Datasets:

vblagoje

/

PubMedQA_instruction

like 5

Does long non-coding RNA ANRIL promote the invasion and metastasis of thyroid cancer cells through TGF-β/Smad signaling pathway?

To investigate the effect of antisense non-coding RNA in the INK4 locus (ANRIL) on invasion and metastasis of thyroid cancer (TC). ANRIL expression was significantly up-regulated in TC tissues and cells (P < 0.001), and ANRIL expression was significantly different regarding histological grade and LNM (both P < 0.01). The siRNA-mediated ANRIL silencing inhibits proliferation, invasion, and metastasis of TPC-1 and SW579 cells, and lung metastasis, which can be reversed by TGF-β1 siRNA. The mRNA levels of p15INK4b, p14ARF and p16INK4a in TPC-1 and SW579 cells increased significantly after silencing ANRIL (all P < 0.001), and TGF-β1 siRNA could reverse the ANRIL siRNA induced increase of p15INK4b; expressions of TGF-β1 and p-Smad2/3 were increased after silencing ANRIL (both P < 0.05). TC and adjacent normal tissues were collected from 105 TC patients. LncRNA ANRIL expressions were detected by qRT-PCR. The siRNA ANRIL and siRNA TGF-β1 were constructed for TPC-1 and SW579 cell line transfection: si-ANRIL group, si-TGF-β1 group, si-ANRIL + si-TGF-β1 group, negative control group and blank group. Effects of ANRIL silencing on proliferation, invasion and metastasis of TC cells was detected by MTT assay, Transwell assay and tail vein injection of nude mice in vitro and in vivo. TGF-β1 and p-Smad2/3 expressions in TGF-β/Smad signaling pathway were detected by western blot.

ANRIL may reduce p15INK4B expression through inhibiting TGF-β/Smad signaling pathway, promoting invasion and metastasis of TC cells, and the silencing of ANRIL inhibits the invasion and metastasis of TPC-1 cells.

closed_qa

Does tollip SNP rs5743899 modulate human airway epithelial responses to rhinovirus infection?

Rhinovirus (RV) infection in asthma induces varying degrees of airway inflammation (e.g. neutrophils), but the underlying mechanisms remain unclear. The major goal was to determine the role of genetic variation [e.g. single nucleotide polymorphisms (SNPs)] of Toll-interacting protein (Tollip) in airway epithelial responses to RV in a type 2 cytokine milieu. DNA from blood of asthmatic and normal subjects was genotyped for Tollip SNP rs5743899 AA, AG and GG genotypes. Human tracheobronchial epithelial (HTBE) cells from donors without lung disease were cultured to determine pro-inflammatory and antiviral responses to IL-13 and RV16. Tollip knockout and wild-type mice were challenged with house dust mite (HDM) and infected with RV1B to determine lung inflammation and antiviral response. Asthmatic subjects carrying the AG or GG genotype (AG/GG) compared with the AA genotype demonstrated greater airflow limitation. HTBE cells with AG/GG expressed less Tollip. Upon IL-13 and RV16 treatment, cells with AG/GG (vs. AA) produced more IL-8 and expressed less antiviral genes, which was coupled with increased NF-κB activity and decreased expression of LC3, a hallmark of the autophagic pathway. Tollip co-localized and interacted with LC3. Inhibition of autophagy decreased antiviral genes in IL-13- and RV16-treated cells. Upon HDM and RV1B, Tollip knockout (vs. wild-type) mice demonstrated higher levels of lung neutrophilic inflammation and viral load, but lower levels of antiviral gene expression.

Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma.

closed_qa

Do logic models help make sense of complexity in systematic reviews and health technology assessments?

To describe the development and application of logic model templates for systematic reviews and health technology assessments (HTAs) of complex interventions. This study demonstrates the development of a method to conceptualize complexity and make underlying assumptions transparent. Examples from systematic reviews with specific relevance to Sub-Saharan Africa (SSA) and other low- and middle-income countries (LMICs) illustrate its usefulness. Two distinct templates are presented: the system-based logic model, describing the system in which the interaction between participants, intervention, and context takes place; and the process-orientated logic model, which displays the processes and causal pathways that lead from the intervention to multiple outcomes.

Logic models can help authors of systematic reviews and HTAs to explicitly address and make sense of complexity, adding value by achieving a better understanding of the interactions between the intervention, its implementation, and its multiple outcomes among a given population and context. They thus have the potential to help build systematic review capacity-in SSA and other LMICs-at an individual level, by equipping authors with a tool that facilitates the review process; and at a system-level, by improving communication between producers and potential users of research evidence.

closed_qa

Do infant and young child feeding practices differ by ethnicity of Vietnamese mothers?

Limited studies have examined ethnic variation in breastfeeding and complementary feeding practices in developing countries. This study investigated ethnic variation in feeding practices in mothers with children 0-23 months old in Vietnam. We used data on 1875 women who came from the ethnic majority, Kinh (n = 989, randomly sampled from 9875 surveyed Kinh mothers, 10 % from each province) and three ethnic minorities: E De-Mnong (n = 309), Thai-Muong (n = 229) and Tay-Nung (n = 348). Ethnic minorities were compared with the Kinh group using logistic regression model. Prevalence of breastfeeding initiation within an hour of birth was 69 % in Thai-Muong, but ~50 % in other ethnicities. In logistic regression, the prevalence of breastfeeding within one hour was lower in Tay-Nung (OR: 0.54; 95 % CI: 0.38, 0.77) than the majority Kinh. Prevalence of exclusive breastfeeding under 6 months was 18, 10, 17, and 33 % in Kinh, Thai-Muong, Tay-Nung, and E De-Mnong, respectively; compared to the majority Kinh, the prevalence was lower in Thai-Muong (OR: 0.42; 95 % CI: 0.25, 0.71) and higher in E De-Mnong (OR: 1.99; 95 % CI: 1.04, 3.82). Overall prevalence of bottle feeding in Thai-Muong and E De-Mnong (~20 %) was lower than in Kinh (~33 %): Thai-Muong (OR: 0.50; 95 % CI: 0.37, 0.68) and E De-Mnong (OR: 0.69; 95 % CI: 0.50, 0.95). Compared with Kinh (75 %), fewer ethnic minority children received minimum acceptable diets (33 % in Thai-Muong, 46 % in E De-Mnong, and 52 % in Tay-Nung; P < 0.05). Prevalence of minimum acceptable diet (met both dietary frequency and diversity) was lower in Thai-Muong (OR: 0.23; 95 % CI: 0.11, 0.46), Tay-Nung (OR: 0.52; 95 % CI: 0.39, 0.69), and E De-Mnong (OR: 0.55; 95 % CI: 0.33, 0.89) than the majority Kinh.

Breastfeeding practices were suboptimal and differed by ethnicity, which suggests need for tailored interventions at multiple levels to address ethnic-specific challenges and norms. Complementary feeding practices were less optimal among ethnic minorities compared to Kinh, which suggests need for broad intervention including improved food availability, accessibility, and security.

closed_qa

Does two Hours of Teamwork Training improve Teamwork in Simulated Cardiopulmonary Arrest Events?

Teamwork during cardiopulmonary arrest events is important for resuscitation. Teamwork improvement programs are usually lengthy. This study assessed the effectiveness of a 2-hour teamwork training program. A prospective, pretest/posttest, quasi-experimental design assessed the teamwork training program targeted to resident physicians, nurses, and respiratory therapists. Participants took part in a simulated cardiac arrest. After the simulation, participants and trained observers assessed perceptions of teamwork using the Team Emergency Assessment Measure (TEAM) tool (ratings of 0 [low] to 4 [high]). A debriefing and 45 minutes of teamwork education followed. Participants then took part in a second simulated cardiac arrest scenario. Afterward, participants and observers assessed teamwork. Seventy-three team members participated-resident physicians (25%), registered nurses (32%), and respiratory therapists (41%). The physicians had significantly less experience on code teams (P < .001). Baseline teamwork scores were 2.57 to 2.72. Participants' mean (SD) scores on the TEAM tool for the first and second simulations were 3.2 (0.5) and 3.7 (0.4), respectively (P < .001). Observers' mean (SD) TEAM scores for the first and second simulations were 3.0 (0.5) and 3.7 (0.3), respectively (P < .001). Program evaluations by participants were positive.

A 2-hour simulation-based teamwork educational intervention resulted in improved perceptions of teamwork behaviors. Participants reported interactions with other disciplines, teamwork behavior education, and debriefing sessions were beneficial for enhancing the program.

closed_qa

Are specific patterns of laryngeal electromyography during wakefulness associated to sleep disordered breathing and nocturnal stridor in multiple system atrophy?

Nocturnal stridor and respiratory abnormalities are important features of multiple system atrophy (MSA) with relevance to patient survival, and they are detected and evaluated mainly through video-polysomnography (video-PSG). Diurnal laryngoscopy seems to yield abnormal findings only in the presence of significant vocal cord (VC) dysfunction. To assess whether specific electrophysiological patterns of diurnal EMG of VC muscles may indicate nocturnal stridor or respiratory dysfunctions in MSA patients. Seventeen patients with probable MSA were examined. A full-night video-PSG to collect standard breathing parameters (apnea/hypopnea index, mean HbSAO Both the laryngeal EMG abnormalities (based on MUAP analysis and kinesiologic EMG investigation of VC muscles) and the laryngoscopic alterations correlated with video-PSG respiratory abnormalities. Specific patterns of EMG findings were consistently found in MSA subjects with nocturnal stridor detected at PSG. In particular, the following EMG findings were related to the severity of breathing abnormalities and the presence of stridor on video-PSG: neurogenic pattern on MUAP analysis of the PCA, paradoxical activation of the TA during inspiration and tonic EMG activity of the TA during quiet breathing.

Electromyographic/kinesiologic investigation of VC muscles during wakefulness provides additional information on the pathophysiology of the respiratory abnormalities in MSA patients that could be useful for guiding the choice of the best appropriate treatment and care.

closed_qa

Does local brain activity persist during apparently generalized postictal EEG suppression?

Postictal generalized EEG suppression (PGES) frequently occurs after generalized convulsive seizures (GCS) and may be involved in the pathophysiology of sudden unexpected death in epilepsy (SUDEP). It is usually determined using conventional scalp EEG which is likely to miss cerebral activity in deeper brain structures. Here, we examined intracranial EEG activity after GCS to unravel the pattern and extent of local brain activity during apparent PGES on scalp EEG (s-PGES). We retrospectively reviewed electroencephalographic data of people with chronic epilepsy who had GCS during presurgical video-EEG monitoring using simultaneous intracranial and scalp EEG (10-20 system) electrodes. Twenty-five GCS (20 with s-PGES) of 15 patients with an average number of 88±42 intracranial electrode contacts were included. The majority of GCS with s-PGES (18 of 20) displayed persisting or reemerging intracranial EEG activity during apparent PGES on scalp EEG. Three patterns were identified: Pattern 1 (11 GCS, 6 patients) consisted of continuous local interictal activity; Pattern 2 (5 GCS, 5 patients) displayed suppressed EEG activity at all intracranial contacts in the early phase of s-PGES, but reemerging local brain activity before s-PGES dissolved; and Pattern 3 (2 GCS, 2 patients) showed persistent local ictal activity during s-PGES. Persisting intracranial EEG activity at PGES onset on scalp EEG was present in 10±14% (range: 0 to 42%) of all intracranial contacts and mostly in the temporal lobe.

Our results reveal that, during apparently generalized postictal EEG suppression, local brain activity persists or reemerges in most GCS. Possible implications of this localized neuronal activity in the context of SUDEP are discussed in the paper.

closed_qa

Does interictal epileptic discharge correlate with global and frontal cognitive dysfunction in temporal lobe epilepsy?

Temporal lobe epilepsy (TLE) with hippocampal sclerosis has widespread effects on structural and functional connectivity and often entails cognitive dysfunction. EEG is mandatory to disentangle interactions in epileptic and physiological networks which underlie these cognitive comorbidities. Here, we examined how interictal epileptic discharges (IEDs) affect cognitive performance. Thirty-four patients (right TLE=17, left TLE=17) were examined with 24-hour video-EEG and a battery of neuropsychological tests to measure intelligence quotient and separate frontal and temporal lobe functions. Hippocampal segmentation of high-resolution T1-weighted imaging was performed with FreeSurfer. Partial correlations were used to compare the number and distribution of clinical interictal spikes and sharp waves with data from imagery and psychological tests. The number of IEDs was negatively correlated with executive functions, including verbal fluency and intelligence quotient (IQ). Interictal epileptic discharge affected cognitive function in patients with left and right TLE differentially, with verbal fluency strongly related to temporofrontal spiking. In contrast, IEDs had no clear effects on memory functions after corrections with partial correlations for age, age at disease onset, disease duration, and hippocampal volume.

In patients with TLE of long duration, IED occurrence was strongly related to cognitive deficits, most pronounced for frontal lobe function. These data suggest that IEDs reflect dysfunctional brain circuitry and may serve as an independent biomarker for cognitive comorbidity.

closed_qa

Is intensity-Modulated Radiation Therapy Associated with Perioperative or Survival Benefit over 3D-Conformal Radiotherapy for Rectal Cancer?

The use of intensity-modulated radiation therapy (IMRT) in rectal cancer has steadily increased over traditional 3D conformal radiotherapy (3D-CRT) due to perceived benefit of delivering higher treatment doses while minimizing exposure to surrounding tissues. However, IMRT is technically challenging and costly, and its effects on rectal cancer outcomes remain unclear. Adults with clinical stage II and III rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy with 45-54 Gy of radiation and surgery were included from the 2006-2013 National Cancer Data Base. Patients were grouped based the modality of radiation received: IMRT or 3D-CRT. Multivariable regression modeling adjusting for demographic, clinical, and treatment characteristics was used to examine the impact of IMRT vs. 3D-CRT on pathologic downstaging, resection margin positivity, sphincter loss surgery, 30-day unplanned readmission and mortality after surgery, and overall survival. Among 7386 patients included, 3330 (45 %) received IMRT and 4056 (55 %) received 3D-CRT. While the mean radiation dose delivered was higher with IMRT (4735 vs. 4608 cGy, p < 0.001), it was associated with higher risks of positive margins (adjusted odds ratio (OR) 1.57; p < 0.001) and sphincter loss surgery (OR 1.32; p < 0.001). There were no differences between IMRT and 3D-CRT in the likelihood of pathologic downstaging (OR 0.89, p = 0.051), unplanned readmission (OR 0.79; p = 0.07), or 30-day mortality (OR 0.61; p = 0.31) after surgery. Additionally, there were no differences in overall survival at 8 years (IMRT vs. 3D-CRT: 64 vs. 64 %; adjusted hazard ratio 1.06, p = 0.47).

IMRT is associated with worse local tumor control without any long-term survival benefit for patients with locally advanced rectal cancer. Given the lack of significant advantage and the higher cost of IMRT, caution should be exercised when using IMRT instead of traditional 3D-CRT for rectal cancer.

closed_qa

Do statin drugs decrease progression to cirrhosis in HIV/HCV co-infected individuals?

Chronic HIV/HCV co-infection carries increased risk of cirrhosis, hepatocellular carcinoma, and death. Due to anti-inflammatory properties, HMG co-A inhibitors (statins) may be useful adjunctive therapy to reduce liver disease progression. Clinical information was extracted from the Veterans Affairs HIV and HCV Clinical Case Registries (1999 - 2010). HIV-related variables included combination anti-retroviral therapy (cART) era of diagnosis, CD4 cell count, and percent time with undetectable HIV viral load. Metabolic variables included diabetes, low-HDL, and hypertension. Statin use was measured as percent time with active prescription (time-updated throughout the follow-up period). Cox proportional hazards analysis was used to determine risk factors for cirrhosis (ICD-9 or APRI>2) overall and in groups stratified by alanine aminotransferase (ALT) level above and below 40 IU/L. The cohort included 5985 HIV/HCV co-infected veterans. The majority was black race, and the mean age at index date was 45 years. Statin use was significantly protective of cirrhosis for patients with ALT ≤40 IU/L; for every 30% increase in time on statin, there was a 32% decreased risk of developing cirrhosis (HR 0.68, 95% CI 0.47 -0.98). Diabetes and low-HDL were significantly associated with cirrhosis in patients with ALT > 40 IU/L (HR 1.15, p < 0.04 and HR 1.3, p < 0.0001).

Statin drug use is beneficial in mitigating the risk of liver disease progression for HIV/HCV co-infected patients without advanced liver disease. Low-HDL and diabetes in co-infected patients with abnormal ALT have greater risk of cirrhosis development.

closed_qa

Does students ' Interest in Surgery affect Laparoscopic Practicing Performance?

Earlier exposure to laparoscopic techniques is thought to be beneficial for medical students. Reports have demonstrated that practice improves performance in laparoscopies. In this study, we intended to evaluate whether medical students' interest in surgery is affected by the amount of practice and the performance on a laparoscopic simulator. A laparoscopic simulation curriculum was introduced at Taipei Medical University, Wan-Fang Medical Center. Study participants included 36 sixth-year and 14 seventh-year students who were divided according to whether they had indicated an interest (group A) or not (group B) in surgery. The students had twice-a-week practice sessions for 2 weeks. They underwent baseline measurement (BM) before training and posttraining measurement (PTM). Self-guided practice on the simulator was allowed. The learning outcomes were assessed comparing the BM and PTM scores by using the interquartile range (IQR) test. We also tested the correlation between total score and number of self-guided practice sessions. All study participants showed improvement. No differences were observed between BM and PTM scores and between 6th- and 7th-year medical students. Significant differences were found in PTM scores between groups A and B (P < .001). Analysis of variance with a post hoc test for different groups revealed that the PTMs were significantly higher for both the 6th- and 7th-year medical students in group A than for those in group B (P < .001). Total performance scores were improved with a higher number of self-guided practice sessions. Linear regression analysis demonstrated a significant correlation between the number of self-guided practice sessions and total performance score (P < .001).

Those clerks and interns interested in surgery who had more sessions for self-guided practice, displayed more improvement than those not interested in surgery did. Improvement in performance correlated highly with trainees' number of self-guided practice sessions.

closed_qa

Does wnt/Beta-Catenin Signal Inhibitor HC-1 sensitize Oral Squamous Cell Carcinoma Cells to 5-Fluorouracil through Reduction of CD44-Positive Population?

Oral squamous cell carcinoma is a prevalent and frequently lethal malignancy worldwide. Existence of treatment-resistant cancer stem cells is considered to be associated with tumor formation, recurrence and metastasis. Wnt/beta-catenin signal is one of the crucial signaling pathways for cancer stem cells. Wnt/beta-catenin signal inhibitor may reduce the population of cancer stem cells and improve therapeutic effects on the cancers. The effects of three derivatives of Wnt/beta-catenin signal inhibitors, HC-1, IC-2 and PN3-13, which we recently developed, on oral squamous cell carcinoma cell line HSC2, were examined by luciferase reporter assay, WST assay, cell sorting assay and apoptosis assay. The reporter assay showed that these small molecule compounds reduced Wnt/beta-catenin transcriptional activity in HSC2 cells. Of these compounds, IC-2 and PN3-13 inhibited cell viability in a dose-dependent manner, whereas HC-1 did not at even higher concentrations. Notably, however, the cell-sorting assay revealed that HC-1 significantly reduces the CD44-positive population of oral squamous cell carcinoma cells, compared to other compounds without affecting cell viability. In addition, HC-1 increases the cytotoxicity of HSC2 cells to 5-fluorouracil. The combination treatment of HC-1 with 5-fluorouracil significantly increased the apoptotic cells whereas treatment by either compound did not.

These data suggest that HC-1 is an effective compound to target cancer stem cells, and the combination treatment of HC-1 and 5-fluorouracil can stimulate the tumor suppressive effect on oral squamous cell carcinoma cells.

closed_qa

Does transcriptome analysis in oak uncover a strong impact of endogenous rhythmic growth on the interaction with plant-parasitic nematodes?

Pedunculate oak (Quercus robur L.), an important forest tree in temperate ecosystems, displays an endogenous rhythmic growth pattern, characterized by alternating shoot and root growth flushes paralleled by oscillations in carbon allocation to below- and aboveground tissues. However, these common plant traits so far have largely been neglected as a determining factor for the outcome of plant biotic interactions. This study investigates the response of oak to migratory root-parasitic nematodes in relation to rhythmic growth, and how this plant-nematode interaction is modulated by an ectomycorrhizal symbiont. Oaks roots were inoculated with the nematode Pratylenchus penetrans solely and in combination with the fungus Piloderma croceum, and the systemic impact on oak plants was assessed by RNA transcriptomic profiles in leaves. The response of oaks to the plant-parasitic nematode was strongest during shoot flush, with a 16-fold increase in the number of differentially expressed genes as compared to root flush. Multi-layered defence mechanisms were induced at shoot flush, comprising upregulation of reactive oxygen species formation, hormone signalling (e.g. jasmonic acid synthesis), and proteins involved in the shikimate pathway. In contrast during root flush production of glycerolipids involved in signalling cascades was repressed, suggesting that P. penetrans actively suppressed host defence. With the presence of the mycorrhizal symbiont, the gene expression pattern was vice versa with a distinctly stronger effect of P. penetrans at root flush, including attenuated defence, cell and carbon metabolism, likely a response to the enhanced carbon sink strength in roots induced by the presence of both, nematode and fungus. Meanwhile at shoot flush, when nutrients are retained in aboveground tissue, oak defence reactions, such as altered photosynthesis and sugar pathways, diminished.

The results highlight that gene response patterns of plants to biotic interactions, both negative (i.e. plant-parasitic nematodes) and beneficial (i.e. mycorrhiza), are largely modulated by endogenous rhythmic growth, and that such plant traits should be considered as an important driver of these relationships in future studies.

closed_qa

Is reactive hyperemia associated with adverse clinical outcomes in heart failure?

Impaired endothelial function, as assessed by brachial artery flow-mediated dilation (FMD), is an established risk factor for cardiovascular events. FMD is impaired in heart failure (HF) patients, but less is known about hyperemic brachial artery flow. We investigated the relationship between FMD and hyperemic flow with adverse clinical outcomes in HF patients. Brachial artery FMD and hyperemic flow were assessed in 156 patients (70.5 % Male; 45.5% Caucasian; mean age (± SD) = 56.2 (±12.4) years) with HF and reduced left ventricular ejection fraction (LVEF). Cox proportional hazard models were used to assess the potential explanatory association of FMD and hyperemic flow with the composite outcome of death or cardiovascular hospitalization over a median 5-year follow-up period. Both FMD and hyperemic flow were negatively correlated with age, but unrelated to sex, race, body mass index, LVEF or N-terminal pro-B-Type natriuretic peptide (NT-ProBNP). Reduced hyperemic flow, but not FMD, was associated with an increased risk of death or cardiac hospitalization after controlling for traditional risk factors.

The association of reduced hyperemic flow with increased risk of adverse clinical outcomes suggests that micro-vascular function may be an important prognostic marker in patients with HF.

closed_qa

Is renal assessment using CKD-EPI equation useful as an early predictor of contrast- induced nephropathy in elderly patients with cancer?

To assess respective roles of serum creatinine (SCr) alone and estimated glomerular filtration rate (eGFR) as an early predictor for contrast-induced nephropathy (CIN) in elderly patients with cancer. eGFR of 348 patients at 65years or older with malignancy who underwent contrast-enhanced computed tomography (CECT) were calculated. eGFR was calculated based on the following three equations: Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI); Modification of Diet in Renal Disease Study (MDRD); Cockcroft-Gault (CG). CIN was subdivided into two groups: CIN After CECT, CIN occurred in 50 (14.4%) patients, including 33 CIN

In elderly patients with cancer who visit the emergency department, renal assessment before CECT using CKD-EPI equation was superior to SCr alone, MDRD equation, or CG formula in predicting the occurrence of CIN related CECT.

closed_qa

Is combined Use of Bivalirudin and Radial Access in Acute Coronary Syndromes Superior to the Use of Either One Separately : Meta-Analysis of Randomized Controlled Trials?

The aim of this meta-analysis was to study the relation between access site and bivalirudin use on outcomes in patients with acute coronary syndrome (ACS). Bivalirudin and radial access use are 2 strategies that are increasingly used to lower major bleeding in patients with ACS undergoing invasive approaches. The interaction between these 2 strategies and the benefit of using them in combination are unclear. This analysis included randomized controlled trials that compared bivalirudin to heparin with or without glycoprotein IIb/IIIa inhibitors in patients with ACS and reported outcomes stratified by arterial access site. Meta-analyses of outcome data were performed on the basis of access site and anticoagulation regimen. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from event rates using random-effects models. Eight trials with a total of 27,491 patients were included. Bivalirudin reduced major bleeding risk in patients with femoral access (OR: 0.51; 95% CI: 0.46 to 0.6; p < 0.001) but not in patients with radial access (OR: 0.75; 95% CI: 0.45 to 1.26; p = 0.28). Moreover, radial access reduced major bleeding risk in patients treated with heparin (OR: 0.57; 95% CI: 0.43 to 0.77; p < 0.001) but not in patients treated with bivalirudin (OR: 0.96; 95% CI: 0.65 to 1.41; p = 0.83). There were no differences in major adverse cardiovascular events or all-cause mortality between bivalirudin and heparin, regardless of access site.

Bivalirudin reduces bleeding risk only with femoral access, and radial access reduces bleeding risk only with heparin anticoagulation. Therefore, there is no additional benefit to the combined use of bivalirudin and radial access strategies in patients with ACS.

closed_qa

Do cancer Patients Are at High Risk of Mortality if Presenting with Sepsis at an Emergency Department?

Sepsis is an emergency condition with high mortality and morbidity rate. There are limited data on the association of cancer as a risk factor for mortality in sepsis patients in the emergency department (ED). This retrospective study was conducted at the ED, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand. The study period was between January 1st and December 31st, 2014. The inclusion criteria were as follows: adult patients over 15 years of age who presented at the ED with suspicion of sepsis, received treatment at the ED, and whose blood culture was found to be positive. Clinical data were recorded from medical records including the Mortality in Emergency Department Sepsis score (MEDS score). The primary outcome of this study was mortality at one month. Multivariate logistic regression analysis was used to identify independent factors associated with death. During the study period, there were 775 eligible patients. The two most common pathogens identified from blood cultures were Staphylococcus aureus (193 patients; 24.9%) and Escherichia coli (158 patients; 20.4%). At one month after presenting at the ED, 110 patients (14.2%) had died. There were four significant factors for death, having cancer, being on an endotracheal tube, initial diagnosis of bacteremia, and high MED scores. Having cancer had an adjusted OR of 2.12 (95% CI of 1.29, 3.47).

Cancer patients have double the risk of mortality if presenting with sepsis at the ED.

closed_qa

Does gT-repeat length polymorphism in heme oxygenase-1 promoter determine the effect of cilostazol on vascular smooth muscle cells?

Cilostazol, a potent type 3 phosphodiesterase inhibitor, is found to reduce neointimal formation by inhibiting vascular smooth muscle cell (VSMC) proliferation. The aim of this study is to investigate whether the inhibitory effect of cilostazol on VSMC proliferation is operated via heme oxygenase-1 (HO-1). In rat carotid arteries, cilostazol up-regulated HO-1 in the neointima of balloon-injured arteries. Treatment of human VSMCs with cilostazol enhanced the expression of HO-1, which was mainly regulated at the transcriptional level. Small interfering RNA knock-down of HO-1 attenuated the inhibitory effect of cilostazol on VSMC proliferation, suggesting the critical role of HO-1 in cilostazol effect. The transcriptional responsiveness of HO-1 to cilostazol was inversely correlated with the length of GT-repeat in human HO-1 promoter. Deletion and mutational analysis of HO-1 promoter along with chromatin immunoprecipitation showed that cyclic AMP response element (CRE)-binding protein (CREB) participated in cilostazol-induced HO-1 transcription. Furthermore, cilostazol triggered a linkage between the CRE and GT-repeat regions in the HO-1 promoter. The promoting effect of cilostazol on HO-1 expression, proliferation inhibition, and chromatin conformation in the HO-1 promoter was greater in VSMCs from subjects with shorter GT-repeat alleles than those with longer alleles.

Cilostazol inhibits VSMC proliferation involving an association between CREB and HO-1. The length polymorphism of GT-repeat in human HO-1 promoter determines the effect of cilostazol.

closed_qa

Does mindfulness-based Intervention Influence Cardiac Autonomic Control or Pattern of Physical Activity in Fibromyalgia During Daily Life : An Ambulatory , Multi-measure Randomized Controlled Trial?

Fibromyalgia is a syndrome characterized by severe pain, fatigue and sleep disturbance. There is evidence of central hyper-responsiveness to sensory stimulation and impaired cardiovascular autonomic control. Laboratory investigations suggest that mindfulness-based stress reduction (MBSR) may improve autonomic functioning in fibromyalgia. However, these findings may not reflect what occurs during naturalistic conditions, and MBSR studies during real-life functioning are lacking. We conducted a randomized controlled, 3-armed study with 168 female FM patients. This report describes cardiac, respiratory and physical activity findings. Eight-week MBSR was compared to wait-list and to active control intervention. Ambulatory accelerometry and cardiorespiratory function were monitored over 24-h periods at 3 time-points: pre- and post-intervention, and 8-week follow-up. Also baseline levels were compared with an age-matched group of 33 healthy women. Activity, heart rate, respiratory sinus arrhythmia and ventilation were measured. Comparison with controls confirmed differences in cardiac autonomic tone and activity pattern among patients. Most measures also showed effects of time-of-day and point of measurement. There were no effects of treatment. Additionally, there were no relations between patient-reported clinical improvement and objective physiological or accelerometry parameters. Intervention-related benefits in wellbeing were not associated with changes in daytime cardiorespiratory measures or pattern of physical activity.

MBSR did not produce cardiac autonomic benefits or changes in daily activity in fibromyalgia. Furthermore, lack of association between patient-experienced clinical improvement and objective autonomic measures suggests subjective changes in wellbeing among fibromyalgia patients over time are not related to alterations in cardiorespiratory autonomic function or activity levels.

closed_qa

Is leukocyte-poor platelet-rich plasma more effective than the conventional therapy with acetaminophen for the treatment of early knee osteoarthritis?

Knee osteoarthritis (OA) is a degenerative and progressive articular cartilage disease. Infiltration of autologous platelet-rich plasma (PRP) has been proposed as a therapeutic alternative due to the content of biologically active cytokines in PRP. We aimed to compare the clinical response of acetaminophen and intra-articular leukocyte-poor PRP (LP-PRP) in early knee OA. A total of 65 patients with clinically and radiographically documented knee OA (grade 1-2) were analyzed. Patients were randomized into two groups: 32 were treated with acetaminophen (500 mg/8 h) over 6 weeks, and 33 received three intra-articular injections of autologous LP-PRP (once every 2 weeks). All patients were evaluated by the Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities (WOMAC) score, and the SF-12 health survey at baseline and 6, 12, and 24 weeks of follow-up. All LP-PRP preparations were analyzed for the platelet, leukocyte, IL-1ra, and TGF-β concentrations. The decrease in the VAS pain level in the LP-PRP group was greater than that in the acetaminophen group (p < 0.05). Patients treated with LP-PRP showed a sustained improvement in knee function at week 24 (p < 0.01). The SF-12 results only indicated an improvement in quality-of-life in the LP-PRP group at 6, 12, and 24 weeks of follow-up (p < 0.01). Both IL-1ra and TGF-β were detected in the LP-PRP samples (313.8 ± 231.6 and 21,183.8 ± 8556.3 pg/mL, respectively).

Treatment with LP-PRP injections resulted in a significantly better clinical outcome than did treatment with acetaminophen, with sustained lower EVA and WOMAC scores and improvement in quality-of-life (higher SF-12 score). Therapy with LP-PRP may positively modify the inflammatory joint environment by counteracting IL-1β action.

closed_qa

Is gene and Protein Expression of Chemokine ( C-C-Motif ) Ligand 19 Upregulated in Unstable Carotid Atherosclerotic Plaques?

The aim was to investigate the expression of genes associated with carotid plaque instability and their protein products at a local and systemic level. Carotid plaques from 24 patients undergoing carotid endarterectomy (CEA) were classified as stable or unstable using clinical, histological, ultrasound, and transcranial Doppler criteria, and compared using whole genome microarray chips. Initial results of differentially expressed genes were validated by quantitative reverse transcriptase polymerase chain reaction in an independent group of 96 patients undergoing CEA. The protein product of genes significantly differentially expressed between patients with stable and unstable plaques were analysed by plaque immunohistochemistry and serum protein quantification by enzyme-linked immunosorbent assay on a further independent cohort. Expression of chemokine (c-c-motif) ligand 19 (CCL19) was significantly upregulated in plaques from patients with clinically unstable disease (p < .001). Cathepsin G expression was upregulated in histologically unstable plaques (p = .04). Serum concentration of CCL19 was significantly higher in patients with clinically unstable plaques (p = .02). Immunohistochemical staining for CCL19 demonstrated positive staining in histologically and clinically unstable plaques (p = .03). CCL19 also co-localised with CD3

CCL19 is significantly overexpressed in patients with unstable carotid atherosclerotic plaques and may be a possible novel biomarker for identifying high-risk patients in whom more urgent intervention may be indicated.

closed_qa

Do socioeconomic Risk Adjustment Models for Reimbursement Are Necessary in Primary Total Joint Arthroplasty?

Alternative payment models, such as bundled payments, aim to control rising costs for total knee arthroplasty (TKA) and total hip arthroplasty (THA). Without risk adjustment for patients who may utilize more resources, concerns exist about patient selection and access to care. The purpose of this study was to determine whether lower socioeconomic status (SES) was associated with increased resource utilization following TKA and THA. Using the Michigan Arthroplasty Registry Collaborative Quality Initiative database, we reviewed a consecutive series of 4168 primary TKA and THA patients over a 3-year period. We defined lowest SES based upon the median household income of the patient's ZIP code. Demographics, medical comorbidities, length of stay, discharge destination, and readmission rates were compared between patients of lowest SES and higher SES. Patients in the lowest SES group had a longer hospital length of stay (2.79 vs 2.22 days, P < .001), were more likely to be discharged to a rehabilitation facility (27% vs 18%, P < .001), and be readmitted to the hospital within 90 days (11% vs 8%, P = .002) than the higher SES group. Multivariate analysis revealed that lowest SES was an independent risk factor for all 3 outcome variables (all P < .001).

Patients in the lowest SES group utilize more resources in the 90-day postoperative period. Therefore, risk adjustment models, including SES, may be necessary to fairly compensate hospitals and surgeons and to avoid potential problems with access to joint arthroplasty care.

closed_qa

Does antibiotic-Induced Gut Microbiota Disruption decrease TNF-α Release by Mononuclear Cells in Healthy Adults?

Broad-spectrum antibiotics disrupt the intestinal microbiota. The microbiota is essential for physiological processes, such as the development of the gut immune system. Recent murine data suggest that the intestinal microbiota also modulates systemic innate immune responses; however, evidence in humans is lacking. Twelve healthy young men were given oral broad-spectrum antibiotics (ciprofloxacin 500 mg bid, vancomycin 500 mg tid and metronidazole 500 mg tid) for 7 days. At baseline, 1 day, and 6 weeks after antibiotics, blood and feces were sampled. Whole blood and isolated mononuclear cells were stimulated with selected Toll-like receptor agonists and heat-killed bacteria. Microbiota diversity and composition was determined using bacterial 16S rDNA sequencing. One day after the antibiotic course, microbial diversity was significantly lower compared with baseline. After antibiotic therapy, systemic mononuclear cells produced lower levels of tumor necrosis factor (TNF)-α after ex vivo stimulation with lipopolysaccharide (LPS). This diminished capacity to produce TNF-α was restored 6 weeks after cessation of antibiotic therapy. In whole blood, a reduced capacity to release interleukin (IL)-1β and IL-6 was observed after LPS stimulation. Antibiotic treatment did not impact on differential leukocyte counts, phagocytosis, and cell surface markers of neutrophils and monocytes.

In this proof-of-principle study of healthy subjects, microbiota disruption by broad-spectrum antibiotics is reversibly associated with decreased systemic cellular responsiveness towards LPS. The implications of these findings in a clinical setting remain to be determined.

closed_qa

Does the downregulation of ANGPTL4 inhibit the migration and proliferation of tongue squamous cell carcinoma?

Tongue squamous cell carcinoma (TSCC) is the most common malignant cancer in the oral cavity, with a high rate of metastasis to the neck lymphoid node. Angiopoietin-like protein 4 (ANGPTL4) and microvessel density (MVD) may be novel indicators for tumor metastasis. The aim of the present study was to investigate the expression and function of ANGPTL4 in TSCC and the relationship between ANGPTL4 and MVD. The expression levels of ANGPTL4 and MVD (CD34) were analyzed in 65 TSCC specimens and the adjacent non-cancerous tissues using immunohistochemistry (IHC). siRNA was delivered into TSCCA cells to downregulate ANGPTL4 expression. Subsequently, validation with real-time RT-PCR and western blot analyses was performed to analyze ANGPTL4 expression levels. In addition, a proliferation assay, migration and invasion assays were carried out. ANGPTL4 expression was associated with tumor stage, lymph node metastasis and MVD expression. Cox regression analysis showed that high levels of ANGPTL4 expression were closely associated with poor survival time. In vitro analyses using qRT-PCR and western blot confirmed that ANGPTL4 was successfully inhibited in TSCCA cells. Suppressing ANGPTL4 resulted in the inhibition of cell proliferation and migration, but neither invasion nor cisplatin resistance was significantly affected.

High expression levels of ANGPTL4 are associated with the T stage, lymphatic metastasis, angiogenesis and poor overall survival in TSCC patients. The downregulation of ANGPTL4 inhibits the migration and proliferation of cells in TSCC. Taken together, ANGPTL4 may serve as a novel biomarker and therapeutic target for TSCC.

closed_qa

Does melatonin Receptor 1-Deficiency affect Feeding Dynamics and Pro-Opiomelanocortin Expression in the Arcuate Nucleus and Pituitary of Mice?

Melatonin, the neurohormone for darkness, mediates photoperiod dependent changes in physiology and behavior by targeting specific membrane bound receptors (MT1 and MT2). In the present study, we investigated the impact of MT1 receptor-deficiency on feeding behavior, locomotor activity and mRNA expression levels encoding for the polypeptide Pomc and neuropeptide Y (Npy) in the hypothalamic arcuate nucleus (ARC) and the adenohypophysis (pars distalis, PD and pars intermedia, PI) in a comparison between wild-type (WT) and MT1-deficient (MT1-/-) mice. The MT1-/- mice spent significantly more time in feeding than the WT-mice, while the general locomotor behavior, body weight and the total amount of food consumed did not differ between both genotypes. The nocturnal expression levels of Pomc in ARC and PD were significantly higher in WT as compared to MT1-/- mice and exogenous melatonin administered during the light phase stimulated Pomc expression in WT mice only. No differences were found between WT and MT1-/- mice with regard to Pomc expression levels in the PI.

Thus, the MT1-mediated signaling stimulates Pomc expression in a region-specific pattern. Since the MT1 mediated changes in Pomc expression do not elicit direct orexigenic or anorexigenic effects such effects are obviously mediated by regulatory systems downstream of the POMC mRNA (e.g. cleavage and release of pro-opiomelanocortin derivatives) which are independent of MT1 signaling.

closed_qa

Do eNPP1 and ESR1 genotypes influence temporomandibular disorders development and surgical treatment response in dentofacial deformities?

Dentofacial deformities are dys-morpho-functional disorders involving the temporomandibular joints (TMJ). Many authors have reported a TMJ improvement in dysfunctional subjects with malocclusion after orthodontic or combined orthodontic and surgical treatment particularly for the relief of pain. In particular, few studies have highlighted the demographic and clinical predictors of response to surgical treatment. To date, no genetic factor has yet been identified as a predictor of response to surgical treatment. The aim of this cohort study is therefore to identify single-nucleotide polymorphisms associated with postoperative temporomandibular disorders (TMD) or with TMJ symptoms after orthognathic surgery. Here, we found the AA genotype of SNP rs1643821 (ESR1 gene) as a risk factor for dysfunctional worsening after orthognathic surgery. In addition, we have identified TT genotype of SNP rs858339 (ENPP1 gene) as a protective factor against TMD in a population of patients with dentofacial deformities. Conversely, the heterozygous genotype AT was identified as a risk factor of TMD with respect to the rest of our population. All these elements are particularly important to bring new screening strategies and tailor future treatment.

This study allows us to identify sub-populations at high risk of developing postoperative temporomandibular disorders after orthognathic surgery procedures. Many other genes of interest could be potential factors influencing the dysfunctional response to orthognathic surgery, particularly genes of the Opera cohort.

closed_qa

Are red deer bone and antler collagen isotopically equivalent in carbon and nitrogen?

Bone and antler collagen δ(13) C and δ(15) N values are often assumed to be equivalent when measured in palaeodietary, palaeoclimate and palaeocological studies. Although compositionally similar, bone grows slowly and is remodelled whereas antler growth is rapid and remodelling does not occur. These different patterns of growth could result in isotopic difference within antler and between the two tissue types. Here we test whether red deer (Cervus elaphus) bone and antler δ(13) C and δ(15) N values are equivalent, and whether intra-antler isotopic values are uniform. Bone and antler were isotopically analysed from six stags that lived in a temperate maritime climate on the Isle of Rum, Scotland. Multiple antlers from different years were sampled per individual, together with a single bone sample per individual. Up to 12 samples were taken along the length of each antler (total of 25 antlers, 259 samples) so that a chronological record of the isotopic composition during antler growth could be obtained. Collagen was extracted and its δ(13) C and δ(15) N values were measured by continuous-flow isotope ratio mass spectrometry. Intra-antler collagen isotope signatures vary, and show that not all antlers from an individual or a growth year are equivalent in carbon and nitrogen isotopic ratios. δ(15) N values typically increase with distance along antler length, but no overall trend is observed in δ(13) C values. An isotopic offset is visible between bone and antler, with bone δ(13) C and δ(15) N values being higher in most cases.

Bone and antler collagen δ(13) C and δ(15) N values are not isotopically equivalent and are therefore not directly comparable in palaeodietary, palaeoclimate and palaeocological studies. Bone and antler collagen isotopic differences probably relate to differential metabolic processes during the formation of the two tissues. Intra- and inter-antler isotopic variations probably reflect the isotopic composition of an individual's diet rather than physiological parameters, and may have the potential to provide high-resolution individual-specific information in modern and ancient cervid populations. Copyright © 2016 John Wiley & Sons, Ltd.

closed_qa

Is excessive bleeding a normal cleansing process : a qualitative study of postpartum haemorrhage among rural Uganda women?

Postpartum haemorrhage (PPH) remains the leading cause of maternal morbidity and mortality worldwide. The main strategy for preventing PPH is the use of uterotonic drugs given prophylactically by skilled health workers. However, in settings where many women still deliver at home without skilled attendants, uterotonics are often inaccessible. In such cases, women and their caregivers need to recognize PPH promptly so, as to seek expert care. For this reason, it is important to understand how women and their caregivers recognize PPH, as well as the actions they undertake to prevent and treat PPH in home births. Such knowledge can also inform programs aiming to make uterotonics accessible at the community level. Between April and June 2012, a phenomenological study was carried out in a rural Ugandan district involving 15 in-depth interviews. Respondents were purposively sampled and included six women who had delivered at home in the past year and nine traditional birth attendants (TBAs). The interviews explored how PPH was recognized, its perceived causes, and the practices that respondents used in order to prevent or treat it. Phenomenological descriptive methodology was used to analyse the data. Bleeding after childbirth was considered to be a normal cleansing process, which if stopped or inhibited would lead to negative health consequences to the mother. Respondents used a range of criteria to recognize PPH: rate of blood flow, amount of blood (equivalent to two clenched fists), fainting, feeling thirsty, collapsing or losing consciousness immediately after birth. As a group, respondents seemed to correctly identify women at risk of PPH (those with twin pregnancies, high parity or prolonged labour), but many individuals did not know all the reasons. Respondents used cold drink, uterine massage and traditional medicine to treat PPH.

The community viewed bleeding after childbirth as a normal process and their methods of determining excessive bleeding are imprecise and varied. This opens the door for intervention for reducing delays in the home diagnosis of PPH. This includes increasing awareness among TBAs, women and their families about the risk of death due to excessive bleeding in the immediate postpartum period.

closed_qa

Is the link between metabolic features and TSH levels in polycystic ovary syndrome modulated by the body weight : an euglycaemic-hyperinsulinaemic clamp study?

To evaluate the link among thyroid function, glucose/insulin metabolism and steroid hormones in women with polycystic ovary syndrome (PCOS), and to verify if the body mass index (BMI) might influence the interplay between PCOS features and subclinical hypothyroidism (SCH). Case-control study conducted from January to December 2014. One-hundred fifty-four young women with PCOS, according to Rotterdam criteria, and 88 controls were enrolled in an academic research environment. Anthropometric evaluation, hormonal and lipid assays, oral glucose tolerance test (OGTT) and euglycaemic-hyperinsulinaemic clamp were performed. Hirsutism was assessed with the Ferriman-Gallwey (FG) score. SCH was found in 14% of PCOS subjects and in 1% of controls (P < 0.01). In PCOS women, TSH levels were directly correlated with fasting glycaemia, but not with other hormonal and metabolic parameters. When PCOS patients were classified on the basis of BMI, TSH levels significantly correlated with insulin secretion, insulin resistance, DHEAS and cortisol levels in obese PCOS women. Inverse correlations were found between TSH and both oestradiol and SHBG in the same group. In nonobese PCOS patients, only waist-to-hip ratio values were correlated with TSH. The prevalence of SCH was not different between nonobese and obese PCOS groups (14 and 15% respectively). However, SCH was associated with higher levels of insulin, DHEAS, cortisol and FG score only in the obese subgroup.

Our data confirm that the prevalence of SCH is increased in PCOS women. The presence of SCH is associated with endocrine and metabolic imbalances of PCOS, and the excessive body weight seems to promote this interplay.

closed_qa

Does lRG1 mRNA expression in breast cancer associate with PIK3CA genotype and with aromatase inhibitor therapy outcome?

PIK3CA is the most frequent somatic mutated oncogene in estrogen receptor (ER) positive breast cancer. We previously observed an association between PIK3CA genotype and aromatase inhibitors (AI) treatment outcome. This study now evaluates whether expression of mRNAs and miRs are linked to PIK3CA genotype and are independently related to AI therapy response in order to define potential expressed biomarkers for treatment outcome. The miR and mRNA expression levels were evaluated for their relationship with the PIK3CA genotype in two breast tumor datasets, i.e. 286 luminal cancers from the TCGA consortium and our set of 84 ER positive primary tumors of metastatic breast cancer patients who received first line AI. BRB Array tools class comparison was performed to define miRs and mRNAs whose expression associate with PIK3CA exon 9 and 20 status. Spearman correlations established miR-mRNA pairs and mRNAs with related expression. Next, a third dataset of 25 breast cancer patients receiving neo-adjuvant letrozole was evaluated, to compare expression levels of identified miRs and mRNAs in biopsies before and after treatment. Finally, to identify potential biomarkers miR and mRNA levels were related with overall survival (OS) and progression free survival (PFS) after first-line AI therapy. Expression of 3 miRs (miR-449a, miR-205-5p, miR-301a-3p) and 9 mRNAs (CCNO, FAM81B, LRG1, NEK10, PLCL1, PGR, SERPINA3, SORBS2, VTCN1) was related to the PIK3CA status in both datasets. All except miR-301a-3p had an increased expression in tumors with PIK3CA mutations. Validation in a publicly available dataset showed that LRG1, PGR, and SERPINA3 levels were decreased after neo-adjuvant AI-treatment. Six miR-mRNA pairs correlated significantly and stepdown analysis of all 12 factors revealed 3 mRNAs (PLCL1, LRG1, FAM81B) related to PFS. Further analyses showed LRG1 and PLCL1 expression to be unrelated with luminal subtype and to associate with OS and with PFS, the latter independent from traditional predictive factors.

We showed in two datasets of ER positive and luminal breast tumors that the expression of 3 miRs and 9 mRNAs associate with the PIK3CA status. Expression of LRG1 is independent of luminal (A or B) subtype, decreased after neo-adjuvant AI-treatment, and is proposed as potential biomarker for AI therapy outcome.

closed_qa

Is indocyanine green retention a potential prognostic indicator after splenectomy and pericardial devascularization for cirrhotic patients?

Splenectomy and pericardial devascularization (SPD) is an effective treatment of upper gastrointestinal bleeding and hypersplenism in cirrhotic patients with portal hypertension. Indocyanine green retention at 15 minutes (ICGR15) was reported to offer better sensitivity and specificity than the Child-Pugh classification in hepatectomy, but few reports describe ICGR15 in SPD. The present study was to evaluate the prognostic value of ICGR15 for cirrhotic patients with portal hypertension who underwent SPD. From January 2012 to January 2015, 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis were admitted in our center and received SPD. The ICGR15, Child-Pugh classification, model for end-stage liver disease (MELD) score, and perioperative characteristics were analyzed retrospectively. Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20; 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17; 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. The optimal ICGR15 threshold for liver function compensation was 31.2%, which offered a sensitivity of 68.4% and a specificity of 70.8%. Univariate analysis showed preoperative ICGR15, MELD score, surgical procedure, intraoperative blood loss, and autologous blood transfusion were significantly different between postoperative liver function compensated and decompensated groups. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery (P=0.020).

ICGR15 has outperformed the Child-Pugh classification for assessing liver function in cirrhotic patients with portal hypertension. ICGR15 may be a suitable prognostic indicator for cirrhotic patients after SPD.

closed_qa

Does release of Cathepsin B in Cytosol cause Cell Death in Acute Pancreatitis?

Experimental studies in acute pancreatitis (AP) suggest a strong association of acinar cell injury with cathepsin B-dependent intracellular activation of trypsin. However, the molecular events subsequent to trypsin activation and their role, if any, in cell death is not clear. In this study, we have explored intra-acinar events downstream of trypsin activation that lead to acinar cell death. Acinar cells prepared from the pancreas of rats or mice (wild-type, trypsinogen 7, or cathepsin B-deleted) were stimulated with supramaximal cerulein, and the cytosolic activity of cathepsin B and trypsin was evaluated. Permeabilized acini were used to understand the differential role of cytosolic trypsin vs cytosolic cathepsin B in activation of apoptosis. Cell death was evaluated by measuring specific markers for apoptosis and necrosis. Both in vitro and in vivo studies have suggested that during AP cathepsin B leaks into the cytosol from co-localized organelles, through a mechanism dependent on active trypsin. Cytosolic cathepsin B but not trypsin activates the intrinsic pathway of apoptosis through cleavage of bid and activation of bax. Finally, excessive release of cathepsin B into the cytosol can lead to cell death through necrosis.

This report defines the role of trypsin in AP and shows that cytosolic cathepsin B but not trypsin activates cell death pathways. This report also suggests that trypsin is a requisite for AP only because it causes release of cathepsin B into the cytosol.

closed_qa

Does aortic prosthesis-patient mismatch strongly affect early results of double valve replacement?

The aim of this retrospective single-center study was to assess the authors' results in mitral-aortic double valve replacement (DVR), with attention focused on the risk factors of in-hospital mortality (HM). As the initial results showed a strong relationship between HM and aortic prosthesis-patient mismatch (PPM), this led to an assessment of the impact of PPM on the early results of DVR. Data from 196 consecutive patients (mean age 60 +/- 10 years) who had undergone DVR between January 1996 and December 2011 at the authors' institution were analyzed. A statistical comparison was made of groups defined by the presence/absence of in-hospital death, postoperative complications, and aortic PPM. A logistic regression analysis of the factors associated with HM and their postoperative evolution was also conducted. Surgery was mostly performed on an elective basis (89.3%), using mainly bileaflet mechanical valves (93.9%). The rate of associated coronary bypass (CABG) was 11.2%. Aortic PPM (i.e., an effective orifice area index (EOAI) < or = 0.85 cm2/m2) was noted in 28.1% of patients. HM (6.63%) was significantly related to PPM (p < 0.002), greater age (p < 0.003), a smaller EOAI (p = 0.005), associated CABG (p < 0.008), and a longer aortic cross-clamp time (p < 0.03). Patients with aortic PPM had a significantly worse early outcome, with higher overall (p < 0.0007) and cardiac (p < 0.05) complication rates, a longer intensive care unit stay (p < 0.03), and an almost six-fold higher rate of HM (16.4% versus 2.8%; p < 0.002). PPM and age as risk factors were included in a predictive model of HM based on logistic regression; a similar model for postoperative complications highlighted PPM, age and cardiopulmonary bypass time as significant risk factors.

Aortic PPM greatly affects the postoperative outcome of DVR, as it is related to an increased complication rate and a higher in-hospital mortality. A strategy of avoiding PPM but without taking additional risks might improve the early results of DVR.

closed_qa

Is nuclear expression of phosphorylated focal adhesion kinase associated with poor prognosis in human colorectal cancer?

To determine whether phosphorylated focal adhesion kinase (P-FAK) has prognostic value in colorectal cancer (CRC) and to test whether it has any association with Tensin 4 (TNS4) expression. P-FAK expression was assessed using immunohistochemistry in 462 CRC cases arrayed on a tissue microarray. P-FAK and TNS4 expression were assessed by immunohistochemistry in 40 cases of paired primary colorectal cancer and corresponding hepatic metastases. Nuclear P-FAK expression was observed in 44% of studied cases. Positive nuclear P-FAK expression was associated with shorter disease-specific survival in univariate (p=0.005) and multivariate analysis (p=0.016). P-FAK expression was greater in metastases than the primary tumours (p<0.001) and showed significant association with nuclear TNS4 (p<0.001) in metastases.

P-FAK expression is an independent prognostic marker in CRC. The present data suggest that the FAK signalling pathway may interact with TNS4, a known oncogene in CRC.

closed_qa

Does chronic kidney disease predict long-term mortality after major lower extremity amputation?

Despite low peri-operative mortality after major lower extremity amputation, long-term mortality remains substantial. Metabolic syndrome is increasing in incidence and prevalence at an alarming rate in the USA. This study was to determine whether metabolic syndrome predicts outcome after major lower extremity amputation. A retrospective review of charts between July 2005 and June 2010. Fifty-four patients underwent a total of 60 major lower extremity amputations. Sixty percent underwent below-knee amputation and 40% underwent above-knee amputation. The 30-day mortality was 7% with no difference in level (below-knee amputation, 8%; above-knee amputation, 4%; P = 0.53). The mean follow-up time was 39.7 months. The 5-year survival was 54% in the whole group, and was independent of level of amputation (P = 0.24) or urgency of the procedure (P = 0.51). Survival was significantly decreased by the presence of underlying chronic kidney disease (P = 0.04) but not by other comorbidities (history of myocardial infarction, P = 0.79; metabolic syndrome, P = 0.64; diabetes mellitus, P = 0.56).

Metabolic syndrome is not associated with increased risk of adverse outcomes after lower extremity amputation. However, patients with chronic kidney disease constitute a sub-group of patients at higher risk of postoperative long-term mortality and may be a group to target for intervention.

closed_qa

Is eD bedside point-of-care lactate in patients with suspected sepsis associated with reduced time to iv fluids and mortality?

Early recognition and treatment of sepsis improves outcomes. We determined the effects of bedside point-of-care (POC) lactate measurement on test turnaround time, time to administration of IV fluids and antibiotics, mortality, and ICU admissions in adult ED patients with suspected sepsis. We hypothesized that bedside lactate POC testing would reduce time to IV fluids and antibiotics. We compared 80 ED patients with suspected sepsis and a lactate level of 2 mmol/L or greater before and 80 similar patients after introduction of POC lactate measurements. Groups were compared with Χ(2) and Mann Whitney U tests. A sample size of 80 patients in each group had 85% power to detect a 30-minute difference in time to IV fluids or antibiotics. Study groups were similar in age, gender, baseline lactate levels, sepsis severity, and Sequential Organ Failure Assessment (SOFA) scores. Introduction of POC lactate was associated with significant reductions in test turnaround time (34 [26-55] vs. 122 [82-149] minutes; P < 0.001), time to IV fluids (55 [34-83] vs. 71 [42-110] minutes; P = 0.03), mortality (6% vs. 19%; P = 0.02), and ICU admissions (33% vs. 51%, P = 0.02), but not time to IV antibiotics (89 [54-156] vs. 88 [60-177] minutes; P = 0.35).

Implementation of bedside POC lactate measurement in adult ED patients with suspected sepsis reduces time to test results and time to administration of IV fluids but not antibiotics. A significant reduction in mortality and ICU admissions was also demonstrated, which is likely due, at least in part, to POC testing.

closed_qa

Is sIRT1 required for oncogenic transformation of neural stem cells and for the survival of `` cancer cells with neural stemness '' in a p53-dependent manner?

Cancer stemness, observed in several types of glioma stem cells (GSCs), has been demonstrated to be an important barrier for efficient cancer therapy. We have previously reported that cancerous neural stem cells (F3.Ras.CNSCs), derived from immortalized human neural stem cells by a single oncogenic stimulation, form glial tumors in vivo. We searched for a commonly expressed stress modulator in both F3.Ras.CNSCs and GSCs and identified silent mating type information regulation 2, homolog (SIRT1) as a key factor in maintaining cancer stemness. We demonstrate that the expression of SIRT1, expressed in "cancer cells with neural stemness," is critical not only for the maintenance of stem cells, but also for oncogenic transformation. Interestingly, SIRT1 is essential for the survival and tumorigenicity of F3.Ras.CNSCs and GSCs but not for the U87 glioma cell line.

These results indicate that expression of SIRT1 in cancer cells with neural stemness plays an important role in suppressing p53-dependent tumor surveillance, the abrogation of which may be responsible not only for inducing oncogenic transformation but also for retaining the neural cancer stemness of the cells, suggesting that SIRT1 may be a putative therapeutic target in GSCs.

closed_qa

Is acinetobacter baumannii infection in prior ICU bed occupants an independent risk factor for subsequent cases of ventilator-associated pneumonia?

We aimed to evaluate risk factors for ventilator-associated pneumonia (VAP) due to Acinetobacter baumannii (AbVAP) in critically ill patients. This was a prospective observational study conducted in an intensive care unit (ICU) of a district hospital (6 beds). Consecutive patients were eligible for enrolment if they required mechanical ventilation for >48 hours and hospitalization for >72 hours. Clinical, microbiological, and laboratory parameters were assessed as risk factors for AbVAP by univariate and multivariate analysis. 193 patients were included in the study. Overall, VAP incidence was 23.8% and AbVAP, 11.4%. Previous hospitalization of another patient with Acinetobacter baumannii infection was the only independent risk factor for AbVAP (OR (95% CI) 12.016 (2.282-19.521) P < 0.001). ICU stay (25 ± 17 versus 12 ± 9  P < 0.001), the incidence of other infections (OR (95% CI) 9.485 (1.640-10.466) P = 0.002) (urinary tract infection, catheter related infection, and bacteremia), or sepsis (OR (95% CI) 10.400 (3.749-10.466) P < 0.001) were significantly increased in patients with AbVAP compared to patients without VAP; no difference was found with respect to ICU mortality.

ICU admission or the hospitalization of patients infected by Acinetobacter baumannii increases the risk of AbVAP by subsequent patients.

closed_qa

Is apoptosis inhibitor-5 overexpression associated with tumor progression and poor prognosis in patients with cervical cancer?

The apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer. API5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues. API5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.

API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.

closed_qa

Does preservation of the rectus femoris origin during periacetabular osteotomy compromise acetabular reorientation?

The early recovery period after periacetabular osteotomy (PAO) can be limited by pain and activity restrictions. Modifications of the Bernese PAO, including sparing the rectus tendon and discontinuing routine arthrotomy, may accelerate early postoperative recovery compared with the standard approach. Does a modified approach for PAO (1) lead to improved pain control immediately after surgery; (2) lead to improved ambulation during the hospital stay; (3) lead to shorter stays, less blood loss, and shorter surgical times; and (4) compromise acetabular correction? We retrospectively reviewed all 75 patients who underwent PAO for developmental dysplasia of the hip between August 2009 and May 2013. The control group included 44 consecutive patients who underwent a standard Bernese PAO with rectus takedown (RT). The study group consisted of 31 consecutive patients who underwent PAO using a modified rectus-sparing (RS) approach without routine arthrotomy. The groups were similar in age, body mass index, and American Society of Anesthesiologists score, but the RT group was comprised of a greater percentage of men than the RS group. Outcome variables were collected from patient charts and included inpatient pain, inpatient ambulation as well as length of stay, estimated blood loss, surgical time, and postoperative radiographic measurements. Cohen's f(2) was used to calculate the effect size in the regression analysis and effects were considered small for values<0.15, moderate for 0.15 to 0.34, and large for values>0.35. Patients who underwent PAO with a RS approach had less overall pain (RT median 4 versus RS median 2); however, the difference may not have been perceptible to the typical patient (p=0.001, f2=0.059). Patients treated with the RS approach ambulated similar distances during the hospital stay with a median 11 feet (interquartile range [IQR], 0-72.5) for the RT group and a median 30 feet (IQR, 0-100) for the RS group (p=0.215, f2=0.095). Patients in the RT group had a median length of stay of 4 days (IQR, 4-5) compared with a median 3 days (IQR, 3-4) in the RS group (p<0.001). The median estimated blood loss was greater (p=0.010) in the RT group (median, 500 mL; IQR, 350-700) versus the RS group (median, 300; IQR, 250-500). The median surgical time was longer (p<0.001) in patients undergoing PAO with the RT approach (median, 159.5 minutes; IQR, 145.5-177) compared with the RS approach (median, 103 minutes; IQR, 75-114). Acetabular reorientation based on postoperative radiographs was not compromised by the modified approach.

The approach modification was straightforward to implement in all patients and did not compromise acetabular fragment mobilization or final positioning. Two of the three key variables that the approach might have influenced-pain and length of stay-were below the minimum clinically important difference and different by only a fraction of a day, respectively. The difference in ambulation was of only modest clinical importance. More definitive evidence for clinical superiority in terms of pain, ambulation, and return of muscle function will likely require more sophisticated instruments such as gait analysis, muscle strength testing, and longer-term outcome studies with sensitive instruments.

closed_qa

Does above 5 cm , size matter anymore in patients with hepatocellular carcinoma?

Solitary hepatocellular carcinoma (HCC) is a good candidate for surgical resection. However, the significance of the size of the tumor in solitary HCC remains unclear. The aim of this study was to evaluate the impact of tumor size on overall and recurrence-free survival of patients with solitary HCC. We retrospectively reviewed 616 patients with histologically confirmed solitary HCC who underwent curative surgical resection between 1994 and 2010. The characteristics and prognosis of patients with HCC were analyzed stratified by tumor size. A total of 403 patients (65 %) had tumors <5 cm, 172 (28 %) had tumors between 5 and 10 cm, and 41 (7 %) had tumors >10 cm. The incidence of microvascular invasion, satellite nodules, and advanced tumor grade significantly increased with tumor size. The 5-year overall and recurrence-free survival rates of HCC <5 cm were 69.6 % and 32 %, respectively, which were significantly better than those of HCC between 5 and 10 cm (58 % and 26 %, respectively) and HCC >10 cm (53 % and 24 %, respectively). On multivariate analysis, cirrhosis (p = 0.0307), Child-Pugh B (p = 0.0159), indocyanine green retention rate at 15 min >10 % (p = 0.0071), microvascular invasion (p < 0.0001), and satellite nodules (p = 0.0009) were independent predictors of poor survival, whereas tumor size >5 cm was not.

Although recurrence rates are high, surgical resection for solitary HCC offers good overall survival. Tumor size was not a prognostic factor. Solitary large HCC >10 cm would be a good candidate for hepatectomy as well as solitary HCC between 5 and 10 cm.

closed_qa

Do both Lewis and secretor status mediate susceptibility to rotavirus infections in a rotavirus genotype-dependent manner?

The live oral rotavirus (RV) vaccines have shown a reduced efficacy in Africa. Recent in vitro studies have shown binding of the RV surface protein (VP4) to histo-blood group antigens (HBGAs) in an RV genotype-dependent manner, suggesting them to be putative receptors for RV. The diversity of HBGA phenotypes in different ethnic populations, combined with prevalence/absence of specific RV genotypes, led us to hypothesize whether the genetic variations in HBGAs in a population limit susceptibility to certain RV genotypes, plausibly leading to reduced vaccine efficacy. Association between HBGAs status and susceptibility to RV P genotypes was investigated in children in Burkina Faso and Nicaragua. In total, 242 children with diarrhea in Burkina Faso and Nicaragua were investigated, 93 of whom were RV positive. In Burkina Faso, the P[8] RV strains (n = 27) infected only Lewis- and secretor-positive children (27/27; P < .0001), but no Lewis-negative children. In contrast, the P[6] strains (n = 27) infected predominantly Lewis-negative children (n = 18; P < .0001) but also Lewis-positive children, irrespective of their secretor status. The results from Nicaragua confirmed that all P[8]-infected children (n = 22) were secretor Lewis positive.

As VP4 of genotype P[8] is a component of current RV vaccines, our finding that Lewis-negative children are resistant to P[8] strains provides a plausible explanation for the reduced vaccine efficacy in populations with a high percentage of Lewis-negative individuals, such as in Africa. Furthermore, our findings provide a plausible explanation as to why P[6] RV strains are more common in Africa.

closed_qa

Does a farnesoid X receptor polymorphism predispose to spontaneous bacterial peritonitis?

In mice, the farnesoid X receptor is involved in bacterial translocation, which can result in spontaneous bacterial peritonitis in patients with cirrhosis. We investigated if polymorphisms in the farnesoid X receptor gene influence the risk for spontaneous bacterial peritonitis. Laboratory and clinical data of 293 cirrhotic patients with ascites and 226 healthy controls were prospectively collected. The rs56163822, rs11110390 and rs12313471 polymorphisms of the farnesoid X receptor were determined. 115 (39%) patients had spontaneous bacterial peritonitis. Distribution of all farnesoid X receptor genotypes matched the Hardy-Weinberg equilibrium. Patients with spontaneous bacterial peritonitis had a higher frequency of the rs56163822 GT genotype (7.0%) than patients without (1.7%, OR=4.4, p=0.02). This genotype was confirmed as predictor of spontaneous bacterial peritonitis by binary logistic regression analysis (OR=6.8, p=0.018).

The farnesoid X receptor rs56163822 GT genotype increases the risk for spontaneous bacterial peritonitis in cirrhotic patients with ascites.

closed_qa

Does adaptive brain shut-down counteract neuroinflammation in the near-term ovine fetus?

Repetitive umbilical cord occlusions (UCOs) in ovine fetus leading to severe acidemia result in adaptive shut-down of electrocortical activity [electrocorticogram (ECoG)] as well as systemic and brain inflammation. We hypothesized that the fetuses with earlier ECoG shut-down as a neuroprotective mechanism in response to repetitive UCOs will show less brain inflammation and, moreover, that chronic hypoxia will impact this relationship. Near-term fetal sheep were chronically instrumented with ECoG leads, vascular catheters, and a cord occluder and then underwent repetitive UCOs for up to 4 h or until fetal arterial pH was <7.00. Eight animals, hypoxic prior to the UCOs (SaO2 <55%), were allowed to recover 24 h post insult, while 14 animals, 5 of whom also were chronically hypoxic, were allowed to recover 48 h post insult, after which brains were perfusion-fixed. Time of ECoG shut-down and corresponding pH were noted, as well as time to then reach pH <7.00 (ΔT). Microglia (MG) were counted as a measure of inflammation in gray matter layers 4-6 (GM4-6) where most ECoG activity is generated. RESULTS are reported as mean ± SEM for p < 0.05. Repetitive UCOs resulted in worsening acidosis over 3-4 h with arterial pH decreasing to 6.97 ± 0.02 all UCO groups' animals, recovering to baseline by 24 h. ECoG shut-down occurred 52 ± 7 min before reaching pH <7.00 at pH 7.23 ± 0.02 across the animal groups. MG counts were inversely correlated to ΔT in 24 h recovery animals (R = -0.84), as expected. This was not the case in normoxic 48 h recovery animals, and, surprisingly, in hypoxic 48 h recovery animals, this relationship was reversed (R = 0.90).

Adaptive brain shut-down during labor-like worsening acidemia counteracts neuroinflammation in a hypoxia- and time-dependent manner.

closed_qa

Is cross-section perimeter a suitable parameter to describe the effects of different baffle geometries in shaken microtiter plates?

Biotechnological screening processes are performed since more than 8 decades in small scale shaken bioreactors like shake flasks or microtiter plates. One of the major issues of such reactors is the sufficient oxygen supply of suspended microorganisms. Oxygen transfer into the bulk liquid can in general be increased by introducing suitable baffles at the reactor wall. However, a comprehensive and systematic characterization of baffled shaken bioreactors has never been carried out so far. Baffles often differ in number, size and shape. The exact geometry of baffles in glass lab ware like shake flasks is very difficult to reproduce from piece to piece due to the hard to control flow behavior of molten glass during manufacturing. Thus, reproducibility of the maximum oxygen transfer capacity in such baffled shake flasks is hardly given. As a first step to systematically elucidate the general effect of different baffle geometries on shaken bioreactor performance, the maximum oxygen transfer capacity (OTRmax) in baffled 48-well microtiter plates as shaken model reactor was characterized. This type of bioreactor made of plastic material was chosen, as the exact geometry of the baffles can be fabricated by highly reproducible laser cutting. As a result, thirty different geometries were investigated regarding their maximum oxygen transfer capacity (OTRmax) and liquid distribution during shaking. The relative perimeter of the cross-section area as new fundamental geometric key parameter is introduced. An empirical correlation for the OTRmax as function of the relative perimeter, shaking frequency and filling volume is derived. For the first time, this correlation allows a systematic description of the maximum oxygen transfer capacity in baffled microtiter plates.

Calculated and experimentally determined OTRmax values agree within ± 30% accuracy. Furthermore, undesired out-of-phase operating conditions can be identified by using the relative perimeter as key parameter. Finally, an optimum well geometry characterized by an increased perimeter of 10% compared to the unbaffled round geometry is identified. This study may also assist to comprehensively describe and optimize the baffles of shake flasks in future.

closed_qa

Does the effect of neighbourhood unemployment on health-risk behaviours in elderly differ between Slovak and Dutch cities?

Health-risk behaviours (HRB) increase the risk of disability and chronic diseases at an older age. This study aimed to compare Slovakia and the Netherlands regarding differences in the prevalence of HRB by neighbourhood and individual deprivation and to determine whether area differences could be explained by the socio-economic position (SEP) of the residents. We obtained data on non-institutionalized residents aged ≥ 65 years from the EU-FP7: EURO-URHIS 2 project from Slovak (N = 665, response rate 44.0%) and Dutch cities (N = 795, response rate 50.2%). HRB concerned daily smoking, binge drinking, physical activity, consumption of fruits and vegetables and body mass index. Area deprivation was measured by the neighbourhood unemployment rate. Individual SEP was measured by education and household income with financial strain. We used multilevel logistic regression. In Slovakia, no HRB was associated with either neighbourhood unemployment or individual SEP. The elderly in the Netherlands from the least favourable neighbourhoods were more likely to be daily smokers [odds ratio (OR) 2.32; 95% confidence interval (CI) 1.25, 4.30] and overweight (OR 1.84; 95% CI 1.24, 2.75) than residents from the most favourable ones. For the Dutch elderly the gradients varied per HRB and per individual-level SEP indicator. Individual SEP explained country differences in the association of area unemployment with smoking and lack of physical activity but not that with overweight.

Countries differed in the associations with HRB of both neighbourhood unemployment and individual SEP among the elderly urban residents. The local importance of socio-economic factors on both levels should be considered when developing health-promotion activities for the elderly.

closed_qa

Does sildenafil enhance the peripheral antinociceptive effect of ellagic acid in the rat formalin test?

Ellagic acid (EA), a major polyphenolic compound of pomegranate juice, produces antinociceptive effects, which are mediated through opioidergic and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathways. The present study was conducted to elucidate the peripheral antinociceptive effect of EA alone and in combination with sildenafil in the rat formalin test. Pain was produced by intraplantar injection of formalin (2.5%) in rats and nociceptive behavior was measured as the number of flinches every 5 min in 60 min after injection. Local administration of EA and sildenafil dose-dependently increased the nociception threshold in both phases of the test. Moreover, sub-effective doses of sildenafil (25 or 50 mcg/paw, i.p.) significantly and dose-dependently enhanced the antinociception induced by a sub-effective dose of EA (60 mcg/paw, i.pl.) in both phases of the test. The antinociception produced by these drugs alone, or in combination, was due to a peripheral site of action, since the administration in the contralateral paw was ineffective.

Our results suggest that EA has local peripheral antinociceptive activity, and enhancement of this effect with sildenafil probably occurs through the inhibition of cGMP metabolism.

closed_qa

Does topical vitamin K1 promote repair of full thickness wound in rat?

Application of vitamin K to the skin has been used for suppression of pigmentation and resolution of bruising. However, in rats, no study was reported on its effect regarding wound healing. Thus, the present study was designed to examine the healing effects of creams prepared from vitamin K1 on full-thickness wound in rats. For inducing full-thickness wound in rats, the excisional wound model was used. Five groups consisting of 8 rats each were used. Vitamin K cream (1% and 2%, w/w) was prepared in eucerin base and applied on the wound once a day until complete healing had occurred. Healing was defined by decreased wound margin (wound contraction), re-epithelialization, tensile strength and hydroxyproline content. Histopathological examination was also done. The effects produced by the topical vitamin K showed significant (P < 0.01) healing when compared with control group in parameters such as wound contraction, epithelialization period, hydroxyproline content and tensile strength. Histopathological studies also showed improvement with vitamin K.

Topical vitamin K demonstrates wound healing potential in full-thickness wound model.

closed_qa

Is fatty acid binding protein-4 expressed in the mouse placental labyrinth , yet is dispensable for placental triglyceride accumulation and fetal growth?

Fatty Acid Binding Protein-4 (FABP4) is a member of a family of FABP proteins that regulate intracellular lipid trafficking in diverse tissues. We recently showed that FABP4 regulates triglyceride accumulation in primary human trophoblasts. To assess the function of placental FABP4 in vivo, we tested the hypothesis that FABP4 is expressed in the murine placenta, and regulates placenta triglyceride accumulation. C57Bl/6 wild type or Fabp4-null mice were time-bred, and fetuses and placentas harvested at different time points during pregnancy. Placental FABP4 expression was assessed at different gestational ages, using quantitative PCR, immunohistochemistry, immunofluorescence and western immunoblotting. FABPs expression was examined by RT-qPCR. Placental lipids were extracted using the Folch method and triglyceride levels determined using a colorimetric quantification kit. Using immunohistochemistry, we found that FABP4 was expressed in the placental labyrinthine layer, predominantly in endothelial cells in association with CD31 positive fetal capillaries. The level of placental FABP4 mRNA and protein increased from E12.5 to E16.5 and slightly decreased at E18.5. Breeding of Fabp4 heterozygous mice resulted in embryonic genotypes that followed a Mendelian distribution and exhibited normal weight and morphology, triglyceride content, and expression of other FABP family members. Exposure to hypoxia (O2 = 12%) between E12.5-E18.5 did not uncover a difference between wild type and Fabp4-null mice.

FABP4 is expressed in the mouse placental labyrinth, with highest expression at E16.5. FABP4 is dispensable for feto-placental growth and placental lipid accumulation.

closed_qa

Is low birth weight associated with adiposity , impaired skeletal muscle energetics and weight loss resistance in mice?

In utero undernutrition is associated with obesity and insulin resistance, although its effects on skeletal muscle remain poorly defined. Therefore, in the current study we explored the effects of in utero food restriction on muscle energy metabolism in mice. We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine offspring from undernourished dams (U) and control offspring from ad libitum-fed dams (C). Weight loss of 10-week-old offspring on a 4-week 40% calorie-restricted diet was also followed. Experimental approaches included bioenergetic analyses in isolated mitochondria, intact (permeabilized) muscle and at the whole body level. U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 40% calorie-restricted diet they lose half as much weight as calorie-restricted controls. Mitochondria from muscle overall from U had decreased coupled (state 3) and uncoupled (state 4) respiration and increased maximal respiration compared to C. Mitochondrial yield was lower in U than C. In permeabilized fiber preparations from mixed fiber-type muscle, U had decreased mitochondrial content and decreased adenylate-free leak respiration, fatty acid oxidative capacity and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity did not differ between U and C but was decreased with calorie restriction.

Our results reveal that in utero undernutrition alters metabolic physiology through a profound effect on skeletal muscle energetics and blunts response to a hypocaloric diet in adulthood. We propose that mitochondrial dysfunction links undernutrition in utero with metabolic disease in adulthood.

closed_qa

Is early repolarization associated with atrial and ventricular tachyarrhythmias in patients with acute ST elevation myocardial infarction undergoing primary percutaneous coronary intervention?

Recent studies found that early repolarization (ER) is significantly more common in survivors of aborted sudden cardiac death. We hypothesized that ER might be more common in patients with ST elevation myocardial infarction (STEMI) who have complications of atrial and ventricular arrhythmias. This study included 266 patients with acute STEMI undergoing primary percutaneous coronary intervention. Twelve-lead electrocardiograms were analyzed for ER, defined as J-point elevation ≥ 0.1 mV and "notching" and "slurring" of the terminal part of the QRS complex in at least 2 lateral or inferior leads. Acute and late atrial and ventricular arrhythmic events were evaluated. The ER pattern was observed in 76 patients (28.6%). Atrial arrhythmia [21/76 (27.6%) vs. 22/190 (11.6%), p=0.001] and ventricular arrhythmia [16/76 (21.1%) vs. 16/190 (8.4%), p=0.004] were more frequently complicated in patients with ER than those without during hospitalization. ER was a significant independent predictor of developing atrial (HR=2.682, 95% CI=1.355-5.310, p=0.005) and ventricular arrhythmia (HR=2.936, 95% CI=1.360-6.335, p=0.006). Three patients with ER and ventricular fibrillation expired during hospitalization [3.9% (3/76) vs. 0% (0/190), p=0.023]. However, the presence of ER did not affect the late recurrence of atrial and ventricular arrhythmia.

The ER pattern is commonly observed in patients with STEMI and associated with atrial and ventricular tachyarrhythmia during acute setting.

closed_qa

Does estradiol bound to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro?

Insulin (INS) resistance associated with hyperestrogenemias occurs in gestational diabetes mellitus, polycystic ovary syndrome, ovarian hyperstimulation syndrome, estrogen therapies, metabolic syndrome, and obesity. The mechanism by which INS and estrogen interact is unknown. We hypothesize that estrogen binds directly to INS and the insulin receptor (IR) producing INS resistance. To determine the binding constants of steroid hormones to INS, the IR, and INS-like peptides derived from the IR; and to investigate the effect of estrogens on the binding of INS to its receptor. Ultraviolet spectroscopy, capillary electrophoresis, and NMR demonstrated estrogen binding to INS and its receptor. Horse-radish peroxidase-linked INS was used in an ELISA-like procedure to measure the effect of estradiol on binding of INS to its receptor. Binding constants for estrogens to INS and the IR were determined by concentration-dependent spectral shifts. The effect of estradiol on INS binding to its receptor was determined by shifts in the INS binding curve. Estradiol bound to INS with a K d of 12 × 10(-9) M and to the IR with a K d of 24 × 10(-9) M, while other hormones had significantly less affinity. Twenty-two nanomolars of estradiol shifted the binding curve of INS to its receptor 0.8 log units to the right.

Estradiol concentrations in hyperestrogenemic syndromes may interfere with INS binding to its receptor producing significant INS resistance.

closed_qa

Do plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation?

Biomarkers predictive of recovery from acute kidney injury (AKI) after liver transplantation (LT) could enhance decision algorithms regarding the need for liver-kidney transplantation or renal sparing regimens. Multianalyte plasma/urine kidney injury protein panels were performed immediately before and 1 month post-LT in an initial test group divided by reversible pre-LT AKI (rAKI = post-LT renal recovery) versus no AKI (nAKI). This was followed by a larger validation set that included an additional group: irreversible pre-LT AKI (iAKI = no post-LT renal recovery). In the test group (n = 16), six pre-LT plasma (not urine) kidney injury proteins (osteopontin [OPN], neutrophil gelatinase-associated lipocalin, cystatin C, trefoil factor 3, tissue inhibitor of metalloproteinase [TIMP]-1, and β-2-microglobulin) were higher in rAKI versus nAKI (P < 0.05) and returned to normal values with renal recovery post-LT. In the validation set (n = 46), a number of proteins were significantly higher in both rAKI and iAKI versus nAKI. However, only pre-LT plasma OPN (P = 0.009) and TIMP-1 (P = 0.019) levels were significantly higher in rAKI versus iAKI. Logistic regression modeling was used to correlate the probability of post-LT rAKI, factoring in both pre-LT protein markers and clinical variables. A combined model including elevated OPN and TIMP-1 levels, age <57, and absence of diabetes had the highest area under the curve of 0.82, compared to protein-only and clinical variable-only models.

These data suggest that plasma protein profiles might improve the prediction of pre-LT kidney injury recovery after LT. However, multicenter, prospective studies are needed to validate these findings and ultimately test the value of such protein panels in perioperative management and decision making.

closed_qa

Does neighborhood influence on recreational physical activity and survival after breast cancer?

Higher levels of physical activity have been associated with improved survival after breast cancer diagnosis. However, no previous studies have considered the influence of the social and built environment on physical activity and survival among breast cancer patients. Our study included 4,345 women diagnosed with breast cancer (1995-2008) from two population-based studies conducted in the San Francisco Bay Area. We examined questionnaire-based moderate/strenuous recreational physical activity during the 3 years before diagnosis. Neighborhood characteristics were based on data from the 2000 US Census, business listings, parks, farmers' markets, and Department of Transportation. Survival was evaluated using multivariable Cox proportional hazards models, with follow-up through 2009. Women residing in neighborhoods with no fast-food restaurants (vs. fewer fast-food restaurants) to other restaurants, high traffic density, and a high percentage of foreign-born residents were less likely to meet physical activity recommendations set by the American Cancer Society. Women who were not recreationally physically active had a 22% higher risk of death from any cause than women that were the most active. Poorer overall survival was associated with lower neighborhood socioeconomic status (SES) (p(trend) = 0.02), whereas better breast cancer-specific survival was associated with a lack of parks, especially among women in high-SES neighborhoods.

Certain aspects of the neighborhood have independent associations with recreational physical activity among breast cancer patients and their survival. Considering neighborhood factors may aide in the design of more effective, tailored physical activity programs for breast cancer survivors.

closed_qa

Is basal and β-adrenergic cardiomyocytes contractility dysfunction induced by dietary protein restriction associated with downregulation of SERCA2a expression and disturbance of endoplasmic reticulum Ca2+ regulation in rats?

The mechanisms responsible for the cardiac dysfunction associated with dietary protein restriction (PR) are poorly understood. Thus, this study was designed to evaluate the effects of PR on calcium kinetics, basal and β-adrenergic contractility in murine ventricular cardiomyocytes. After breastfeeding male Fisher rats were distributed into a control group (CG, n = 20) and a protein-restricted group (PRG, n = 20), receiving isocaloric diets for 35 days containing 15% and 6% protein, respectively. Biometric and hemodynamic variables were measured. After euthanasia left ventricles (LV) were collected for histopathological evaluation, SERCA2a expression, cardiomyocytes contractility and Ca(2+)sparks analysis. PRG animals showed reduced general growth, increased heart rate and arterial pressure. These animals presented extracellular matrix expansion and disorganization, cardiomyocytes hypotrophy, reduced amplitudes of shortening and maximum velocity of contraction and relaxation at baseline and after β-adrenergic stimulation. Reduced SERCA2a expression as well as higher frequency and lower amplitude of Ca(2+)sparks were observed in PRG cardiomyocytes.

The observations reveal that protein restriction induces marked myocardial morphofunctional damage. The pathological changes of cardiomyocyte mechanics suggest the potential involvement of the β-adrenergic system, which is possibly associated with changes in SERCA2a expression and disturbances in Ca(2+) intracellular kinetics.

closed_qa

Does autocrine secretion of 15d-PGJ2 mediate simvastatin-induced apoptotic burst in human metastatic melanoma cells?

Despite new therapeutic approaches, metastatic melanomas still have a poor prognosis. Statins reduce low-density lipoprotein cholesterol and exert anti-inflammatory and anti-proliferative actions. We have recently shown that simvastatin triggers an apoptotic burst in human metastatic melanoma cells by the synthesis of an autocrine factor. The current in vitro study was performed in human metastatic melanoma cell lines (A375, 518a2) and primary human melanocytes and melanoma cells. The secretome of simvastatin-stressed cells was analysed with two-dimensional difference gel electrophoresis and MS. The signalling pathways involved were analysed at the protein and mRNA level using pharmacological approaches and siRNA technology. Simvastatin was shown to activate a stress cascade, leading to the synthesis of 15-deoxy-12,14-PGJ2 (15d-PGJ2 ), in a p38- and COX-2-dependent manner. Significant concentrations of 15d-PGJ2 were reached in the medium of melanoma cells, which were sufficient to activate caspase 8 and the mitochondrial pathway of apoptosis. Inhibition of lipocalin-type PGD synthase, a key enzyme for 15d-PGJ2 synthesis, abolished the apoptotic effect of simvastatin. Moreover, 15d-PGJ2 was shown to bind to the fatty acid-binding protein 5 (FABP5), which was up-regulated and predominantly detected in the secretome of simvastatin-stressed cells. Knockdown of FABP5 abolished simvastatin-induced activation of PPAR-γ and amplified the apoptotic response.

We characterized simvastatin-induced activation of the 15d-PGJ2 /FABP5 signalling cascades, which triggered an apoptotic burst in melanoma cells but did not affect primary human melanocytes. These data support the rationale for the pharmacological targeting of 15d-PGJ2 in metastatic melanoma.

closed_qa

Is t-cell receptor diversity selectively skewed in T-cell populations of patients with Wiskott-Aldrich syndrome?

Wiskott-Aldrich syndrome (WAS) is a severe disorder characterized by thrombocytopenia, eczema, immunodeficiency, and increased risk of autoimmune disease and lymphoid malignancies. The immunodeficiency caused by a lack of WAS protein expression has been mainly attributed to defective T-cell functions. Whether WAS mutations differentially influence the T-cell receptor (TCR) diversity of different T-cell subsets is unknown. We aimed to identify the degree and pattern of skewing in the variable region of the TCR β-chain (Vβ) in different T-cell subsets from patients with WAS. The TCR repertoire diversity in total peripheral T cells, sorted CD4(+) and CD8(+) T cells, and CD45RA(+) (CD45RA(+)CD45RO(-) cells) and CD45RO(+) (CD45RA(-)CD45RO(+) cells) CD4(+) and CD8(+) T cells from patients with WAS and age-matched healthy control subjects was analyzed and compared by using spectratyping of complementarity-determining region 3. The complementarity-determining region 3 of TCRβ transcripts in CD45RA(+)CD4(+) and CD45RA(+)CD8(+) T cells, CD45RO(+)CD4(+) T cells, CD8(+) terminally differentiated effector memory T (Temra) cells, and naive CD8(+) T cells (CD8(+)CD45RO(-)CCR7(+) cells) from patients and control subjects were analyzed and compared by using high-throughput sequencing. The TCR repertoire diversity in CD45RO(+)CD4(+) T cells and CD8(+) Temra cells of patients with WAS was significantly skewed in comparison with that seen in age-matched control subjects.

Our results indicate that WAS gene mutations selectively influence TCR repertoire development or expansion in CD45RO(+) (memory) CD4(+) T cells.

closed_qa

Does greater body mass independently predict less radiographic progression on X-ray and MRI over 1-2 years?

Greater body mass index (BMI) has been associated with less radiographic progression in rheumatoid arthritis (RA). We evaluated the association between BMI and joint damage progression as measured by X-ray and MRI. 1068 subjects with RA from two clinical trials of golimumab (GO-BEFORE and GO-FORWARD) had radiographs performed at weeks 0, 52 and 104 and evaluated using the van der Heijde-Sharp (vdHS) scoring system. Contrast-enhanced MRIs of the dominant wrist and hand were obtained at weeks 0, 12, 24, 52 and 104. Multivariable logistic regression evaluated the risk of radiographic progression for each BMI category (<25, 25-30, >30 kg/m(2)). Within GO-BEFORE, piecewise, robust generalised estimating equations marginal models assessed the probability of MRI erosion progression for each BMI category. Multivariable linear regression models assessed baseline associations between BMI and bone oedema (a precursor of bone erosion). Higher BMI category was associated with a lower probability of progression in vdHS score at weeks 52 and 104 independent of potential confounders. Higher BMI was also independently associated with a lower probability of progression in MRI erosion score over 2 years. Subjects with greater BMI demonstrated less bone oedema independent of differences in other disease severity measures, including MRI synovitis in the same joints.

Greater BMI is associated with a lower risk of progression on X-ray and MRI over 2 years. Subjects with greater BMI also demonstrate less bone oedema at baseline. Greater BMI may indicate a less aggressive RA phenotype and aid in risk stratification.

closed_qa

Does comparison of gene expression microarray data with count-based RNA measurements inform microarray interpretation?

Although numerous investigations have compared gene expression microarray platforms, preprocessing methods and batch correction algorithms using constructed spike-in or dilution datasets, there remains a paucity of studies examining the properties of microarray data using diverse biological samples. Most microarray experiments seek to identify subtle differences between samples with variable background noise, a scenario poorly represented by constructed datasets. Thus, microarray users lack important information regarding the complexities introduced in real-world experimental settings. The recent development of a multiplexed, digital technology for nucleic acid measurement enables counting of individual RNA molecules without amplification and, for the first time, permits such a study. Using a set of human leukocyte subset RNA samples, we compared previously acquired microarray expression values with RNA molecule counts determined by the nCounter Analysis System (NanoString Technologies) in selected genes. We found that gene measurements across samples correlated well between the two platforms, particularly for high-variance genes, while genes deemed unexpressed by the nCounter generally had both low expression and low variance on the microarray. Confirming previous findings from spike-in and dilution datasets, this "gold-standard" comparison demonstrated signal compression that varied dramatically by expression level and, to a lesser extent, by dataset. Most importantly, examination of three different cell types revealed that noise levels differed across tissues.

Microarray measurements generally correlate with relative RNA molecule counts within optimal ranges but suffer from expression-dependent accuracy bias and precision that varies across datasets. We urge microarray users to consider expression-level effects in signal interpretation and to evaluate noise properties in each dataset independently.

closed_qa

Is a novel BHLHE41 variant associated with short sleep and resistance to sleep deprivation in humans?

Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loophelix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts. Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase. We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function.

There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis.

closed_qa

Is subcortical atrophy associated with cognitive impairment in mild Parkinson disease : a combined investigation of volumetric changes , cortical thickness , and vertex-based shape analysis?

The involvement of subcortical deep gray matter and cortical thinning associated with mild Parkinson disease remains poorly understood. We assessed cortical thickness and subcortical volumes in patients with Parkinson disease without dementia and evaluated their associations with cognitive dysfunction. The study included 90 patients with mild Parkinson disease without dementia. Neuropsychological assessments classified the sample into patients with mild cognitive impairment (n = 25) and patients without cognitive impairment (n = 65). Volumetric data for subcortical structures were obtained by using the FMRIB Integrated Registration and Segmentation Tool while whole-brain, gray and white matter volumes were estimated by using Structural Image Evaluation, with Normalization of Atrophy. Vertex-based shape analyses were performed to investigate shape differences in subcortical structures. Vertex-wise group differences in cortical thickness were also assessed. Volumetric comparisons between Parkinson disease with mild cognitive impairment and Parkinson disease with no cognitive impairment were performed by using ANCOVA. Associations of subcortical structures with both cognitive function and disease severity were assessed by using linear regression models. Compared with Parkinson disease with no cognitive impairment, Parkinson disease with mild cognitive impairment demonstrated reduced volumes of the thalamus (P = .03) and the nucleus accumbens (P = .04). Significant associations were found for the nucleus accumbens and putamen with performances on the attention/working memory domains (P < .05) and nucleus accumbens and language domains (P = .04). The 2 groups did not differ in measures of subcortical shape or in cortical thickness.

Patients with Parkinson disease with mild cognitive impairment demonstrated reduced subcortical volumes, which were associated with cognitive deficits. The thalamus, nucleus accumbens, and putamen may serve as potential biomarkers for Parkinson disease-mild cognitive impairment.

closed_qa

Is gOLP3 a predictor of survival in patients with hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) is one of the most common solid tumors and ranks the third leading cause of cancer mortality worldwide. The purpose of this study was to examine the expression dynamics of GOLPH3 in HCC tissue samples, and explore the correlation between GOLPH3 expression and prognosis in patients with HCC. The levels of Golgi phosphoprotein 3 (GOLPH3) mRNA and protein in liver cancer cell lines and fresh tissues were determined by qRT-PCR and Western blotting. Additionally, the protein expression of GOLPH3 was detected by immunohistochemistry. High GOLPH3 expression was positively correlated with serum AFP level (P=0.015) and tumor recurrence or metastasis (P=0.010). In addition, liver cancer patients with high GOLPH3 expression had significantly poorer overall survival (HR, 1.87; 95% CI, 1.19-2.94; P=0.006) and poorer disease-free survival (HR, 1.90; 95% CI, 1.21-2.98; P=0.005) than those with low GOLPH3 expression. The cumulative 5-year survival rate was only 35.19% (95% CI, 26.18%-44.20%) in the high GOLPH3 expression group, whereas it was 55.93% (95% CI, 43.26%-68.60%) in the low GOLPH3 expression group. Furthermore, multivariate Cox regression analysis demonstrated that the expression of GOLPH3, tumor size and tumor multiplicity were independent prognostic predictors for HCC patients.

GOLPH3 was overexpressed in HCC at both the mRNA and protein levels, and the presence of high levels of expression of GOLPH3 could serve as a novel and potential prognostic biomarker for liver cancer patients.

closed_qa

Do lymph node metastases impact survival in follicular variant papillary thyroid cancer?

Follicular variant of papillary thyroid cancer (FVPTC) is the most common and fastest growing subtype of papillary thyroid cancer (PTC) with features of both PTC and follicular thyroid cancer (FTC). The purpose of this study was to determine the patient and tumor features associated with lymph node metastases (LNM) in FVPTC. This was a retrospective review of adult (≥18) patients with histologically confirmed diagnoses of FVPTC within the SEER database between 1988 and 2009. LNM were defined by at least two lymph nodes with metastatic disease. To determine factors associated with LNM, we constructed a multivariate logistic regression model from significant variables (p < 0.05) identified on univariate analysis. Similarly, we used a Cox proportional hazards model to understand the relative importance of LNM in determining disease-specific mortality (DSM). Of the 20,357 cases of FVPTC with lymph node data available, 1,761 (8.7%) had LNM; 61.1% of these LNM were located in the central neck and 38.9% were in the lateral neck. Extrathyroidal extension (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.2-3.0, p < 0.01) and multifocality (OR 3.0, 95% CI 2.5-3.6, p < 0.01) were the strongest predictors of LNM. Importantly, LNM did not independently predict DSM (p = 0.52). Tumor size >4 cm (hazards ratio [HR] 5.3, 95% CI 2.2-12.8, p < 0.01) and extrathyroidal extension (HR 8.2, 95% CI 3.0-22.0, p < 0.01) were the strongest predictors of DSM.

LNM occur in less than 10% of patients with FVPTC but do not impact DSM. Instead, DSM in FVPTC is related to size and local invasion.

closed_qa

Do histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells?

Extracellular histones exert part of their prothrombotic activity through the stimulation of blood cells. Besides platelets, histones can bind to red blood cells (RBCs), which are important contributors to thrombogenesis, but little is known about the functional consequences of this interaction. To evaluate the effect of histones on the procoagulant potential of human RBCs with particular regard to the expression of surface phosphatidylserine (PS). PS exposure on human RBCs treated with a natural mixture of histones or recombinant individual histones was evaluated with fluorescein isothiocyanate-annexin-V binding and measured with flow cytometry. Calcium influx in RBCs loaded with the calcium-sensitive fluorophore Fluo-4 AM was assessed with flow cytometry. The procoagulant potential of histone-treated RBCs was evaluated with a purified prothrombinase assay and a one-stage plasma recalcification clotting test. Natural histones induced PS exposure on RBCs in a dose-dependent manner, and neutralization or cleavage of histones by heparin or activated protein C, respectively, abolished PS externalization. H4 was mainly responsible for the stimulating activity of histones, whereas the other subtypes were almost ineffective. Similarly, natural histones and H4 induced influx of calcium into RBCs, whereas the other individual histones did not. Histone-induced exposure of PS on RBCs translated into increased prothrombinase complex-mediated prothrombin activation and accelerated fibrin formation in plasma.

Histones induce RBCs to express a procoagulant phenotype through the externalization of PS. This finding provides new insights into the prothrombotic activity of extracellular histones.

closed_qa

Does aMP-activated protein kinase deficiency rescue paraquat-induced cardiac contractile dysfunction through an autophagy-dependent mechanism?

Paraquat, a quaternary nitrogen herbicide, is a highly toxic prooxidant resulting in multi-organ failure including the heart although the underlying mechanism still remains elusive. This study was designed to examine the role of the cellular fuel sensor AMP-activated protein kinase (AMPK) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type and transgenic mice with overexpression of a mutant AMPK α2 subunit (kinase dead, KD), with reduced activity in both α1 and α2 subunits, were administered with paraquat (45 mg/kg) for 48 h. Paraquat elicited cardiac mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic diameter and reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, reduced cell survival, and overt mitochondrial damage (loss in mitochondrial membrane potential). In addition, paraquat treatment promoted phosphorylation of AMPK and autophagy. Interestingly, deficiency in AMPK attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) derangement. The beneficial effect of AMPK inhibition was associated with inhibition of the AMPK-TSC-mTOR-ULK1 signaling cascade. In vitro study revealed that inhibitors for AMPK and autophagy attenuated paraquat-induced cardiomyocyte contractile dysfunction.

Taken together, our findings revealed that AMPK may mediate paraquat-induced myocardial anomalies possibly by regulating the AMPK/mTOR-dependent autophagy.

closed_qa

Is depigmentation caused by application of the active brightening material , rhododendrol , related to tyrosinase activity at a certain threshold?

Tyrosinase, the rate-limiting enzyme required for melanin production, has been targeted to develop active brightening/lightening materials for skin products. Unexpected depigmentation of the skin characterized with the diverse symptoms was reported in some subjects who used a tyrosinase-competitive inhibiting quasi-drug, rhododendrol. To investigate the mechanism underlying the depigmentation caused by rhododendrol-containing cosmetics, this study was performed. The mechanism above was examined using more than dozen of melanocytes derived from donors of different ethnic backgrounds. The RNAi technology was utilized to confirm the effect of tyrosinase to induce the cytotoxicity of rhododendrol and liquid chromatography-tandem mass spectrometry was introduced to detect rhododendrol and its metabolites in the presence of tyrosinase. Melanocyte damage was related to tyrosinase activity at a certain threshold. Treatment with a tyrosinase-specific siRNA was shown to dramatically rescue the rhododendrol-induced melanocyte impairment. Hydroxyl-rhododendrol was detected only in melanocytes with higher tyrosinase activity. When an equivalent amount of hydroxyl-rhododendrol was administered, cell viability was almost equally suppressed even in melanocytes with lower tyrosinase activity.

The generation of a tyrosinase-catalyzed hydroxyl-metabolite is one of the causes for the diminishment of the melanocyte viability by rhododendrol.

closed_qa

Is adherence to exercise programs for older people influenced by program characteristics and personal factors : a systematic review?

How has adherence been measured in recent prospective studies focusing on adherence to exercise programs among older people? What is the range of adherence rates? Which factors are associated with better adherence? Systematic review of prospective studies that had a primary aim of assessing adherence to exercise programs. Older people undertaking exercise programs. Exercise programs. Measures of adherence, adherence rates and factors associated with adherence. Nine eligible papers were identified. The most common adherence measures were the proportion of participants completing exercise programs (ie, did not cease participation, four studies, range 65 to 86%), proportion of available sessions attended (five studies, range 58 to 77%) and average number of home exercise sessions completed per week (two studies, range 1.5 to 3 times per week). Adherence rates were generally higher in supervised programs. The person-level factors associated with better adherence included: demographic factors (higher socioeconomic status, living alone); health status (fewer health conditions, better self-rated health, taking fewer medications); physical factors (better physical abilities); and psychological factors (better cognitive ability, fewer depressive symptoms).

Older people's adherence to exercise programs is most commonly measured with dropout and attendance rates and is associated with a range of program and personal factors.

closed_qa

Does comparative characterization of GmSPX members reveal that GmSPX3 is involved in phosphate homeostasis in soybean?

Proteins containing the SPX (SYG1/Pho81/XPR1) domain are vital components in the phosphorus (P) signalling pathway, and regulate phosphate (Pi) homeostasis in plants. However, the characteristics and functions of GmSPX members in soybean (Glycine max) remain largely unknown. BLAST searching revealed nine GmSPX members in the soybean genome. Subsequently, expression patterns of GmSPX members were investigated in various tissues of soybean grown in nutrient solution or sand culture through quantitative real-time PCR (qPCR) analysis. Sub-cellular localization of GmSPX was examined via transient expression of 35S:GmSPX-GFP in epidermal cells of onion (Allium cepa). Finally, soybean transgenic composite plants were generated to study GmSPX3 functions. Nine GmSPX members were identified, which were classified into three groups based on phylogenetic analysis. Diverse responses of GmSPX members to deficiencies of nutrients (nitrogen, phosphorus, potassium and iron) or inoculation of arbuscular mycorrhizal fungi and rhizobia were observed in soybean. In addition, variations of sub-cellular localization of GmSPX members were found. Among them, GmSPX3, GmSPX7 and GmSPX8 were localized in the nuclei, and the other GmSPX members were confined to the nuclei and cytoplasm. The nuclear-localized and Pi starvation responsive-gene, GmSPX3, was functionally analysed in soybean transgenic composite plants. Overexpression of GmSPX3 led to increased P concentrations in both shoots and roots in the high-P treatment, and increased transcription of seven Pi starvation-responsive genes in soybean hairy roots.

Taken together, the results suggest that GmSPX3 is a positive regulator in the P signalling network, and controls Pi homeostasis in soybean.

closed_qa

Does pancreatic intubation facilitated by methylene blue injection decrease the risk for postpapillectomy acute pancreatitis?

Endoscopic snare papillectomy (ESP) is a viable alternative to surgical treatment of ampullary adenomas and T1N0 stage ampullary carcinomas. The main drawback of this technique is the high risk of acute pancreatitis post procedure.The aim of this study was to assess the efficacy, safety, and long-term results of this procedure, and to determine whether routine pancreatic intubation facilitated by intraductal methylene blue (MB) injection reduces the risk for pancreatitis. Between 2004 and 2011, 56 consecutive patients underwent ESP. Before resection, the pancreatic duct was cannulated, and MB was injected intraductally to facilitate stent placement after ampullectomy. ESP was performed en bloc in 45 patients with histological findings of low-grade dysplasia (39%), high-grade dysplasia (25%), carcinoma (32.5%), and others (3.5%). The morbidity rate was 19.5%: acute pancreatitis (n=6), bleeding (n=4), perforation (n=1), and sepsis (n=1). Pancreatic intubation was performed in 89% of the patients. Postprocedure pancreatitis occurred significantly less in the patients with a pancreatic stent than in those without: 3/49 versus 3/6, P=0.013. ESP was considered as curative in 39 patients (75%). Of the 12 recurrences (25%), 10 were managed endoscopically, but with higher morbidity (acute pancreatitis=40%).

Endoscopic papillectomy is safe and effective in the hands of experts. Pancreatic-duct stent placement in fewer cannulation attempts could be facilitated by injection of MB before papillectomy, and this decreases the risk for postprocedure pancreatitis. Recurrences can be managed endoscopically, but with a higher risk for pancreatitis.

closed_qa

Does short-hairpin RNA-mediated MTA2 silencing inhibit human breast cancer cell line MDA-MB231 proliferation and metastasis?

To observe the effects of metastasis-associated tumor gene family 2 (MTA2) depletion on human breast cancer cell proliferation and metastasis. A short-hairpin RNA targeting MTA2 was chemically synthesized and transfected into a lentivirus to construct Lv-shMTA2 for infection into the MDA-MB231 human breast cancer cell line. At 48 hours after infection cells were harvested and mRNA and protein levels of MTA2 were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. Cell viability and metastasis were assessed by CCK-8, wound-healing assay and Transwell assay, respectively. In addition, a xenograft model of human breast cancer was constructed to investigate cancerous cell growth and capacity for metastasis. After infection with Lv-shMTA2, mRNA and protein levels of MTA2 was significantly reduced (p<0.05) and MDA-MB231 cell proliferation and metastasis were inhibited (p<0.05). In addition, mean tumor size was smaller than that in control group nude mice (p<0.05) and numbers of metastatic deposits in lung were lower than in control group mice (p<0.05). Depletion of MTA2 affected MMP-2 and apoptosis-related protein expression.

For the first time to our knowledge we showed that MTA2 depletion could significantly inhibit human breast cancer cell growth and metastasis, implying that MTA2 might be involved in the progression of breast cancer. The role of MTA2 in breast cancer growth and metastasis might be linked with regulation of matrix metalloproteinase and apoptosis.

closed_qa

Does high or low calcium intake increase cardiovascular disease risks in older patients with type 2 diabetes?

We investigated the effects of dietary calcium (Ca) and magnesium (Mg) intakes on cardiovascular disease risks in older patients with diabetes. In this cross-sectional study, 197 patients with type 2 diabetes aged 65 years and above were recruited. The 24-h dietary recalls and 1-week self-reported typical dietary intake patterns were collected. The Ca and Mg intakes of <67% of the recommended dietary allowance (RDA), 67%-100% of RDA, and >100% of RDA were defined as low, moderate, and high Ca and Mg intakes, respectively. Anthropometric measurements were determined and biochemical analysis of blood and urine was performed. Our data indicated that 60.9% and 87.3% of our patients were Ca and Mg intakes below RDA, respectively. Patients whose Ca intake was high or low (81.2%) had significantly higher C-reactive protein (CRP) than those whose Ca intake was moderate (p = 0.043). Furthermore, patients whose Mg intake was low (87.3%) had significantly higher CRP than that of those who took adequate Mg (p = 0.025). The dietary Ca:Mg intake ratios were highly correlated with CRP, platelet counts, and red blood cell distribution (p < 0.05). A dietary Ca:Mg intake ratio of 2.0-2.5 was significantly correlated to lower CRP levels (p = 0.013).

High or low calcium intake increases cardiovascular disease risks. We suggest that "moderate" intake of 402-600 mg Ca/day (approximately 67%-100% of Taiwan RDA for Ca) and adequate Mg intake (or meeting RDA for Mg) with Ca:Mg intake ratio of 2.0-2.5 are important for reducing cardiovascular disease risks in older patients with diabetes.

closed_qa

Does long-term , low-dose lithium treatment impair renal function in the elderly : a 2-year randomized , placebo-controlled trial followed by single-blind extension?

Recent studies evaluated the disease-modifying properties of lithium in mild cognitive impairment and dementia. Although potentially effective for these purposes, chronic lithium use in regard to safety in the elderly needs to be better explored. To evaluate the effect of long-term lithium treatment at subtherapeutic doses on renal function in older adults. Secondary aims were to evaluate the clinical safety and tolerability of this treatment and its effects on thyroid, immune, and glycemic functions. Between February 2007 and October 2011, a 2-year randomized, double-blind, placebo-controlled trial followed by a single-blinded phase for an additional 2 years. Sixty-one patients with mild cognitive impairment (Mayo Clinic criteria) were randomized to receive lithium or placebo. Renal function was estimated by the abbreviated Modification of Diet in Renal Disease (aMDRD) and the Chronic Kidney Disease-Epidemiology study (CKD-EPI) equations. Leukocytes, serum thyroid-stimulating hormone (TSH) and free thyroxine (T₄), and serum glucose and insulin were determined. Tolerability was evaluated at 3-month intervals through systematic clinical examinations and by the UKU Side Effect Rating Scale. Analysis of longitudinal regression indicated that no significant changes in renal function were detected by the aMDRD (P = .453) and CKD-EPI (P = .213) equations after 4 years of lithium treatment. Significant increases in the number of neutrophils (P = .038), serum TSH (P = .034), and body weight (P = .015) were observed in the lithium group. The lithium group presented more overall adverse events (P = .045), particularly interfering in daily activities (P < .001). In addition, those patients had a higher incidence of diabetes mellitus (P = .037) and arrhythmia (P = .028).

Chronic use of lithium at low doses did not affect renal function and was clinically safe. However, some other potentially relevant adverse events were observed and others could not be ruled out due to limitations of the study design.

closed_qa

Does comparative genomic hybridization show complex genomic changes of plasmacytoid urothelial carcinoma?

To describe genomic imbalances in plasmacytoid urothelial carcinoma (PUC), which is a rare and aggressive variant of urothelial carcinoma (UC). In total, 25 formalin-fixed paraffin-embedded PUCs were analyzed by metaphase comparative genomic hybridization. Genomic imbalances were considered to be characteristic if they were detected in ≥ 20% of the cases. Chromosome regions deviating by ≥ 3 standard deviations from the average chromosome profile were scored as chromosomal gains or losses. Copy-number variations (CNVs) of CDH1 (16q 22.1), SNAI1 (20q 13.1), CCND1 (11q13.3), ERBB2 (17q12), and FOXO3 (6q21) were validated using quantitative polymerase chain reaction. Chromosomal aberrations were detected in every PUC analyzed, and the average number of aberrations was 10.24 (ranging from 1-15). Characteristic aberrations were gains on 1q (48%), 3p (20%), 6p (32%), 11q (72%), 15q (36%), 16q (44%), 17p (76%), 17q (88%), and 20q (88%) and losses on 2q (24%) 4p (36%), 4q (84%), 5q (44%), 6q (68%), 13q (20%), and Xq (52%). polymerase chain reaction-based analysis of CNV for CCND1 (11q13) showed a deletion in 73% of the cases. CDH1 (16q22) was deleted in 72% and amplified in 5%. ERBB2 (17q12) displayed remarkably few copy-number alterations, with only 14% showing an amplification. SNAI1 (20q13) showed reduced gene copy numbers in 59.1% of the cases, whereas no copy-number gains were detected. FOXO3 (6q21) exhibited the lowest number of copy-number alterations, with 9% of all cases showing an amplification.

In PUCs, the frequency of aneuploidy and the complexity of genomic changes per tumor are greater than those described in conventional UC. The aberrations described in PUC involve the same regions that are associated with aggressive biological behavior in conventional UC. Gains on 11q, 17q, 17p, and 20q and losses on 4q and 6q affect most PUCs and seem to harbor important chromosomal regions for PUC carcinogenesis. Large-scale deletions on chromosome 9 were not detected. CNV analysis indicates heterozygous deletion of CDH1 as one underlying mechanism of loss of membranous E-cadherin in PUC. Loss of CCND1 and SNAI1 is a common molecular feature and could contribute to the aggressive biological behavior of PUC.

closed_qa

Is impaired subjective well-being in schizophrenia associated with reduced anterior cingulate activity during reward processing?

Patients with schizophrenia have substantially reduced subjective well-being (SW) compared to healthy individuals. It has been suggested that diminished SW may be related to deficits in the neural processing of reward but this has not been shown directly. We hypothesized that, in schizophrenia, lower SW would be associated with attenuated reward-related activation in the reward network. Twenty patients with schizophrenia with a range of SW underwent a functional magnetic resonance imaging (fMRI) reward task. The brain activity underlying reward anticipation and outcome in schizophrenia was examined and compared to that of 12 healthy participants using a full factorial analysis. Region of interest (ROI) analyses of areas within the reward network and whole-brain analyses were conducted to reveal neural correlates of SW. Reward-related neural activity in schizophrenia was not significantly different from that of healthy participants; however, the patients with schizophrenia showed significantly diminished SW. Both ROI and whole-brain analyses confirmed that SW scores in the patients correlated significantly with activity, specifically in the dorsal anterior cingulate cortex (dACC), during both reward anticipation and reward outcome. This association was not seen in the healthy participants.

In patients with schizophrenia, reduced activation of the dACC during multiple aspects of reward processing is associated with lower SW. As the dACC has been widely linked to coupling of reward and action, and the link to SW is apparent over anticipation and outcome, these findings suggest that SW deficits in schizophrenia may be attributable to reduced integration of environmental rewarding cues, motivated behaviour and reward outcome.

closed_qa

Does mPGES-2 deletion remarkably enhance liver injury in streptozotocin-treated mice via induction of GLUT2?

Microsomal prostaglandin E synthase-2 (mPGES-2) deletion does not influence in vivo PGE2 production and the function of this enzyme remains elusive. The present study was undertaken to investigate the role of mPGES-2 in streptozotocin (STZ)-induced type-1 diabetes and organ injuries. mPGES-2 wild type (WT) and knockout (KO) mice were treated by a single intraperitoneal injection of STZ at the dose of 120 mg/kg to induce type-1 diabetes. Subsequently, glycemic status and organ injuries were evaluated. Following 4 days of STZ administration, mPGES-2 KO mice exhibited severe lethality in contrast to the normal phenotype observed in WT control mice. In a separate experiment, the analysis was performed at day 3 of the STZ treatment in order to avoid lethality. Blood glucose levels were similar between STZ-treated KO and WT mice. However, the livers of KO mice were yellowish with severe global hepatic steatosis, in parallel with markedly elevated liver enzymes and remarkable stomach expansion. However, the morphology of the other organs was largely normal. The STZ-treated KO mice displayed extensive hepatocyte apoptosis compared with WT mice in parallel with markedly enhanced inflammation and oxidative stress. More interestingly, a liver-specific 50% upregulation of GLUT2 was found in the KO mice accompanied with a markedly enhanced STZ accumulation and this induction of GLUT2 was likely to be associated with the insulin/SREBP-1c pathway. Primary cultured hepatocytes of KO mice exhibited an increased sensitivity to STZ-induced injury and higher cellular STZ content, which was markedly blunted by the selective GLUT2 inhibitor phloretin.

mPGES-2 deletion enhanced STZ-induced liver toxicity possibly via GLUT2-mediated STZ uptake, independently of diabetes mellitus.

closed_qa

Does switching types of drug-eluting stents prevent repeated in-stent restenosis in patients with coronary drug-eluting stent restenosis?

We treated patients experiencing drug-eluting stent (DES) restenosis with plain old balloon angioplasty (POBA), implantation of the same type of DES [homogeneous drug-eluting stent (HOMO-DES)], or implantation of a different type of DES [heterogeneous drug-eluting stent (HETERO-DES)], and compared the efficacy and safety of these procedures for the prevention of repeated in-stent restenosis (ISR). In patients with de-novo coronary lesions, DES implantation is associated with a markedly reduced restenosis rate as compared with that associated with a bare metal stent and POBA. However, the optimal management strategy for patients with DES ISR remains unknown. We identified 191 consecutive DES ISR lesions from 183 patients who required clinically driven revascularization and divided them into three groups according to the treatment: 38 lesions were treated with POBA, 38 with HOMO-DES, and 115 with HETERO-DES. The incidence of target lesion revascularization (TLR) was 42.1% (16/38), 15.8% (6/38), and 16.5% (19/115) in the POBA, HOMO-DES, and HETERO-DES groups (POBA vs. HOMO, HETERO-DES; P=0.002, respectively). Multivariate analysis indicated that diabetes [odds ratio (OR), 3.4], hemodialysis (OR, 7.74), nonfocal ISR patterns (OR, 3.35), previous myocardial infarction (OR, 3.26), and POBA (OR, 8.84) were independent predictors of TLR.

A strategy involving repeated DES implantation was superior to POBA for preventing recurrent restenosis. Treatment with a different type or generation of DES does not appear to reduce the incidence of TLR. Moreover, we identified certain useful factors for facilitating appropriate and early triage in the patients with repeated DES ISR.

closed_qa

Does change in adiposity minimally affect the lipid profile in youth with recent onset type 1 diabetes?

Dyslipidemia contributes to the increased risk of cardiovascular disease in persons with type 1 diabetes (T1D). Weight control is commonly recommended as a treatment for dyslipidemia. However, the extent to which decreases in weight affect the lipid profile in youth with T1D is not known. Therefore, we tested the hypothesis that decreases in body mass index z-score (BMIz) were associated with concomitant changes in the lipid profile in youth with T1D. We studied 1142 youth with incident T1D, who had at least two fasting lipid measurements over 2 yr (initial visit mean: age = 10.8 ± 3.9 yr, BMIz = 0.55 ± 0.97, T1D duration = 10.7 ± 7.6 months; 47.5% female, 77.9% non-Hispanic white) in the SEARCH for Diabetes in Youth Study. Longitudinal mixed models were used to examine the relationships between changes in BMIz and changes in total, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL cholesterol, and log triglycerides (TG) adjusted for initial age, sex, race/ethnicity, clinical site, season of study visit, T1D duration, and glycated hemoglobin A1c (HbA1c). We found that over 2 yr all lipid levels, except LDL-C, increased significantly (p < 0.05). Decreases in BMIz were associated with favorable changes in HDL-C and TG only and the magnitude of these changes depended on the initial BMIz value (interaction p < 0.05), so that greater improvements were seen in those with higher BMIz.

Our data suggest that weight loss may be an effective, but limited, therapeutic approach for dyslipidemia in youth with T1D.

closed_qa

Is endoscopic gastric volume reduction with a novel articulating plication device safe and effective in the treatment of obesity ( with video )?

Endoscopic volume reduction of the stomach may provide a minimally invasive alternative for surgical procedures in the treatment of obesity. To assess safety and preliminary effectiveness in the first human application of a novel endoscopic stapling technique. Prospective, observational, phase 1 study. Two university hospitals in The Netherlands. Patients with a body mass index (BMI) of 40 to 45 kg/m(2) or 30 to 39.9 kg/m(2) with obesity-related comorbidity. Gastric volume reduction with an endoscopic stapler. Primary outcome measure was the prevalence of serious or mild adverse events. Reduction of excess body weight after 12 months was assessed as a secondary outcome measure for effectiveness of the procedure. Seventeen patients with a median BMI of 40.2 kg/m(2) (interquartile range [IQR] 37.6-42.8) underwent an endoscopic stapling procedure. Median procedure time was 123 minutes (IQR 95-129). No serious adverse events occurred. Adverse events were gastric pain (n = 7, range 1-3 days), sore throat (n = 4, 2-3 days), diarrhea (n = 4, 2-15 days), nausea (n = 3, 2-4 days), constipation (n = 4, 3-14 days), and vomiting (n = 3, 1-4 days). All adverse events were mild and resolved with conservative treatment within 15 days after surgery. The median percentage excess weight loss in the first year was 34.9% (IQR 17.8-46.6).

Limited number of patients.

closed_qa

Is environmental lead exposure associated with visit-to-visit systolic blood pressure variability in the US adults?

The association between environmental lead exposure and blood pressure variability, an important risk factor for cardiovascular disease, is unexplored and unknown. The objective of the study was to test the hypothesis that lead exposure is associated with blood pressure variability. American participants 17 years of age or older from National Health and Nutrition Examination Survey III were included in the analysis. Participants' blood lead concentrations expressed as micrograms per deciliter were determined. The standard deviations of visit-to-visit systolic and diastolic blood pressure were calculated to determine blood pressure variability. Multivariable regression analyses adjusted for age, gender, race, smoking and socioeconomic status were employed. The participants' mean age and mean blood lead concentration were 42.72 years and 3.44 mcg/dl, respectively. Systolic blood pressure variability was significantly associated with environmental lead exposure after adjusting for the effect of the confounders. The unadjusted and adjusted means of visit-to-visit systolic blood pressure variability and the β coefficient of lead exposure were 3.44, 3.33 mcg/dl, β coefficient = 0.07, P < 0.01.

This study documents a positive linear relationship between environmental lead exposure and systolic blood pressure variability. Screening adults with fluctuating blood pressure for lead exposure could be warranted.

closed_qa

Are residual perfusion defects in patients with pulmonary embolism related to impaired fibrinolytic capacity?

Few studies investigated the relationship between fibrinolysis abnormalities and residual pulmonary perfusion defects after acute pulmonary embolism (PE). To assess the fibrinolytic profile in patients with prior PE in relation to the extent of scintigraphically detectable residual perfusion abnormalities. We studied 71 consecutive patients with a prior episode of PE, who were examined after one year of the incident embolic event, and at least one month after anticoagulation withdrawal. They underwent lung scintigraphy to assess the recovery of pulmonary perfusion, echocardiography and chest radiography to look for signs of pulmonary hypertension. Clot formation and lysis were evaluated by two turbidimetric methods: Clot and Lysis Assay and Clot Lysis Time. We also measured the in vitro plasmin-mediated lysis of fibrin from purified fibrinogen, and the circulating levels of fibrinolytic inhibitors. The sample was split in two categories based on the extent of residual perfusion defects: <10% (n=53), ≥ 10% (n=18). Patients with perfusion defects >10% had significantly longer lysis time (p<0.05), and higher levels of plasminogen activator inhibitor-1 (p<0.01) than those with perfusion defects <10%. The time interval between symptoms onset and PE diagnosis (time-to-diagnosis) was significantly longer in patients with perfusion defects >10% than in the others (p=0.005). In multivariate logistic regression, both lysis time and time-to-diagnosis were independently associated with perfusion defects >10% (p<0.001). None of the sampled patients had echocardiographic or radiologic signs of pulmonary hypertension.

Prolonged time-to-diagnosis and fibrinolysis imbalance are independent predictors of incomplete perfusion recovery after acute PE.

closed_qa

Is chromogranin A a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas?

Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas. Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining. Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10-9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25-164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39-94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27-9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA.

CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.

closed_qa

Is expression of A disintegrin and metalloprotease 8 associated with cell growth and poor survival in colorectal cancer?

A disintegrin and metalloprotease 8 (ADAM8) has been reported to be associated with various malignancies. However, no studies have examined ADAM8 association in colorectal cancer (CRC). The aim of this study was to investigate the expression and function of ADAM8 in CRC. Expression level of ADAM8 in CRC was evaluated by quantitative RT-PCR, western blot and immunohistochemical staining analysis. The role of ADAM8 in colorectal carcinogenesis was evaluated by in vitro assays. The correlations between ADAM8 status and clinicopathological features including survival were analyzed. ADAM8 was highly expressed in CRC tissues compared with adjacent normal tissues. Knockdown of ADAM8 in two CRC cell lines resulted in reduced cellular growth and proliferation, and increased apoptosis. Immunohistochemistry analysis showed no significant correlations of ADAM8 protein expression with clinicopathologic features. Survival analysis indicated that patients with ADAM8-positive tumors had worse 5-year overall survival (OS, p = 0.037) and 5-year disease free survival (DFS, p = 0.014) compared with those with ADAM8-negative tumors. Multivariate analysis indicated ADAM8 expression was an independent prognostic factor for both OS and DFS (both p< 0.001). Subgroup analysis showed that 5-year OS of colon cancer, T3-T4 stage and N0 stage was worse for patients with ADAM8-positive tumors than those with ADAM8-negative tumors (p < 0.05). The 5-year DFS in colon cancer, T3-T4 stage, N0 stage, TNM stage II, adenocarcinoma, moderate differentiation and male patient subgroups was also worse for patients with ADAM8-positive tumors than those with ADAM8-negative tumors (p < 0.05).

Our results show that ADAM8 is overexpressed in CRC, promotes cell growth and correlates with worse OS and DFS, and thus could serve as a biomarker for individual CRC patient therapy.

closed_qa

Is functional recovery considered the most important target : a survey of dedicated professionals?

The aim of this study was to survey the relative importance of postoperative recovery targets and perioperative care items, as perceived by a large group of international dedicated professionals. A questionnaire with eight postoperative recovery targets and 13 perioperative care items was mailed to participants of the first international Enhanced Recovery After Surgery (ERAS) congress and to authors of papers with a clear relevance to ERAS in abdominal surgery. The responders were divided into categories according to profession and region. The recovery targets 'To be completely free of nausea', 'To be independently mobile' and 'To be able to eat and drink as soon as possible' received the highest score irrespective of the responder's profession or region of origin. Equally, the care items 'Optimizing fluid balance', 'Preoperative counselling' and 'Promoting early and scheduled mobilisation' received the highest score across all groups.

Functional recovery, as in tolerance of food without nausea and regained mobility, was considered the most important target of recovery. There was a consistent uniformity in the way international dedicated professionals scored the relative importance of recovery targets and care items. The relative rating of the perioperative care items was not dependent on the strength of evidence supporting the items.

closed_qa

Does successive exposure to moderate hypoxia affect glucose metabolism and substrate oxidation in young healthy men?

Exposure to hypoxia has been suggested to acutely alter glucose regulation. However, the effects of successive exposure to moderate hypoxia on postprandial glucose regulation and substrate oxidation pattern after multiple meals have not been elucidated. We examined the effects of successive exposure to moderate hypoxia on metabolic responses and substrate oxidation pattern. Eight healthy men (21.0 ± 0.6 yrs, 173 ± 2.3 cm, 70.6 ± 5.0 kg, 23.4 ± 1.1 kg/m(2)) completed two experimental trials on separate days: a rest trial under normoxic conditions (FiO2 = 20.9%) and a rest trial under hypoxic conditions (FiO2 = 15.0%). Experimental trials were performed over 7 h in an environmental chamber. Blood and respiratory gas samples were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after entering the chamber. Although each meal significantly increased blood glucose and serum insulin concentrations (P < 0.05), these responses did not differ significantly between the trials. There were no significant differences in areas under the curves for glucose or insulin concentrations over 7 h between the trials. No significant differences were observed in blood lactate, serum cortisol, free fatty acid, or glycerol concentrations over 7 h between the trials. The oxygen consumption ( [Formula: see text]) and carbon dioxide production ( [Formula: see text]) 3 h after entering the chamber were significantly higher in the hypoxic trial than in the normoxic trial (P < 0.05). However, the differences did not affect respiratory exchange ratio (RER). The average values of [Formula: see text], [Formula: see text], and RER did not differ between the trials.

Seven hours of moderate hypoxia did not alter postprandial glucose responses or substrate oxidation in young healthy men.

closed_qa

Is the CCR5Δ32 allele a major predisposing factor for severe H1N1pdm09 infection?

Host genetic factors are thought to modulated the severity of disease caused by infection with the 2009 H1N1 pandemic influenza virus (H1N1pdm09). The human CCR5 gene encodes a cytokine receptor important for cell-mediated immune response against H1N1pdm09. A 32-bp polymorphic deletion in the coding sequence of CCR5, the so-called CCR5Δ32 allele, segregates in populations of European ancestry with a frequency of 8-15%. A high proportion of CCR5Δ32 heterozygotes was reported in a sample of white Canadian critically-ill H1N1pdm09 infected subjects, suggesting an association with disease severity. We recruited 29 H1N1pdm09 infected subjects from Southern Europe (mostly Italians) with a wide clinical spectrum of disease symptoms; the sample included 7 subjects who developed acute respiratory distress syndrome requiring extracorporeal membrane oxygenation. The CCR5Δ32 variant was genotyped in all subjects. The CCR5Δ32 allele was found in one single subject, who developed a very mild form and was not hospitalized.

The CCR5Δ32 allele was not found to be associated with the risk of H1N1pdm09 infection or with a severe disease course.

closed_qa

Does repetitive electric brain stimulation reduce food intake in humans?

The dorsolateral prefrontal cortex (DLPFC) plays an important role in appetite and food intake regulation. Because previous data revealed that transcranial direct current stimulation (tDCS) of the DLPFC reduces food cravings, we hypothesized that repetitive electric stimulation of the right DLPFC would lower food intake behavior in humans. In a single-blind, code-based, placebo-controlled, counterbalanced, randomized crossover experiment, 14 healthy young men with body mass index (in kg/m(2)) from 20 to 25 were examined during 8 d of daily tDCS or a sham stimulation. After tDCS or sham stimulation on the first and the last day of both experimental conditions, participants consumed food ad libitum from a standardized test buffet. One week of daily anodal tDCS reduced overall caloric intake by 14% in comparison with sham stimulation. Moreover, repetitive tDCS diminished self-reported appetite scores.

Our study implies that the application of anodal direct currents to the right DLPFC represents a promising option for reducing both caloric intake and appetite in humans. This trial was registered at the German Clinical Trials Register (www.germanctr.de) as DRKS00005811.

closed_qa

Do progesterone receptor and PTEN expression predict survival in patients with low- and intermediate-grade pancreatic neuroendocrine tumors?

The PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) pathway plays a crucial role in a subset of advanced pancreatic neuroendocrine tumors (PanNETs). In breast and endometrial carcinoma, activation of this pathway inhibits progesterone receptor (PR) expression. To determine whether combined low expression of PR and phosphatase and tensin homologue (PTEN), a negative regulator of the PI3K-AKT-mTOR pathway, is a prognostic factor. A total of 160 resected PanNETs (89 low grade and 71 intermediate grade) were analyzed for PR and PTEN immunohistochemical positivity and staining was correlated with metastasis-free survival (MFS) and overall survival (OS). Progesterone receptor staining was scored as positive by using 1% or greater as cutoff. Weak/faint staining in greater than 90% of tumor cells was considered low PTEN positivity. Most PanNETs (110 cases, 69%) were both PR and PTEN positive, 45 (28%) were either PR or PTEN positive, and only 5 (3%) had a PR-negative and PTEN-low profile. Combined PR-PTEN positivity was significantly associated with MFS in patients with stage I and II disease (P <.001) and OS in all patients (P < .001) and remained a significant predictor of survival after adjusting for other factors. Patients with PR-negative-PTEN-low PanNETs had the shortest median MFS and OS, compared to those with tumors that were either PR or PTEN positive and with tumors positive for both PR and PTEN (P ≤ .001).

Combined immunohistochemical assessment of PR and PTEN may help identify a small subset of PanNETs with more aggressive behavior and may aid in risk stratification.

closed_qa

Does the yeast histone chaperone hif1p function with RNA in nucleosome assembly?

Hif1p is an H3/H4-specific histone chaperone that associates with the nuclear form of the Hat1p/Hat2p complex (NuB4 complex) in the yeast Saccharomyces cerevisiae. While not capable of depositing histones onto DNA on its own, Hif1p can act in conjunction with a yeast cytosolic extract to assemble nucleosomes onto a relaxed circular plasmid. To identify the factor(s) that function with Hif1p to carry out chromatin assembly, multiple steps of column chromatography were carried out to fractionate the yeast cytosolic extract. Analysis of partially purified fractions indicated that Hif1p-dependent chromatin assembly activity resided in RNA rather than protein. Fractionation of isolated RNA indicated that the chromatin assembly activity did not simply purify with bulk RNA. In addition, the RNA-mediated chromatin assembly activity was blocked by mutations in the human homolog of Hif1p, sNASP, that prevent the association of this histone chaperone with histone H3 and H4 without altering its electrostatic properties.

These results suggest that specific RNA species may function in concert with histone chaperones to assemble chromatin.

closed_qa

Do obese children and adolescents need increased gastric volumes in order to perceive satiety?

In order to develop effective weight management strategies, it is important to identify factors that influence energy intake. Portion size has been discussed as one such factor. To date, most studies focusing on the relationship between portion size, energy intake, and weight have analyzed questionnaire data and 24-h records. In this study, we assessed the onset of satiety using the water-load test in normal-weight and obese children and adolescents. 60 obese and 27 normal-weight children and adolescents aged between 9 and 17 years participated in the water load test which involved drinking water for 3 min or until feeling full. The amount of water consumed was recorded. Obese children and adolescents drank 20% more water until the onset of satiety when compared with normal-weight participants (478 ± 222 ml vs. 385 ± 115 ml, P < 0.05).

Obese children and adolescents need to ingest greater volumes to feel full which may predispose toward the consumption of larger portion sizes. This may easily lead to overeating if predominantly energy-dense foods are consumed. A reduction in energy-dense foods in the diet of obese children and adolescents appears to be a necessary strategy for managing body weight.

closed_qa

Does anesthetic preconditioning inhibit isoflurane-mediated apoptosis in the developing rat brain?

We hypothesized that preconditioning (PC) with a short exposure to isoflurane (ISO) would reduce neurodegeneration induced by prolonged exposure to ISO in neonatal rats, as previously shown in neuronal cell culture. We randomly divided 7-day-old Sprague-Dawley rats into 3 groups: control, 1.5% ISO, and PC + 1.5% ISO. The control group was exposed to carrier gas (30% oxygen balanced in nitrogen) for 30 minutes and then to carrier gas again for 6 hours the following day. The 1.5% ISO group was exposed to carrier gas for 30 minutes and then to 1.5% ISO for 6 hours the following day. The PC + 1.5% ISO group was preconditioned with a 30-minute 1.5% ISO exposure and then exposed to 1.5% ISO for 6 hours the following day. Blood and brain samples were collected 2 hours after the exposures for determination of neurodegenerative biomarkers, including caspase-3, S100β, caspase-12, and an autophagy biomarker Beclin-1. Prolonged exposure to ISO significantly increased cleaved caspase-3 expression in the cerebral cortex of 7-day-old rats compared with the group preconditioned with ISO and the controls using Western blot assays. However, significant differences were not detected for other markers of neuronal injury.

The ISO-mediated increase in cleaved caspase-3 in the postnatal day 7 rat brain is ameliorated by PC with a brief anesthetic exposure, and differences were not detected in other markers of neuronal injury.

closed_qa

Is cFI-rs7356506 a genetic protective factor for acute anterior uveitis in Chinese patients?

Complement Factor I (CFI) and the CD46 complement regulator (CD46) play an important role in the complement activation pathways, which is known to affect the development of uveitis. The present study was performed to investigate the association of the CFI and CD46 genes with acute anterior uveitis (AAU). A total of 600 subjects (300 patients with AAU and 300 healthy controls) were recruited for this case-control study. Six CFI single nucleotide polymorphisms (SNP) (rs7356506, rs10029485, rs11726949, rs12512308, rs7438961, rs998538) and four CD46 SNPs (rs12138764, rs2466571, rs2796278, rs7545126) were genotyped using Sequenom MassARRAY technology. Allele and genotype frequencies were compared between patients and controls using the χ(2) test. Analyses were stratified for gender, human leukocyte antigen (HLA)-B27, and ankylosing spondylitis status. Rs7356506 in the CFI gene was found to be protective against AAU. There was a significant increase in the frequency of the A allele (p=0.003, pc=0.03, OR=0.684, CI 0.534 to 0.876) and AA homozygosity (p=0.004, pc=0.04, OR=0.624, CI 0.452 to 0.862) in AAU patients as compared to controls. Stratified analysis, according to gender and HLA-B27 status for AAU, also revealed the association with CFI-rs7356506. None of the tested SNPs of CD46 were associated with AAU.

This study has revealed a significant association between AAU and CFI-rs7356506, suggesting that CFI is involved in the pathogenesis of AAU, and that its influence on AAU may differ depending on gender and HLA-B27 status.

closed_qa

Is early elevated serum gamma glutamyl transpeptidase after liver transplantation associated with better survival?

Gamma glutamyl transpeptidase (GGT) is a membrane bound enzyme that plays a key role in the synthesis of the antioxidant glutathione. Epidemiological studies have linked high GGT with an increased risk of morbidity and cardiovascular mortality. In contrast, GGT is usually elevated in liver transplant recipients that experience good outcomes. To study if and how GGT is correlated with mortality following liver transplantation. We analyzed the prognostic relevance of serum GGT levels during the early and late postoperative period after liver transplantation in 522 consecutive adults. We also studied alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels. Early after transplantation, the peak median (interquartile range) GGT levels were significantly higher in patients who survived more than 90 days compared to non-survivors: 293 (178-464) vs. 172 (84-239) U/l, p<0.0001. In contrast, late after transplantation, GGT levels were significantly lower in patients who survived more than 5 years than those who did not ( p<0.01). The pattern of GGT levels also differed from those of alanine aminotransferase, aspartate aminotransferase, and total bilirubin early after transplantation, while these patterns were congruent late after transplantation. Kaplan-Meier survival analysis showed that early after transplantation the higher the GGT levels, the better the 90-day survival ( p<0.001). In contrast, late after transplantation, higher GGT levels were associated with a lower 5-year survival ( p<0.001).

  These paradoxical findings may be explained by the time-dependent role of GGT in glutathione metabolism. Immediate postoperative elevation of GGT may indicate a physiological systemic response while chronic elevation reflects a pathological response.

closed_qa

Do sodium hypochlorite chemical burn in an endodontist 's eye during canal treatment using operating microscope?

This study describes a case of eye burn induced by sodium hypochlorite used as an irrigant during root canal preparation. A 24-year-old female endodontist was using an operating microscope during root canal treatment, and as the root canal was irrigated, the pressure cannula burst and the irrigant (3.5% sodium hypochlorite) came into direct contact with her left eye. She immediately sought ophthalmologic emergency care for pain, redness of the cornea, burning sensation, photophobia, intraocular pressure, and blurred vision. The initial treatment consisted of washing the eye with saline solution and administering analgesic and anti-inflammatory (steroid) medications. One day after the accident, a topical demulcent and hydroxypropyl medication were applied to the eyeball (conjunctiva), the eye was bandaged for 24 hours, and rest was prescribed for 7 days. Eight days later, a corneal ulcer was diagnosed, and antibiotic and anti-inflammatory (steroid) medications were used. Vision was restored without any sequelae 4 weeks after the accident. The endodontist was instructed to apply control medication (Lagricel; Sophia SA, Caracas, Venezuela) for 3 months and to return for ophthalmologic follow-up every 6 months.

Sodium hypochlorite is an effective antibacterial irrigant indicated for the treatment of root canal infections. The tissue cytotoxicity highlights the need to inform the patient of the risk factors of accidents and enhance care with individual protection equipment for the patient and the professional during clinical procedures.

closed_qa

Is human fetal growth constrained below optimal for perinatal survival?

The use of fetal growth charts assumes that the optimal size at birth is at the 50(th) birth-weight centile, but interaction between maternal constraints on fetal growth and the risks associated with small and large fetal size at birth may indicate that this assumption is not valid for perinatal mortality rates. The objective of this study was to investigate the distribution and timing (antenatal, intrapartum or neonatal) of perinatal mortality and morbidity in relation to birth weight and gestational age at delivery. Data from over 1 million births occurring at 28-43 weeks' gestation from singleton pregnancies without congenital abnormalities in the period from 2002 to 2008 were collected from The Netherlands Perinatal Registry. The distribution of perinatal mortality according to birth-weight centile and gestational age at delivery was studied. In the 1 170 534 pregnancies studied, there were 5075 (0.43%) perinatal deaths. The highest perinatal mortality occurred in those with a birth weight below the 2.3(rd) centile (25.4/1000 births) and the lowest mortality was in those with birth weights between the 80(th) and 84(th) centiles (2.4/1000 births), according to routinely used growth charts. Antepartum deaths were lowest in those with birth weight between the 90(th) and 95(th) centiles. Data were almost identical when the analysis was restricted to infants born at ≥ 37 weeks' gestation.

From an immediate survival perspective, optimal fetal growth requires a birth weight between the 80(th) and 84(th) centiles for the population. Median birth weight in the population is, by definition, substantially lower than these centiles, implying that the majority of fetuses exhibit some form of maternal constraint on growth. This finding is consistent with adaptations that have evolved in humans in conjunction with a large head and bipedalism, to reduce the risk of obstructed delivery. These data also fit remarkably well with those on long-term adult cardiovascular and metabolic health risks, which are lowest in cases with a birth weight around the 90(th) centile.

closed_qa

Does zinc treatment ameliorate diarrhea and intestinal inflammation in undernourished rats?

WHO guidelines recommend zinc supplementation as a key adjunct therapy for childhood diarrhea in developing countries, however zinc's anti-diarrheal effects remain only partially understood. Recently, it has been recognized that low-grade inflammation may influence stunting. In this study, we examined whether oral zinc supplementation could improve weight, intestinal inflammation, and diarrhea in undernourished weanling rats. Rats were undernourished using a northeastern Brazil regional diet (RBD) for two weeks, followed by oral gavage with a saturated lactose solution (30 g/kg) in the last 7 days to induce osmotic diarrhea. Animals were checked for diarrhea daily after lactose intake. Blood was drawn in order to measure serum zinc levels by atomic absorption spectroscopy. Rats were euthanized to harvest jejunal tissue for histology and cytokine profiles by ELISA. In a subset of animals, spleen samples were harvested under aseptic conditions to quantify bacterial translocation. Oral zinc supplementation increased serum zinc levels following lactose-induced osmotic diarrhea. In undernourished rats, zinc improved weight gain following osmotic diarrhea and significantly reduced diarrheal scores by the third day of lactose intake (p < 0.05), with improved jejunum histology (p < 0.0001). Zinc supplementation diminished bacterial translocation only in lactose-challenged undernourished rats (p = 0.03) compared with the untreated challenged controls and reduced intestinal IL-1β and TNF-α cytokines to control levels.

Altogether our findings provide novel mechanisms of zinc action in the setting of diarrhea and undernutrition and support the use of zinc to prevent the vicious cycle of malnutrition and diarrhea.

closed_qa

Does silibinin administration improve hepatic failure due to extensive liver infiltration in a breast cancer patient?

Silibinin exerts hepatoprotective, anti-inflammatory and anti-fibrotic effects. Several pre-clinical studies have shown anti-tumoral activity of silibinin in breast cancer cell lines. We present the case of a heavily pre-treated breast cancer patient with extensive liver infiltration. The patient presented with progressive liver failure despite several chemotherapy treatments, including paclitaxel, capecitabine and vinorelbine. After four cycles of a fourth-line chemotherapy treatment consisting of carboplatin and gemcitabine, the patient's liver blood test results deteriorated to life-threatening levels. The compassionate use of Legasil®, a new commercially available nutraceutical product containing a new silibinin formulation, was offered to the patient according to article 37 of the 2013 Declaration of Helsinki. After treatment initiation, the patient presented clinical and liver improvement, which permitted the patient to continue palliative chemotherapy.

This is the first case report of a clinical benefit of silibinin administration in a breast cancer patient.

closed_qa

Is spa typing alone sufficient to demonstrate endemic establishment of meticillin-resistant Staphylococcus aureus in a low-prevalence country?

The prevalence of meticillin-resistant Staphylococcus aureus (MRSA) in Norway is low but increasing. Over the last decade, numerous nursing homes have experienced MRSA outbreaks. One genetic lineage, spa type t304, has been identified at multiple nursing homes and has caused large outbreaks lasting for several years. To evaluate whether spa typing is sufficient for the detection of MRSA spread and endemic establishment in a low-prevalence area, using spa type t304 as the test organism. All spa type t304 isolates detected in 1991-2010 in the most densely populated area of Norway were included. Time and place of bacterial sampling were recorded. The isolates were analysed using multi-locus sequence typing, staphylococcal cassette chromosome mec typing, detection of lukS/F-PV and pulsed-field gel electrophoresis (PFGE). In total, 181 spa type t304 isolates were identified in three of 23 municipalities. Most (91%) of the isolates could be linked to 13 nursing homes, eight of which experienced outbreaks. PFGE analysis revealed three PFGE types, consisting of 19 PFGE patterns; 95% of the isolates were PFGE type 2. In total, PFGE types 2 and 3 accounted for 99% of all nursing home isolates, and included isolates from different nursing homes, different outbreaks and different time periods. Additional genetic analyses did not further differentiate between the spa type t304 isolates.

MRSA spa type t304 appears to have established itself as an endemic genetic lineage in the study area. spa typing does not provide sufficient resolution when investigating the spread of an endemic-like genetic lineage in a low-prevalence area, and should be supplemented by additional typing techniques.

closed_qa

Is total antioxidant capacity significantly lower in cocaine-dependent and methamphetamine-dependent patients relative to normal controls : results from a preliminary study?

Oxidative stress can result in damage to the brain and other organs. To protect from oxidative damage, the human body possesses molecular defense systems, based on the activity of antioxidants, and enzymatic defense systems, including the enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). Although pre-clinical research has shown that stimulant use is associated with oxidative damage, oxidative stress and the antioxidant defense systems have not been evaluated in clinical samples of stimulant-dependent patients. This study aimed to investigate the link between stimulant dependence and oxidative stress. Peripheral blood samples from 174 methamphetamine (n = 48) and/or cocaine-dependent (n = 126) participants as well as 30 normal control participants were analyzed for the enzyme activities of CAT, SOD, and GSH-Px in the erythrocytes and the total antioxidant capacity and the malondialdehyde concentration in the plasma. We could show an association of stimulant dependence with a depletion of total antioxidant capacity to 54.6 ± 4.7%, which correlates with a reduced activity of the SOD to 71.3 ± 0.03% compared with healthy control participants (100%).

Stimulant-dependent patients had significantly lower antioxidant capacity relative to controls, suggesting that they may be at greater risk for oxidative damage to the brain and other organs.

closed_qa

Is neoplastic progression in short-segment Barrett 's oesophagus associated with impairment of chemical clearance , but not inadequate acid suppression by proton pump inhibitor therapy?

Pathophysiological mechanisms associated with neoplastic progression in patients with short-segment Barrett's oesophagus (SSBO), who represent the vast majority of the Barrett population, have not been defined. To evaluate pathophysiological characteristics of patients with SSBO and dysplasia detected at 3-year surveillance endoscopy (incident dysplasia). Patients with SSBO underwent impedance-pH monitoring during heartburn-suppressing PPI therapy. Fifteen patients (12 males, median age 62 years) with incident dysplasia and 50 patients (43 males, median age 59 years) without dysplasia were compared. Impedance-pH parameters, including chemical clearance assessed by the post-reflux swallow-induced peristaltic wave (PSPW) index, were evaluated. All patients declared persisting heartburn suppression on maintenance PPI therapy at 3-year follow-up, 58/65 (89%) with standard dosages. The median gastric and oesophageal acid exposure time (GAET and OAET) did not differ between patients with and without incident dysplasia at the time of surveillance (36% and 0.6% vs. 33% and 0.5%) or index endoscopy (33% and 0.3% vs. 41% and 0.5%) (P > 0.05). Contrastingly, the median PSPW index was significantly lower in patients with than in patients without incident dysplasia at the time of surveillance (15%, vs. 32%) and index endoscopy (12% vs. 30%) (P = 0.001). The PSPW index, the GAET and the OAET did not vary over time (P > 0.05). A PSPW index <26% was predictive of incident dysplasia with a 75% accuracy.

Neoplastic progression in SSBO is associated with impairment of chemical clearance, but not inadequate acid suppression by PPI therapy. Neoplastic progression in SSBO can be predicted by a low PSPW index.

closed_qa

Does nADPH oxidase 2 mediate angiotensin II-dependent cellular arrhythmias via PKA and CaMKII?

Angiotensin II (Ang II) signaling has been implicated in cardiac arrhythmogenesis, which involves induction of reactive oxygen species (ROS). It was shown that Ang II can activate Ca/Calmodulin kinase II (CaMKII) by oxidation via a NADPH oxidase 2 (NOX2)-dependent pathway leading to increased arrhythmic afterdepolarizations. Interestingly, cAMP-dependent protein kinase A (PKA) which regulates similar targets as CaMKII has recently been shown to be redox-sensitive as well. This study aims to investigate the distinct molecular mechanisms underlying Ang II-related cardiac arrhythmias with an emphasis on the individual contribution of PKA vs. CaMKII. Isolated ventricular cardiac myocytes from rats and mice were used. Ang II exposure resulted in increased NOX2-dependent ROS generation assessed by expression of redox-sensitive GFP and in myocytes loaded with ROS indicator MitoSOX. Whole cell patch clamp measurements showed that Ang II significantly increased peak Ca and Na current (ICa and INa) possibly by enhancing steady-state activation of ICa and INa. These effects were absent in myocytes lacking functional NOX2 (gp91phox(-/-)). In parallel experiments using PKA inhibitor H89, the Ang II effects on peak INa and ICa were also absent. In contrast, genetic knockout of CaMKIIδ (CaMKIIδ(-/-)) did not influence the Ang II-dependent increase in peak ICa and INa. On the other hand, Ang II enhanced INa inactivation, increased late INa and induced diastolic SR (sarcoplasmic reticulum) Ca leak (confocal Ca spark measurements) in a CaMKIIδ-, but not PKA-dependent manner. Surprisingly, only the increase in diastolic SR Ca leak was absent in gp91phox(-/-)myocytes suggesting that Ang II regulates INa inactivation in a manner dependent on CaMKII- but not on NOX2. Finally, we show that Ang II increased the propensity for cellular arrhythmias, for which PKA and CaMKII contribute, both dependent on NOX2.

Ang II activates PKA and CaMKII via NOX2, which results in disturbed Na and Ca currents (via PKA) and enhanced diastolic SR Ca leakage (via CaMKII). Oxidative activation of PKA and CaMKII via NOX2 may represent important pro-arrhythmogenic pathways in the setting of increased Ang II stimulation, which may be relevant for the treatment of arrhythmias in cardiac disease.

closed_qa