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Background: Although FD may affect up to 10% of the general population, the therapy for FD is not standard. Recently, ginger-based food supplements have been proposed in order to restore FD symptoms. Our aim was to assess the efficacy of a new nutraceutical formulation containing extract of gingerol and thymus as a possible natural treatment in managing the symptoms of functional dyspepsia (FD). Methods: We retrospectively analyzed the efficacy and safety profiles of a nutraceutical formulation containing Zingiber officinalis root extract and a standardized Thymus extract. It was administered as 1 ml/day twice a day for 90 days. Patients were assessed at baseline and after 1, 2 and 3 months of treatment, following a month of pharmacological washout by completing a questionnaire reporting the trend of the following symptoms: epigastric pain, epigastric heaviness, early satiety, belching, and regurgitation. Every symptom was assessed by a Visual Analogic Scale (VAS), ranging from 0= absence to 10= maximal severity. Results: We enrolled 272 patients (99 males and 173 females; median IQR age 49.5, 36-64 yrs). Obesity (BMI>30) was present in 28 (12.5%) patients; smokers were 83 (30.5%); and comorbidities were present in 107 (39.3%) patients. Improvement of symptom scores during treatment and one month after its suspension was extremely significant (p Conclusion: This large study found that nutraceutical formulation could be one of the tools for an empirical approach to treat patients with FD, especially when a non-conventional drug treatment is preferable for the patient and considered suitable by the physician.

Although hyperkalemia (HK) is often associated with adverse clinical outcomes in renal patients, few studies are available in the setting of kidney transplantation. Therefore, we evaluated prevalence and clinical correlates of HK in stable kidney transplant recipients (KTRs) on standard of care immunosuppressive therapy. We studied 160 stable KTRs (post-transplant vintage 46.6 ± 16.6 months), most of whom (96.2%) on calcineurin inhibitor (CNI)-based immunosuppressive therapy. HK was defined as plasma potassium levels above 5 mEq/L, confirmed in two consecutive samples. Office blood pressure was measured, and renal graft function was expressed by estimated glomerular filtration rate (eGFR), calculated according to the CKD-EPI formula. HK prevalence was 8.8%, and plasma K above 5.5 mEq/L was found in 2.5% of all KTRs. In the univariate logistic regression analysis HK was significantly associated with serum urea concentration (OR 1.03, 95% CI 1.01–1.05 for each 1 mg/dL increase), tCO2 (OR 0.77, 95% CI 0.66–0.90 for each 1 mmol/L increase), the presence of arterial hypertension (OR 4.01, 95% CI 1.3–12.64), the use of RAAS inhibitors (OR 5.26, 95% CI 1.6–17.7), and eGFR less than 30 ml/min/1.73 m2 (OR 7.51, 95% CI 2.37–23.77). By multivariable backward stepwise regression analysis, the presence of metabolic acidosis (OR 0.83, 95% CI 0.69–0.99, P = 0.04), arterial hypertension (OR 4.65 95% CI 1.01–17.46 P = 0.03), and to be administered RAAS inhibitors (OR 6.11, 95% CI 1.03–25.96 P = 0.03) remained significantly associated with HK. We conclude that in stable KTRs the prevalence of HK is about 9%, slightly lower than previously reported. Moreover, it is not associated with eGFR, but with metabolic acidosis, arterial hypertension, and the use of RAAS inhibitors.

Tacrolimus is a cornerstone in the immunosuppressive therapy of kidney transplantation. The once-daily formulation of tacrolimus has been shown to improve adherence of patients without affecting short-term efficacy. However, long-term proof of once-daily tacrolimus efficacy and safety is still lacking. From January 2009 to November 2013, 170 clinically stable kidney transplant patients were offered to change from the ongoing twice-daily tacrolimus (TDT) formulation to a once-daily tacrolimus (ODT) regimen. Kidney transplant recipients agreeing to the change to be treated with an ODT regimen (n = 105, estimated glomerular filtration rate [eGFR] 57.1 ± 1.6 mL/min/1.73 m2) and patients continuing on a TDT formulation (n = 65, eGFR 52.0 ± 2.2 mL/min/1.73 m2) were prospectively followed (median follow-up time 10.4 and 12.6 years in the ODT and TDT groups, respectively, P = not significant). At the end of the follow-up, patients in both groups experienced similar eGFR (50.4 ± 2.2 vs 48.0 ± 2.7 mL/min/1.73 m2 in the ODT and TDT groups, respectively, P = not significant). No differences were observed in biopsy-proven acute rejection, overall graft survival, doubling of serum creatinine, and new onset of proteinuria. The 2 groups also had a comparable rate of death, sepsis, and neoplasia. In conclusion, ODT appears safe and effective in stable kidney graft recipients even 10 years after transplantation. These findings support the use of ODT as a primary tacrolimus formulation in patients with kidney transplantation.

Objectives and study aim Colonoscopy prevents colorectal cancer by removing adenomatous polyps, but missed adenomas lead to interval cancers. Different devices have been used to increase adenoma detection rates (ADR). Two such devices of interest are the transparent cap (Olympus) and Endocuff (ARC Medical). Our study aimed to compare differences in ADR between Endocuff-assisted colonoscopy (EAC), cap-assisted colonoscopy (CAC) and standard colonoscopy (SC). Patients and methods A sample size of 126 subjects was calculated to determine an effect size of 30 %. Patients undergoing screening or surveillance colonoscopy between March 2016 and January 2017 were randomized to SC, CAC or EAC groups. Three experienced endoscopists performed all colonoscopies. Patient demographics, procedure indication, Boston Bowel Prep Score (BBPS), withdrawal time, polyp size, location, histopathology, were analyzed. Results There was no difference in ADR (52 %, 40 % and 54 %) in the SC, CAC and EAC groups respectively (P = 0.4). Similar findings were also observed for proximal ADR (45 %, 35 %, and 50 %, P = 0.4) and SSA detection rate (16 %, 14 %, and 23 %, P = 0.5). EAC detected higher mean ADR per colonoscopy compared to CAC (1.70 vs 0.76, P = 0.01). However, there was no significant difference in mean ADR per positive colonoscopy (2.08, 1.63, and 2.59, P = 0.21). Conclusion In a randomized controlled trial comparing AC to CAC and SC, neither device conferred additional benefits in ADR among high detectors. When comparing each device, EAC may be better than CAC at detecting more total adenomas.

Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.

Malnutrition is common in AH, and almost all patients with severe AH have some component of malnutrition. The classic phenotype of malnutrition in AH is sarcopenia, but this has become more difficult to discern clinically as patients have become more obese. Patients with AH are often drinking 10–15 standard drinks/day. This substantial alcohol consumption becomes a major source of calories, but these should be considered “empty” calories that contain little nutritional value. Malnutrition is associated with liver complications such as hepatic encephalopathy and worse liver outcomes. Nutrition support, including interventions such as late-night snacks, can improve nutrition status and reduce complications.

Enteral access procedures can represent a significant proportion of many surgical and gastroenterologist’s practices (Reference) and a fundamental understanding of coding and reimbursement practices can assist in ensuring compensation for time, energy, and expertise devoted to these efforts. There is minimal medical literature and training available to clinicians to allow for some rudimentary comprehension of this very complex system. This review will discuss the basics of coding terminology and focus specifically on factors relevant to enteral access.

Cardiac fibrosis is a maladaptive remodeling of the myocardium hallmarked by contraction impairment and excessive extracellular matrix deposition (ECM). The disease progression, nevertheless, remains poorly understood and present treatments are not capable of controlling the scarring process. This is partly due to the absence of physiologically relevant, easily operable, and low-cost in vitro models, which are of the utmost importance to uncover pathological mechanisms and highlight possible targets for anti-fibrotic therapies. In classic models, fibrotic features are usually obtained using substrates with scar mimicking stiffness and/or supplementation of morphogens such as transforming growth factor β1 (TGF-β1). Qualities such as the interplay between activated fibroblasts (FBs) and cardiomyocytes (CMs), or the mechanically active, three-dimensional (3D) environment, are, however, neglected or obtained at the expense of the number of experimental replicates achievable. To overcome these shortcomings, we engineered a micro-physiological system (MPS) where multiple 3D cardiac micro-tissues can be subjected to cyclical stretching simultaneously. Up to six different biologically independent samples are incorporated in a single device, increasing the experimental throughput and paving the way for higher yielding drug screening campaigns. The newly developed MPS was used to co-culture different ratios of neonatal rat CMs and FBs, investigating the role of CMs in the modulation of fibrosis traits, without the addition of morphogens, and in soft substrates. The expression of contractile stress fibers and of degradative enzymes, as well as the deposition of fibronectin and type I collagen were superior in microtissues with a low amount of CMs. Moreover, high CM-based microconstructs simulating a ratio similar to that of healthy tissues, even if subjected to both cyclic stretch and TGF-β1, did not show any of the investigated fibrotic signs, indicating a CM fibrosis modulating effect. Overall, this in vitro fibrosis model could help to uncover new pathological aspects studying, with mid-throughput and in a mechanically active, physiologically relevant environment, the crosstalk between the most abundant cell types involved in fibrosis., High percentages of cardiomyocytes mitigate the onset of fibrotic traits induced by fibroblasts in a mid-throughput, mechanically active microdevice.

BackgroundShared etiological pathways of dopamine and serotonin neurotransmission play a central role in heavy alcohol intake and exacerbation in the symptoms of depression.We investigated the role of depression ratings and patterns of heavy drinking on the treatment efficacy of Quetiapine fumarate XR in lowering alcohol intake in alcohol use disorder (AUD) patients.MethodsOne hundred and eight male and female heavy drinking AUD patients in the age range of 18–64 yrs. received 12 weeks of active treatment. Participants were grouped by the severity grading of depression using Montgomery-Asberg Depression Rating Scale (MADRS) (clinically relevant≥8 [CR], clinically non-relevant≤7 [CNR]) at baseline. Drinking history and depression ratings were assessed at the patients visits.ResultsHeavy drinking days (HDD) and total drinks (TD) were significantly fewer in CR patients at the treatment end. A true positive response in AUROC analysis supported the lowering of TD in CR patients. The number of drinking days (NDD) and average drinks per drinking day (AvgD) were lower in the CNR patients at treatment-end. Significant associations with increasing effect sizes were observed for all the heavy drinking measures (HDD, TD, NDD and AvgD) and MADRS scores by the end of the treatment course.ConclusionsBaseline elevated depressive symptoms could likely predict the course of heavy alcohol drinking during the treatment, and efficacy outcome of a treatment. AUD patients with baseline clinically significant depression had a progressive lowering in heavy drinking markers significantly corresponding to the lowering of depression symptoms by the end of treatment with Quetiapine fumarate XR.ClinicalTrials.govNCT#0049862 (https://clinicaltrials.gov/ct2/show/NCT00498628?term=litten&draw=2&rank=3)

Background: Reported 10-year survival rates in Caucasian, black, and Hispanic women with breast cancer are 80%, 66%, and 78%, respectively. One barrier to understanding disparities in these survival rates is the lack of data due to underrepresentation in clinical trials (including black, Hispanic, Native American, and Pacific Islander populations). US physicians at sites that treat minority patients with breast cancer identified lack of access to and financial burden of clinical trials as 2 key barriers to enrollment. Insufficient knowledge of genetic mutations specific to breast cancer is also a key barrier to identifying ideal treatment to extend survival in minorities. Patient-specific initiatives for the CompLEEment-1 study (CLEE011A2404; NCT02941926), a single-arm, international Phase 3b study of ribociclib (600 mg/d, 3 weeks on/1 week off) plus letrozole (2.5 mg/d) in adults with hormone receptor–positive, human epidermal growth factor–negative advanced breast cancer, were developed in the United States to increase the enrollment of diverse populations and better understand the disease and patient response to treatment. Methods: The enrollment initiatives included formation of a board of leading physicians and academics to advise on awareness initiatives and the cultural competency of tools used in clinical trials, a site selection process that brought the trial to the patient's clinic, a simplified expense reimbursement program to reduce patient economic burden, and partnerships with the Bridge Group and the National Black Church Initiative to bring clinical trial awareness and education to the African American church community. A tumor collection companion study (NCT03050398) was created to identify mechanisms of resistance among racial and ethnic groups. These initiatives aimed to increase the percentage of minorities from previous trials (eg, 5.7% in the MONALEESA-2 trial) and identify potential biological differences associated with race or ethnicity that might affect treatment response. Results: Enrollment in the CompLEEment-1 study is ongoing. Among the first 57 US patients enrolled, 8 (14.0%) were minorities (not identified as Caucasian or Asian), 32 (56.1%) were 30 miles outside of metropolitan areas. Of the open study sites with enrolled patients, 16 enrolled 1, 8 enrolled 2, and 5 enrolled ≥3 patients. Conclusions: Following discussions with physicians and assessments of patient feedback to identify reasons for underrepresentation of minority patient populations in clinical trials, patient-centered initiatives were developed for the CompLEEment-1 study in the United States to simultaneously reduce barriers to trial participation, reduce economic burden of enrolled patients, and identify biomarkers of therapeutic sensitivity and resistance. These initiatives resulted in an initial increase in the percentage of minorities enrolled to better reflect real-world populations. Citation Format: Small T, Marsano-Feeley J, Fernandez A, Grasso T, Feldman K, Petrone S, Bugazia N, Wong C, Meyer J, Schutta K, Purkayastha D, Saintil K, Spatz Caplan E, Waltman-Johnson K. Patient-centered initiatives for improving trial participation of diverse patient populations in the open-label phase 3b compLEEment-1 study of ribociclib plus letrozole in the treatment of HR+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-07.

Nicotinamide is the precursor of nicotinamide adenine dinucleotide (NAD+), an essential cofactor for adenosine triphosphate (ATP) production. It has recently been reported to be effective in reducing the rates of new non-melanoma skin cancers (NMSCs) and actinic keratosis (AKs). We studied the efficacy of oral nicotinamide as treatment for AKs in transplant recipients. We recruited 38 transplant (eight liver and 30 kidney) patients with single or multiple AKs. Nineteen patients were randomly assigned to Group 1 and took nicotinamide 500 mg/daily (cases); the other 19 patients were randomly assigned to Group 2 without nicotinamide (controls). At base-line, AKs were identified, measured, and photographed for follow-up. Five patients underwent an AK biopsy for histopathology. Statistical analyses were performed using the Student t test. At baseline, no statistically significant differences were observed regarding AK size between the two groups. After six months, among the cases, AKs had significantly decreased in size in 18/19 patients (88%). Among these 18 patients, seven patients (42%) had shown complete clinical regression and no patient developed new AKs. Conversely, among the controls, 91% showed an increase in AK size and/or developed new AKs. Seven pre-existing AKs progressed to squamous-cell carcinoma. Nicotinamide appears to be effective in preventing and treating AKs, although the mechanisms are still unclear. Further studies with a larger sample of organ transplant recipients and a longer follow-up period are needed to further support our conclusions.

There is no specific therapy for polyoma BK virus nephropathy (BKVN) in kidney transplant recipients, a condition associated with poor outcomes. Everolimus showed promising antiviral effects, but data from prospective studies are limited. Therefore, we converted ten consecutive kidney transplant recipients with biopsy-proven BKVN from standard exposure Calcineurin inhibitors and Mycophenolate to Everolimus and reduced exposure Calcineurin inhibitors. Ten patients not administered Everolimus, on reduced exposure Calcineurin inhibitor and halved MPA doses served as controls. All kidney transplant recipients continued steroid therapy. Each patient underwent kidney graft biopsy, BKV replication by PCR, and de novo DSA determination. During a 3-year follow-up no graft loss occurred in kidney transplant recipients on Everolimus but it was observed in 5/10 controls (P = 0.032). eGFR improved on Everolimus and worsened in controls (between group difference + 25.6 ml/min/1.73 m2, 95% CI 10.5–40.7, P = 0.002). BKV replication declined in the Everolimus group alone (from 6.4 ± 0.8 to 3.6 ± 1.6 Log 10 genomic copies, P = 0.0001), and we found a significant inverse relationship between eGFR and BKV genomic copy changes (P = 0.022). Average Calcineurin inhibitors trough levels did not differ between the two study groups during follow-up. By multivariable Cox regression analysis, Everolimus treatment resulted the only significant predictor of survival free of a combined endpoint of graft loss and 57% eGFR reduction (P = 0.02). Kidney transplant recipients on Everolimus had a higher survival free of adverse graft outcome (log-rank test, P = 0.009). In conclusion an Everolimus-based immunosuppressive protocol with minimization of Calcineurin inhibitors and antimetabolite discontinuation effectively treated BKVN in kidney transplant recipients.

Efforts to provide early enteral nutrition in critical illness are thwarted by gastrointestinal dysfunction and feeding intolerance. While many of the signs and symptoms of this dysfunction reflect gastroparesis and intestinal dysmotility, other symptoms which may or may not be related are often included such as diarrhea, bleeding, and intra-abdominal hypertension. This paper discusses the need to monitor tolerance of nutritional therapy in the critical care setting and reviews the results of those clinical trials which have helped establish objective measures, define feeding intolerance, and provide a tool to guide continued delivery of the enteral regimen. While definitions vary, the presence of gastrointestinal dysfunction and feeding intolerance correlates with adverse clinical outcomes, including prolonged duration of mechanical ventilation, greater length of stay in the intensive care unit, and increased mortality. Despite their prognostic value, it is not clear to what extent these scoring systems should direct nutritional therapy. The clinician should be astute in the careful selection of monitors, in identifying and addressing signs and symptoms of intolerance, and by responding appropriately with feeding strategies that are effective and safe. Early enteral feeding in critical illness has been shown to be optimized by following protocols which allow monitoring patient tolerance while providing individualized care.

Myotonia congenita is an inherited disease that is characterized by impaired muscle relaxation after contraction caused by loss-of-function mutations in the skeletal muscle ClC-1 channel. We report a novel ClC-1 mutation, T335N, that is associated with a mild phenotype in 1 patient, located in the extracellular I-J loop. The purpose of this study was to provide a solid correlation between T335N dysfunction and clinical symptoms in the affected patient as well as to offer hints for drug development. Our multidisciplinary approach includes patch-clamp electrophysiology on T335N and ClC-1 wild-type channels expressed in tsA201 cells, Western blot and quantitative PCR analyses on muscle biopsies from patient and unaffected individuals, and molecular dynamics simulations using a homology model of the ClC-1 dimer. T335N channels display reduced chloride currents as a result of gating alterations rather than altered surface expression. Molecular dynamics simulations suggest that the I-J loop might be involved in conformational changes that occur at the dimer interface, thus affecting gating. Finally, the gene expression profile of T335N carrier showed a diverse expression of K+ channel genes, compared with control individuals, as potentially contributing to the phenotype. This experimental paradigm satisfactorily explained myotonia in the patient. Furthermore, it could be relevant to the study and therapy of any channelopathy.—Imbrici, P., Altamura, C., Camerino, G. M., Mangiatordi, G. F., Conte, E., Maggi, L., Brugnoni, R., Musaraj, K., Caloiero, R., Alberga, D., Marsano, R. M., Ricci, G., Siciliano, G., Nicolotti, O., Mora, M., Bernasconi, P., Desaphy, J.-F., Mantegazza, R., Camerino, D. C. Multidisciplinary study of a new ClC-1 mutation causing myotonia congenita: a paradigm to understand and treat ion channelopathies.

Mitochondrial disorders associated with genetic defects of the ATP synthase are among the most deleterious diseases of the neuromuscular system that primarily manifest in newborns. Nevertheless, the number of established animal models for the elucidation of the molecular mechanisms behind such pathologies is limited. In this paper, we target the Drosophila melanogaster gene encoding for the ATP synthase subunit c, ATPsynC, in order to create a fruit fly model for investigating defects in mitochondrial bioenergetics and to better understand the comprehensive pathological spectrum associated with mitochondrial ATP synthase dysfunctions. Using P-element and EMS mutagenesis, we isolated a set of mutations showing a wide range of effects, from larval lethality to complex pleiotropic phenotypes encompassing developmental delay, early adult lethality, hypoactivity, sterility, hypofertility, aberrant male courtship behavior, locomotor defects and aberrant gonadogenesis. ATPsynC mutations impair ATP synthesis and mitochondrial morphology, and represent a powerful toolkit for the screening of genetic modifiers that can lead to potential therapeutic solutions. Furthermore, the molecular characterization of ATPsynC mutations allowed us to better understand the genetics of the ATPsynC locus and to define three broad pathological consequences of mutations affecting the mitochondrial ATP synthase functionality in Drosophila: i) pre-adult lethality; ii) multi-trait pathology accompanied by early adult lethality; iii) multi-trait adult pathology. We finally predict plausible parallelisms with genetic defects of mitochondrial ATP synthase in humans., This work was supported by grants from Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) to C.C. and University of Bari D.R. n. 12939 to D.P.

Cell-based therapies show promising results in cardiac function recovery mostly through paracrine-mediated processes (as angiogenesis) in chronic ischemia. In this study, we aim to develop a 2D (two-dimensional) in vitro cardiac hypoxia model mimicking severe cardiac ischemia to specifically investigate the prosurvival paracrine effects of adipose tissue-derived stromal vascular fraction (SVF) cell secretome released upon three-dimensional (3D) culture. For the 2D-cardiac hypoxia model, neonatal rat cardiomyocytes (CM) were cultured for 5 days at

Early antidepressant response (2nd week) has been reported as the result of a true antidepressant effect and a predictor of subsequent stable response. With the purpose to study the clinical profile of early response/remission (2nd week) compared to late response/remission (4th-6th weeks), two independent major depressive disorder (MDD) samples (the Sequenced Treatment Alternatives to Relieve Depression or STAR*D n=1922 and an Italian sample n=171) were investigated. Patients were treated with citalopram in the STAR*D while in a naturalistic setting in the Italian sample. Depressive symptomatology was assessed by the Hamilton Depressive Rating Scale weekly in the Italian sample and biweekly by the Quick Inventory of Depressive Symptomatology Clinician Rated in the STAR*D. Logistic regression was used to investigate possible predictors of early response and the Bonferroni correction was applied. In the STAR*D, higher levels of baseline core depressive symptoms (Bech subscale) were associated with early response (p=0.00017), as well as lower baseline insomnia (p=0.003) and higher work and social functioning (p=0.001). In the Italian sample none of these variables were associated with the phenotype, but a non significant trend of lower baseline quality of life (p=0.078) was observed in late remitters. In the STAR*D late responders reported higher levels of antidepressant induced side effects, especially difficulty in sleeping (p=5.68e-13), with a non significant trend in the same direction in the Italian sample (p=0.09). The identification of late versus early antidepressant responders at the beginning of the treatment may be useful to guide therapeutic choices in clinical settings.

BACKGROUND Asymptomatic left ventricular hypertrophy (LVH) is highly prevalent and associated with an adverse outcome in renal transplant recipients (RTRs). Nonetheless, there are currently no available studies analyzing the effect of LVH regression on solid clinical endpoints in these patients. METHODS This study is the prospective observational extension of two randomized controlled trials aimed at assessing the effect of active intervention on post-transplant LVH in RTRs. We evaluated the incidence of a composite of death and any cardiovascular (CV) or renal event in 60 RTRs in whom LVH regression was observed and in 40 whose LVH remained unchanged or worsened. RESULTS During an 8.4 ± 3.5-year follow-up, 8 deaths, 18 CV events and 6 renal events occurred in the entire cohort. Multivariable analysis showed that age [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.03-1.12 each 1 year, P = 0.002] and LVH regression (HR 0.42, 95% CI 0.22-0.87, P = 0.019) were significant predictors of the composite endpoint. Kaplan-Meier estimates showed better survival rates in patients in whom actual LVH regression was achieved (P < 0.001, log-rank test). Age (HR 1.09, 95% CI 1.03-1.15 each 1 year, P = 0.004), better graft function (HR 0.95, 95% CI 0.91-0.99 each 1 mL/min/1.73 m(2) increase in estimated glomerular filtration rate, P = 0.03) and LVH regression (HR 0.41, 95% CI 0.22-0.79, P = 0.01) were significant predictors of the CV endpoint. Patients with a left ventricular mass index decrease also showed better cardiac event-free survival (P = 0.0022, log-rank test). CONCLUSIONS This is the first study to demonstrate that LVH regression, regardless of the therapeutic strategy adopted to achieve it, portends better long-term clinical outcome in RTRs.

We here describe a leukemogenic role of the homeobox gene UNCX, activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of UNCX in a leukemia patient harboring a t(7;10)(p22;p14) translocation, in 22 of 61 of additional cases [a total of 23 positive patients out of 62 (37.1%)], and in 6 of 75 (8%) of AML cell lines. UNCX is embedded within a low-methylation region (canyon) and encodes for a transcription factor involved in somitogenesis and neurogenesis, with specific expression in the eye, brain, and kidney. UNCX expression turned out to be associated, and significantly correlated, with DNA methylation increase at its canyon borders based on data in our patients and in archived data of patients from The Cancer Genome Atlas. UNCX-positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as MAP2K1 and CCNA1, was revealed. Similar results were obtained in UNCX-transduced CD34+ cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that UNCX expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type NPM1. We also observed that UNCX expression significantly associates with an increased frequency of acute promyelocytic leukemia with PML-RARA and AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of UNCX, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.

In vitro cardiac models able to mimic the fibrotic process are paramount to develop an effective anti-fibrosis therapy that can regulate fibroblast behaviour upon myocardial injury. In previously developed in vitro models, typical fibrosis features were induced by using scar-like stiffness substrates and/or potent morphogen supplementation in monolayer cultures. In our model, we aimed to mimic in vitro a fibrosis-like environment by applying cyclic stretching of cardiac fibroblasts embedded in three-dimensional fibrin-hydrogels alone. Using a microfluidic device capable of delivering controlled cyclic mechanical stretching (10% strain at 1 Hz), some of the main fibrosis hallmarks were successfully reproduced in 7 days. Cyclic strain indeed increased cell proliferation, extracellular matrix (ECM) deposition (e.g. type-I-collagen, fibronectin) and its stiffness, forming a scar-like tissue with superior quality compared to the supplementation of TGFβ1 alone. Taken together, the observed findings resemble some of the key steps in the formation of a scar: (i) early fibroblast proliferation, (ii) later phenotype switch into myofibroblasts, (iii) ECM deposition and (iv) stiffening. This in vitro scar-on-a-chip model represents a big step forward to investigate the early mechanisms possibly leading later to fibrosis without any possible confounding supplementation of exogenous potent morphogens.

Summary Background Autologous native cartilage from the nasal septum, ear, or rib is the standard material for surgical reconstruction of the nasal alar lobule after two-layer excision of non-melanoma skin cancer. We assessed whether engineered autologous cartilage grafts allow safe and functional alar lobule restoration. Methods In a first-in-human trial, we recruited five patients at the University Hospital Basel (Basel, Switzerland). To be eligible, patients had to be aged at least 18 years and have a two-layer defect (≥50% size of alar subunit) after excision of non-melanoma skin cancer on the alar lobule. Chondrocytes (isolated from a 6 mm cartilage biopsy sample from the nasal septum harvested under local anaesthesia during collection of tumour biopsy sample) were expanded, seeded, and cultured with autologous serum onto collagen type I and type III membranes in the course of 4 weeks. The resulting engineered cartilage grafts (25 mm × 25 mm × 2 mm) were shaped intra-operatively and implanted after tumour excision under paramedian forehead or nasolabial flaps, as in standard reconstruction with native cartilage. During flap refinement after 6 months, we took biopsy samples of repair tissues and histologically analysed them. The primary outcomes were safety and feasibility of the procedure, assessed 12 months after reconstruction. At least 1 year after implantation, when reconstruction is typically stabilised, we assessed patient satisfaction and functional outcomes (alar cutaneous sensibility, structural stability, and respiratory flow rate). Findings Between Dec 13, 2010, and Feb 6, 2012, we enrolled two women and three men aged 76–88 years. All engineered grafts contained a mixed hyaline and fibrous cartilage matrix. 6 months after implantation, reconstructed tissues displayed fibromuscular fatty structures typical of the alar lobule. After 1 year, all patients were satisfied with the aesthetic and functional outcomes and no adverse events had been recorded. Cutaneous sensibility and structural stability of the reconstructed area were clinically satisfactory, with adequate respiratory function. Interpretation Autologous nasal cartilage tissues can be engineered and clinically used for functional restoration of alar lobules. Engineered cartilage should now be assessed for other challenging facial reconstructions. Funding Foundation of the Department of Surgery, University Hospital Basel; and Krebsliga beider Basel.

Background: Patients with major depression (MD) show reduced social adjustment when compared with healthy controls. However, even among treatment responders, significant differences in social adjustment occur. The main aim of the present work is to study several socio-demographic and clinical variables possibly influencing social adjustment in MD patients who responded to treatment. Methods: Two hundred and eleven MD patients experiencing a depressive episode who responded to their current treatment were recruited within the context of a large European multicentre project. Our primary outcome measure was the association between 19 socio-demographic and clinical variables and total social adjustment scores, as measured with the Social Adjustment Scale (SAS). Secondary outcome measures included the associations between the same variables and SAS sub-scales, and the associations between these variables and self-esteem, as measured with the Rosenberg Self-Esteem Scale. Results: A co-morbidity with anxiety disorders and the severity of residual depression symptoms were the strongest independent factors associated with poorer social adjustment, in terms of total and most sub-areas' SAS scores. Other variables associated with total and sub-areas' SAS scores were identified as well, although some variations across different areas were observed. Limitations: The cross-sectional design, the retrospective assessment of data and the lack of a placebo control group. Conclusions: Our results confirm that a co-morbidity with anxiety disorders and higher residual depression symptoms could reduce social adjustment among responder MD patients. Further longitudinal studies are needed to confirm our results. (C) 2013 Elsevier B.V. All rights reserved.

Key requirements for cardiac tissue engineering include the maintenance of cell viability and function and the establishment of a perfusable vascular network in millimeters thick and compact cardiac constructs upon implantation. We investigated if these requirements can be met by providing an intrinsic vascularization stimulus (via sustained action of VEGF secreted at a controlled rate by transduced myoblasts) to a cardiac patch engineered under conditions of effective oxygen supply (via medium flow through channeled elastomeric scaffolds seeded with neonatal cardiomyocytes). We demonstrate that this combined approach resulted in increased viability, vascularization and functionality of the cardiac patch. After implantation in a mouse model of myocardial infarction, VEGF-expressing patches displayed significantly improved engraftment, survival and differentiation of cardiomyocytes, leading to greatly enhanced contractility as compared to controls not expressing VEGF. Controlled VEGF expression also mediated the formation of mature vascular networks, both within the engineered patches and in the underlying ischemic myocardium. We propose that this combined cell-biomaterial approach can be a promising strategy to engineer cardiac patches with intrinsic and extrinsic vascularization potential.

Despite encouraging preclinical results for therapeutic angiogenesis in ischemia, a suitable approach providing sustained, safe and efficacious vascular growth in the heart is still lacking. Vascular Endothelial Growth Factor (VEGF) is the master regulator of angiogenesis, but it also can easily induce aberrant and dysfunctional vascular growth if its expression is not tightly controlled. Control of the released level in the microenvironment around each cell in vivo and its distribution in tissue are critical to induce stable and functional vessels for therapeutic angiogenesis. The present review discusses the limitations and perspectives of VEGF gene therapy and of different cell-based approaches for the implementation of therapeutic angiogenesis in the treatment of cardiac ischemia.

The aim of the study was to compare differences in dosimetric, clinical and quality-of-life end points among patients treated with helical tomotherapy (HT) and segmental multileaf collimator (SMLC)-based intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma.From June 2005 to August 2009, 30 consecutive patients were treated with IMRT for nasopharyngeal carcinoma to a dose of 70 Gy. 14 patients (47%) were treated using HT and 16 (53%) were treated using SMLC-based IMRT. 28 patients (93%) received concurrent chemotherapy. The patients were evenly balanced between the two radiotherapy groups with respect to clinical and pathological characteristics. Median follow-up was 30 months (range, 6-62 months).The 2-year estimates of overall survival, local-regional control and progression-free survival were 81%, 87% and 82%, respectively. There were no significant differences in any of these end points with respect to IMRT technique (p0.05 for all). Dosimetric analysis revealed that patients treated by HT had significantly improved salivary sparing with respect to mean dose (27.3 vs 34.1 Gy, p=0.03) and volume receiving greater than or equal to 30 Gy (31.7% vs 47.3%, p=0.01) to the contralateral (spared) parotid gland. The incidence of Grade 3+ late xerostomia was 13 and 7% among patients treated with SMLC-based IMRT and HT, respectively (p=0.62). The corresponding proportion of patients who subjectively reported "too little" or "no" saliva at final follow-up was 38% and 7%, respectively (p=0.04).The superior dosimetric outcome observed with HT appeared to translate into moderately improved clinical outcomes with respect to salivary sparing. Prospective trials are needed to validate this gain in the therapeutic ratio.

To compare differences in dosimetric, clinical, and quality-of-life endpoints among a cohort of patients treated by intensity-modulated radiotherapy (IMRT) and conventional radiotherapy (CRT) for head-and-neck cancer of unknown primary origin.The medical records of 51 patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Twenty-four patients (47%) were treated using CRT, and 27 (53%) were treated using IMRT. The proportions of patients receiving concurrent chemotherapy were 54% and 63%, respectively.The 2-year estimates of overall survival, local-regional control, and disease-specific survival for the entire patient population were 86%, 89%, and 84%, respectively. There were no significant differences in any of these endpoints with respect to radiation therapy technique (p0.05 for all). Dosimetric analysis revealed that the use of IMRT resulted in significant improvements with respect to mean dose and V30 to the contralateral (spared) parotid gland. In addition, mean doses to the ipsilateral inner and middle ear structures were significantly reduced with IMRT (p0.05 for all). The incidence of severe xerostomia in the late setting was 58% and 11% among patients treated by CRT and IMRT, respectively (p0.001). The percentages of patients who were G-tube dependent at 6 months after treatment were 42% and 11%, respectively (p0.001).IMRT results in significant improvements in the therapeutic ratio among patients treated by radiation therapy for head-and-neck cancer of unknown primary origin.

Malnutrition, both protein energy malnutrition (PEM) and deficiencies in individual nutrients, is a frequent complication of alcoholic liver disease (ALD). Severity of malnutrition correlates with severity of ALD. Malnutrition also occurs in patients with cirrhosis due to etiologies other than alcohol. The mechanisms for malnutrition are multifactorial, and malnutrition frequently worsens in the hospital due to fasting for procedures and metabolic complications of liver disease, such as hepatic encephalopathy. Aggressive nutritional support is indicated in inpatients with ALD, and patients often need to be fed through an enteral feeding tube to achieve protein and calorie goals. Enteral nutritional support clearly improves nutrition status and may improve clinical outcome. Moreover, late-night snacks in outpatient cirrhotics improve nutritional status and lean body mass. Thus, with no FDA-approved therapy for ALD, careful nutritional intervention should be considered as frontline therapy.

Alcoholic liver disease (ALD) remains a major cause of liver-related mortality in the US and worldwide. The correct diagnosis of ALD can usually be made on a clinical basis in conjunction with blood tests, and a liver biopsy is not usually required. Abstinence is the hallmark of therapy for ALD, and nutritional therapy is the first line of therapeutic intervention. The role of steroids in patients with moderate to severe alcoholic hepatitis is gaining increasing acceptance, with the caveat that patients be evaluated for the effectiveness of therapy at 1 week. Pentoxifylline appears to be especially effective in ALD patients with renal dysfunction/hepatorenal syndrome. Biologics such as specific anti-TNFs have been disappointing and should probably not be used outside of the clinical trial setting. Transplantation is effective in patients with end-stage ALD who have stopped drinking (usually for ≥6 months), and both long-term graft and patient survival are excellent.

Cardiac tissue engineering aims to create functional tissue constructs that can reestablish the structure and function of injured myocardium. Engineered constructs can also serve as high-fidelity models for studies of cardiac development and disease. In a general case, the biological potential of the cell—the actual “tissue engineer”—is mobilized by providing highly controllable three-dimensional environments that can mediate cell differentiation and functional assembly. For cardiac regeneration, some of the key requirements that need to be met are the selection of a human cell source, establishment of cardiac tissue matrix, electromechanical cell coupling, robust and stable contractile function, and functional vascularization. We review here the potential and challenges of cardiac tissue engineering for developing therapies that could prevent or reverse heart failure.

The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17 –/– mice.

Alcoholic Liver Disease (ALD) is a major cause of morbidity and mortality both in the United States and worldwide. In the United States, it is projected that over 2,000,000 persons have ALD, and the mortality for cirrhosis with superimposed alcoholic hepatitis is much worse than that of many common types of cancer. Unfortunately, there is no FDA approved therapy for ALD. We have made major strides in the last decade in identifying mechanisms for the development of liver injury in ALD, and therapies are evolving directed at specific mechanisms. It is clear that life style modification with abstinence, cessation of smoking and weight loss (if overweight) are beneficial. It is also clear that most patients with advanced liver disease have some form of malnutrition, and nutritional supplementation is of benefit. Patients with alcoholic hepatitis that is relatively severe in nature, but not complicated by issues such as infection or GI bleeding, appear to benefit from steroids. A drop in bilirubin should be monitored in steroid treated patients. Pentoxifylline appears to be beneficial in patients with alcoholic hepatitis, especially those with early hepatorenal syndrome. A variety of other agents such as PTU, lecithin, colchicine, and anabolic steroids are probably not effective. Complementary and alternative medicine agents such as zinc, milk thistle, and SAM have great therapeutic rationale. Results of ongoing NIH studies evaluating agents such as specific anti-TNF's, SAM and Milk Thistle are eagerly awaited. Transplantation is clearly an option for end stage ALD in patients who are abstinent.

The aim of the present work is to investigate the existence of epistatic interactions possibly influencing psychotropic agents' response between rs6740584 within Cyclic adenosine monophosphate Response Element Binding (CREB) and rs12775799 within cAMP response element-modulator (CREM) variants in bipolar disorder (BD) and major depressive disorder (MDD). All BD and MDD patients were administered with the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAMD) at baseline and at endpoint, respectively. A multiple regression model was employed to investigate the existence of possible epistatic interactions between the two variants and diverse clinical factors including drug response in affective disorders. No significant epistatic interaction was observed between rs6740584 within CREB and rs12775799 within CREM on both symptom improvement and other clinical factors in affective disorders. Our preliminary results suggest that no epistatic interaction between rs6740584 within CREB and rs12775799 within CREM should exist on clinical improvement and clinical factors in affective disorders.

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The clinical spectrum of ALD includes fatty liver, steatohepatitis with or without fibrosis, and cirrhosis. The diagnosis of ALD is made in patients with evidence of liver injury based on clinical history, physical findings, and laboratory abnormalities, when there is evidence of significant alcohol consumption and after other causes of chronic liver disease have been excluded. Signs and symptoms may be essentially nonexistent in steatosis or possibly mild fatigue and abdominal discomfort. On the other hand, those with decompensated disease may present with massive ascites, muscle wasting, gastrointestinal bleeding, and encephalopathy. Many people drink heavily, yet only a limited number (~35 %) develop more advanced liver diseases (alcoholic hepatitis or cirrhosis). Thus, there must be modifying factors that either prevent or facilitate disease activity/progression. These modifiers can either be fixed (e.g., genetic) or can undergo intervention (e.g., continued drinking, smoking, diet). We review ten disease modifiers of particular importance to ALD. Patients with steatosis only may “normalize” with cessation of drinking; however, outcomes are highly variable once the patient has progressed to cirrhosis. Some subjects die quickly with acute-on-chronic liver disease; other patients who abstain from alcohol and correct other disease modifiers may live a relatively normal life; others may do well for long periods of time only to expire from hepatocellular carcinoma. The biggest variable is continued drinking, and cessation of this and modification of other disease modifiers such as smoking should be aggressively pursued.

Despite the well-known efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in the treatment of major depressive disorder, there is a lack of indications for each drug in different groups of patients. The aim of this study is to investigate the possible role of clinical sociodemographic factors as moderators of clinical response to venlafaxine (SNRI) and sertraline (SSRI). Research was performed on Medline and EMBASE for randomized control trials in English focused on sertraline and venlafaxine in the treatment of major depressive disorder and 59 studies were included. Clinical efficacy of each treatment was assessed on the basis of Hamilton Depressive Rating Scale and Montgomery-Asberg Depression Rating Scale. A metaregression analysis was performed to evaluate the role of clinical and sociodemographic factors as moderators of outcome, calculating the effect of each variable with the random-effects method. Gender, ethnicity and duration of depressive episode could have a role in prediction of clinical response to both antidepressants. Venlafaxine seems to have better effects in females and in Caucasian patients. Sertraline seems to be more efficacious in the treatment of females. Both drugs were more efficacious in patients who suffered a shorter episode of illness. Our results could represent an interesting point of view in the perspective of choosing the most suitable therapy based on clinical and social features for each patient. Metaregression is a retrospective analysis, based on the cumulative results of previous studies, so the lack of original data could represent the main limitation in this report and in the interpretation of the results obtained.

Among the several genes associated with late-onset Alzheimer’s disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer’s disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.

Hepatic steatosis and steatohepatitis are common histologic findings that can be caused by multiple etiologies. The three most frequent causes for steatosis/steatohepatitis are alcohol (alcoholic steatohepatitis, ASH), obesity/metabolic syndrome (nonalcoholic steatohepatitis, NASH), and environmental toxicants (toxicant-associated steatohepatitis, TASH). Hepatic steatosis is an early occurrence in all three forms of liver disease, and they often share common pathways to disease progression/severity. Disease progression is a result of both direct effects on the liver as well as indirect alterations in other organs/tissues such as intestine, adipose tissue, and the immune system. Although the three liver diseases (ASH, NASH, and TASH) share many common pathogenic mechanisms, they also exhibit distinct differences. Both shared and divergent mechanisms can be potential therapeutic targets. This review provides an overview of selected important mechanistic similarities and differences in ASH, NASH, and TASH. Keywords: Alcoholic Steatohepatitis, Mechanisms, Nonalcoholic Steatohepatitis, Toxicant-Associated Steatohepatitis

Background.Solidorgantransplantedpatientshaveathree-tofourfoldhigherlifetimeriskofdevelopingacancerthan the general population. However, the incidence of a second primary cancer in transplanted patients has never been studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them a very attractive model. Methods. We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney, liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years. Results. During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.610,000 PY), and 22 of them developed a SPC (annual incidence: 3.910,000 PY). The annual incidence of a SPC in the transplanted patients who developed a first cancer was 107.810,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83–1.41). Conclusions. This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy.

Background. Fracture is a disabling clinical outcome after transplantation, but there is little histopathological information on long-term renal recipients with severe osteopenia. Methods. Twenty kidney recipients (8.3±1.9 years after transplantation), 13 males and 7 females (five postmenopausal) with nearly normal renal function, affected by severe osteopenia (T-score: males= -4.9±0.28; females= -5.08±0.47) underwent bone biopsy and morphometric X-ray absorptiometry to evaluate vertebral fractures. Results. Histopathological diagnosis was osteoporosis-osteopenia in seven patients, osteitis fibrosa in six, prevalent osteomalacic lesion in six, and "normal" bone in one patient. Significant increases in osteoid volume (OV/BV), osteoid surface, osteoblastic surface (ObS/BS) and osteoid thickness were observed. OV/BV and Obs/BS ratios were inversely correlated to cumulative doses of MPRED (r 2 = 0.85 P

Previous studies of neuropsychological performance in borderline personality disorder (BPD) have exhibited mixed results. The high rate of co-occurring major depressive disorder (MDD) in BPD makes it difficult to specify whether neuropsychological deficits in BPD predominantly reflect co-occurring MDD or unique aspects of their psychopathology. To address this issue, 22 participants with borderline personality disorder and concurrent major depressive disorder (BPD-MDD) and 33 participants with MDD and no concurrent personality disorder were compared on a neuropsychological battery that assessed seven domains of performance: general intellectual functioning, motor skill, psychomotor speed, attention, memory, working memory, and executive function. Neuropsychological performance did not differ between BPD-MDD and MDD. However, BPD-MDD participants reported higher levels of anger, anxiety, and of overall emotional distress compared to MDD. When levels of anxiety were controlled, BPD-MDD participants exhibited superior general intellectual performance, psychomotor speed, and attention. Deficits found in previous BPD samples may reflect their susceptibility to co-occurring MDD. The impact of anxiety on neuropsychological performance in BPD, though, indicates a need for future experimental studies of the effects of mood on cognitive function to determine whether mood dysregulation, rather than core depressive symptoms, underlie cognition impairments in BPD.

Albumin is the predominant product of hepatic protein synthesis and one of the more abundant plasma proteins. Among its multiple physiologic roles, it plays an essential part in the generation of colloid-oncotic pressure. In the United States, the indications for which albumin therapy are considered include hypovolemia or shock, burns, hypoalbuminemia, surgery or trauma, cardiopulmonary bypass, acute respiratory distress syndrome, hemodialysis, and sequestration of protein-rich fluids. The use of this relatively expensive therapy accounts for up to 30% of the total pharmacy budget in certain hospitals. The use of albumin therapy in different clinical situations and its influence in morbidity and mortality have been reviewed in multiple randomized controlled trials and meta-analyses. Despite frequent reviews, the use of albumin remains controversial in several clinical situations. At the same time, these valuable reviews seem to have documented the advantages of albumin therapy in the management of ascites and clarified the use of albumin in volume resuscitation. More studies have been recommended to investigate the use of albumin in different doses and its role in hypoalbuminemia. This article will provide an overview of albumin metabolism, use of albumin for volume expansion, the potential therapeutic role of albumin in liver disease, and the role of albumin therapy in nutrition.

It was suggested that the gene encoding for sorLa, (SORL1) may affect Alzheimer's disease (LOAD) through a female-specific mechanism. The aims of this study were to confirm the role of gender in modulating the association between SORL1 and LOAD and to ascertain the influence of SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and secretion of pro-inflammatory cytokines. Ninety six outpatients with LOAD and 120 unrelated controls were genotyped for APOE and three SNPs at the 5' end of SORL1(intron 6): SNP 8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). ELISPOT assays were used to measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma) production in peripheral blood mononuclear cell (PBMC) supernatant from AD patients. SORL1 SNPs were not associated with LOAD in overall sample. Instead the G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype (p=0.02) were associated with LOAD in the women subgroup. The TAA haplotype was marginally protective in AD patients being associated with lower BPSD scores (p=0.01). The same haplotype was also associated with higher IL-1beta (p=0.01) production. These genetic effects were not modified by APOE4 allele and controlled for illness duration and treatment. In conclusion, SORL1 does not appear to be a major risk factor for LOAD. Its contribution could be underestimated in our small sample. Sex-specific factors could modulate the association between SORL1 and AD. The influence of SORL1 variants on production of inflammatory cytokines warrants further investigation.

There are few data evaluating plasma and/or peripheral blood monocyte cytokine concentrations/production or attempts to manipulate proinflammatory cytokines in nonalcoholic steatohepatitis (NASH). A pilot project in a general clinical research center evaluated the effects of a step 1 American Heart Association diet plus aerobic exercise with or without 800 IU of vitamin E daily on cytokine profiles and liver enzyme levels in 16 patients with biopsy-proven NASH. Biochemical assessment of liver function, lipid profiles, and body mass index significantly improved during the first 6 weeks of therapy and remained stable during the following 6 weeks. Plasma hyaluronic acid (HA) concentrations decreased in parallel with weight loss. Plasma tumor necrosis factor (TNF) concentrations were significantly elevated in patients with NASH and similar to patients with stable alcoholic cirrhosis but not as elevated as in patients with acute alcoholic steatohepatitis (AH). Although plasma TNF, interleukin 8 (IL-8), and IL-6 concentrations were all significantly elevated compared with control values, only plasma IL-6 levels significantly decreased with therapy. Peripheral blood monocyte TNF, IL-8, and IL-6 production was significantly elevated in patients with NASH but did not significantly decrease. Independent effects of vitamin E were not observed in this small sample. In conclusion, patients with NASH have dysregulated cytokine metabolism similar to, but less pronounced than abnormalities documented in AH. Cytokine values generally did not decrease significantly with weight loss with or without vitamin E over the duration of the study. Lifestyle modifications (low-fat diet and exercise) were associated with improvement in liver enzymes, cholesterol, and plasma HA levels in patients with NASH, whereas the level of vitamin E supplementation used in this short-term pilot study provided no apparent added benefit.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to fibrosis and cirrhosis over time. NAFLD is often associated with obesity, insulin resistance, and diabetes. The interactions between the liver and the gut, the so-called "gut-liver axis", play a critical role in NAFLD onset and progression. Compelling evidence links the gut microbiome, intestinal barrier integrity, and NAFLD. The dietary factors may alter the gut microbiota and intestinal barrier function, favoring the occurrence of metabolic endotoxemia and low grade inflammation, thereby contributing to the development of obesity and obesity-associated fatty liver disease. Therapeutic manipulations with prebiotics and probiotics to modulate the gut microbiota and maintain intestinal barrier integrity are potential agents for NAFLD management. This review summarizes the current knowledge regarding the complex interplay between the gut microbiota, intestinal barrier, and dietary factors in NAFLD pathogenesis. The concepts addressed in this review have important clinical implications, although more work needs to be done to understand how dietary factors affect the gut barrier and microbiota, and to comprehend how microbe-derived components may interfere with the host's metabolism contributing to NAFLD development.