values of hematological parameters within groups. The mean values of hemoglobin, red blood cells, packed cell volume, and mean corpuscular hemoglobin concentration were significantly lower, while the mean corpuscular volume of erythrocytes and erythrocyte sedimentation rate were significantly higher in group A patients compared to those in group B, indicating mild anemia.

Severe periodontal disease can be linked with anemic status.

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Does progressive periodontal disease have a simultaneous incremental elevation of gingival crevicular fluid and serum CRP levels?

Increased C-reactive protein levels have been found in all active inflammations, including periodontitis. This study aims to assess the C-reactive protein levels in periodontal disease progression. Forty-five patients were divided into the following three groups (n=15) based on gingival index, probing pocket depth, and clinical attachment level: healthy (group I), gingivitis (group II), and chronic periodontitis (group III). Gingival crevicular fluid and serum samples were quantified for C-reactive protein using enzyme-linked immunosorbent assay. The mean C-reactive protein concentration in gingival crevicular fluid and serum was found to be highest in group III (1233.33ng/mL for gingival crevicular fluid, 5483.33ng/mL for serum), and least in group I (60 ng/mL and 413 ng/mL for gingival crevicular fluid and serum, respectively) The mean C-reactive protein concentration in group II (453.33ng/mL for gingival crevicular fluid and 3565.33 ng/mL for serum) was found to be intermediate.

C-reactive protein levels in gingival crevicular fluid and serum increased proportionately with the severity of periodontal disease. They correlated positively with clinical parameters, including gingival index, probing pocket depth, and clinical attachment level. Thus, it can be considered as a periodontal inflammatory biomarker and deserves further consideration.

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Is the anterior cingulate cortex a critical hub for pain-induced depression?

Besides chronic stress, chronic pain is a prevalent determinant for depression. Changes induced in specific brain regions by sustained pain may alter the processing of affective information, thus resulting in anxiodepressive disorders. Here, we compared the role of the anterior cingulate cortex (ACC) and the posterior insular cortex in the anxiodepressive, sensory, and affective aspects of chronic pain. Neuropathic pain was induced by cuffing the right sciatic nerve of C57BL/6J mice. Lesions were performed by local injection of ibotenic acid and chronic activation of the ACC by optogenetic stimulation. Anxiodepressive-related behaviors were evaluated through the novelty suppressed feeding, marble burying, splash, and forced swimming tests. Mechanical thresholds were determined using von Frey filaments, and the relief of spontaneous pain was determined by using place conditioning. The ACC lesion prevented the anxiodepressive consequences of chronic pain without affecting the sensory mechanical allodynia. Conversely, the tonic or spontaneous pain and the anxiodepressive consequences of pain remained present after posterior insular cortex lesion, even though the mechanical allodynia was suppressed. Furthermore, optogenetic stimulation of the ACC was sufficient to induce anxiety and depressive-like behaviors in naïve animals.

Our results show that, at cortical level, the sensory component of chronic pain remains functionally segregated from its affective and anxiodepressive components. Spontaneous tonic pain and evoked allodynia can be experimentally dissociated. Furthermore, the ACC appears as a critical hub for mood disorders, including for the anxiodepressive consequences of chronic pain, and thus constitutes an important target for divulging the underlying mechanism.

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Is the low level of glucagon-like peptide-1 ( glp-1 ) a risk factor of type 2 diabetes mellitus?

Glucagon like peptide-1 (GLP-1), an incretin hormone, regulates glucose metabolism by inducing insulin secretion and suppressing glucagon secretion. The aim of the study is to assess the levels of fasting and post-prandial GLP-1 and their risk for T2DM. A case control study was conducted at the diabetes clinic Sanglah Hospital Denpasar Bali, involving 40 subjects who were native Indonesian citizens and 18-70 years of age. Twenty subjects were allocated as the case group (subjects with T2DM) and 20 subjects were allocated as the control group (subjects with normal glucose tolerance [NGT]). Both fasting intact GLP-1 (FGLP-1) and 60 minutes post-75 gram glucose loading intact GLP-1 (1hGLP-1) levels were measured. Both fasting and post-prandial GLP-1 levels were significantly lower in subjects with T2DM than those with NGT (2.06 ± 0.43 vs. 2.87 ± 0.67 pg/L, p < 0.01; and 2.49 ± 0.60 vs. 3.42 ± 0.85 pg/L, p = 0.02; respectively). Low levels of FGLP-1 (OR, 13.5; p = 0.001) and 1hGLP-1 (OR, 5.667, p = 0.018), with no response after glucose loading (∆GLP-1), were a significant risk for T2DM. According to the ∆GLP-1, there was a tendency of decreasing response of GLP-1 after glucose loading among subjects with T2DM (∆ = 0.43 pg/L) compared to subjects with NGT (∆ = 0.55 pg/L).

From this study it can be concluded that levels of intact GLP-1 are an important risk factor for T2DM in the Indonesian population.

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Does shinzami Korean purple-fleshed sweet potato extract prevent ischaemia-reperfusion-induced liver damage in rats?

This study was designed to investigate the hepatoprotective effect of an extract from Shinzami, a variety of purple sweet potato, in rats injured by hepatic ischaemia-reperfusion (I/R). Pretreatment with Shinzami extract decreased the aspirate aminotransferase and alanine aminotransferase serum levels in our hepatic I/R rat model. The glutathione level and superoxide dismutase activity level were significantly higher in the rats pretreated with the Shinzami extract compared with the hepatic I/R rats, and the glutathione peroxidase activity level was higher in pretreated rats. The total anthocyanins extracted from Shinzami, however, only increased the superoxide dismutase activity level in the hepatic I/R rats. Rats pretreated with the Shinzami extract or anthocyanins demonstrated attenuated hepatic pathological changes, such as hepatic distortion, haemorrhage, necrosis and inflammatory cell infiltration compared with the hepatic I/R control rats.

Shinzami extract and anthocyanins have a hepatoprotective effect on the liver damage induced by hepatic I/R by improving antioxidant status. Furthermore, the Shinzami extract may have a more potent effect on the antioxidant status compared with the Shinzami anthocyanins alone.

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Does vagus nerve stimulation have antidepressant effects in the kainic acid model for temporal lobe epilepsy?

Depression is the most common psychiatric comorbidity in epilepsy patients. The lack of success with current pharmacological interventions for this patient population, highlights the importance of optimizing non-pharmacological neuromodulatory treatments such as vagus nerve stimulation (VNS). Studies on the antidepressant effect of VNS in epilepsy patients may be confounded by concurrent anti-epileptic drug therapy. To date, studies in epilepsy models overcoming this problem are lacking. We investigated whether VNS affects anhedonia, a key symptom of major depression, in the kainic acid rat model for temporal lobe epilepsy. Anhedonia was assessed in kainic acid (KA) and saline (SAL) injected rats using the saccharin preference test (SPT). To exclude differences in taste perception, the quinine aversion test (QAT) was performed. Both groups were randomly subdivided in a VNS and a SHAM group, yielding 4 experimental arms: KA-VNS, KA-SHAM, SAL-VNS and SAL-SHAM. Both VNS groups received 2 weeks of VNS, while the SHAM groups were not stimulated. Thereafter, the SPT and QAT were repeated. Saccharin preference was significantly reduced in the KA compared to the SAL rats (P < 0.05), without differences in quinine aversion. Two weeks of VNS significantly increased the saccharin preference in the KA-VNS group (P < 0.05), while it had no effect on quinine aversion. No effects of VNS or SHAM were found in the other groups.

The KA rats displayed anhedonia which was significantly decreased by VNS, indicating that this neuromodulatory treatment could likewise diminish depressive symptoms in patients suffering from temporal lobe epilepsy and comorbid depression.

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Is epidermal growth factor receptor mutation associated with longer local control after definitive chemoradiotherapy in patients with stage III nonsquamous non-small-cell lung cancer?

To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non-small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT). Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse-free rate, initial relapse sites, and overall survival of the patients were investigated. A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficient specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR.

Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC.

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Is epidemic MRSA clone ST22-IV more resistant to multiple host- and environment-related stresses compared with ST228-I?

ST22-IV is a successful hospital-associated MRSA clone. Due to its known ability to replace other MRSA clones in hospitals, it became a dominant clone in Europe and beyond. So far, there are no studies investigating the relationship between the epidemiological success of MRSA clones and their capacity to withstand commonly encountered stresses. We investigated the fitness of ST22-IV in comparison with the replaced clone ST228-I, evaluating its resistance to oxidative stress, autolytic activity, growth at high osmolarity and in acid and alkaline environments and survival under desiccation and heat shock. We also compared their phenotypic characteristics and examined the impact of antibiotic consumption on epidemiological success. Here we demonstrate that the dominance of ST22-IV is linked neither to changes in antibiotic consumption nor to acquisition of additional resistances over time. Strong α-haemolysin activity, the production of β-haemolysin and the presence of an active agr could partly explain the virulence of ST22-IV previously observed in a murine model of pneumonia. Most importantly, we show that ST22-IV compared with ST228-I, besides retaining susceptibility to most antibiotics over time, has a superior capacity to survive under all stress conditions tested, which bacteria commonly face during their life cycle.

Our results support our hypothesis that ST22-IV has a fitness advantage over ST228-I. This fitness advantage could have allowed ST22-IV to displace ST228-I without acquiring additional resistances and could help explain its epidemic success in hospital settings and its spread in Europe and beyond.

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Is virological failure after 1 year of first-line ART associated with HIV minority drug resistance in rural Cameroon?

The aim of this study was to describe clinical and virological outcomes in therapy-naive HIV-1-positive patients treated in a routine ART programme in rural Cameroon. In a prospective cohort, 300 consecutive patients starting first-line ART were enrolled and followed for 12 months. Among 238 patients with available viral load data at Month 12, logistic regression was used to analyse risk factors for virological failure (≥1000 HIV RNA copies/mL) including clinical, immunological and virological parameters, as well as data on drug adherence. Population sequencing was performed to detect the presence of drug-resistance mutations in patients with virological failure at Month 12; minority drug-resistance mutations at baseline were analysed using next-generation sequencing in these patients and matched controls. At Month 12, 38/238 (16%) patients experienced virological failure (≥1000 HIV RNA copies/mL). Patients with virological failure were younger, had lower CD4 cell counts and were more often WHO stage 3 or 4 at baseline. Sixty-three percent of patients with virological failure developed at least one drug-resistance mutation. The M184V (n = 18) and K103N (n = 10) mutations were most common. At baseline, 6/30 patients (20%) experiencing virological failure and 6/35 (17%) matched controls had evidence of minority drug-resistance mutations using next-generation sequencing (P = 0.77). Lower CD4 count at baseline (OR per 100 cells/mm(3) lower 1.41, 95% CI 1.02-1.96, P = 0.04) and poorer adherence (OR per 1% lower 1.05, 95% CI 1.02-1.08, P < 0.001) were associated with a higher risk of virological failure. Unavailability of ART at the treatment centre was the single most common cause for incomplete adherence.

Virological failure after 1 year of ART was not associated with minority drug resistance at baseline but with incomplete adherence. Strategies to assure adherence and uninterrupted drug supplies are pivotal factors for therapy success.

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Is blood transfusion associated with recurrence of hepatocellular carcinoma after hepatectomy in Child-Pugh class A patients?

Previous reports have indicated an association between blood transfusion and prognosis of hepatocellular carcinoma (HCC) after hepatectomy. However, clinicopathological biases were not adjusted in these studies. We aimed to clarify the effect of blood transfusions in patients with HCC and Child-Pugh class A after hepatectomy by using inverse probability of treatment weighting (IPTW) analysis for selection bias control. We enrolled 479 patients with primary HCC and Child-Pugh class A retrospectively (91 transfused and 388 nontransfused patients) who underwent curative hepatectomy. After adjusting for different covariate distributions for both groups by IPTW, we analyzed the prognostic outcomes. In the unweighted analyses, overall survival (OS) rate of transfused patients was significantly lower than in nontransfused patients (P < 0.0001). Recurrence-free survival (RFS) rate of transfused patients was significantly lower than that of nontransfused patients (P = 0.0024). Multivariate analysis showed that blood transfusion was an independent prognostic factor of OS and RFS. The different distributive covariates between the two groups were age, presence of liver cirrhosis, serum level of alpha-fetoprotein, maximum tumor diameter, and amount of intraoperative blood loss. After IPTW by these covariates, OS rate of transfused patients was not significantly lower than those of nontransfused patients, whereas RFS rate of transfused patients remained significantly lower than those of nontransfused patients (P = 0.038, adjusted HR 1.45; 95% CI 1.0-2.1).

These results suggest that blood transfusion was associated with recurrence of HCC after hepatectomy in patients with HCC and Child-Pugh class A.

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Does transcutaneous oxygen tension measurements following peripheral transluminal angioplasty procedure have more specificity and sensitivity than ankle brachial index?

To evaluate the superiority of transcutaneous oxygen pressure (TcPO2) before, during and after peripheral transluminal angioplasty (PTA) in comparison with ankle brachial index (ABI) in patients with diabetes. 40 consecutive patients with diabetes treated by PTA where included. This study shows results before, during and after PTA and their progression for 8 weeks. The TcPO2 increased from 28.11 ± 8.1 to 48.03 ± 8.4 mmHg, 8 weeks after PTA (p < 0.001). The ABI increased from 0.48 ± 0.38 to 0.77 ± 0.39 after PTA (p < 0.001). After PTA, the stenosis of the vessel decreased from 58.33 ± 20.07% to 21.87 ± 13.57% (p < 0.001). TcPO2 was determined in all the patients, but ABI could not be determined in all patients. Furthermore, we determined patients with "false negatives" with an improvement in ABI and "false positives" in 12.5% of patients. Additionally, in this study, we monitored TcPO2 while performing PTA, revealing variations in each phase of the radiological procedure.

The increase in TcPO2 measurements following PTA procedure has more specificity and sensitivity than does ABI. The use of TcPO2 may represent a more accurate alternative than traditional methods (ABI) used in assessing PTA results. The TcPO2 also allows the radiologist to assess changes in tissue oxygenation during PTA, allowing changes to the procedure and subsequent treatment.

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