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Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age‐dependent manner in all mouse models of LD. In this study, we applied home‐cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin‐deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6–7 months, and ∼12 months of age, malin‐deficient mice ("KO") and wild‐type (WT) littermates underwent a standardized home‐cage behavioral assessment designed to non‐obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel‐running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age‐related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel‐running. Neuropathological examinations in subsets of the same mice revealed expected age‐dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home‐cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse. [ABSTRACT FROM AUTHOR]

Early detection of cognitive and functional decline is difficult given that current tools are insensitive to subtle changes. The present study evaluated whether cognitive dispersion on neuropsychological testing improved prediction of objectively assessed daily functioning using unobtrusive monitoring technologies. Hierarchical linear regression was used to evaluate whether cognitive dispersion added incremental information beyond mean neuropsychological performance in the prediction of objectively assessed IADLs (i.e., computer use, pillbox use, driving) in a sample of 104 community‐dwelling older adults without dementia (Mage = 74.59, 38.5% Female, 90.4% White). Adjusting for age, sex, education, and mean global cognitive performance, cognitive dispersion improved prediction of average daily computer use duration (R2 Δ = 0.100, F Change, p = 0.005), computer use duration variability (R2 Δ = 0.089, F Change p = 0.009), and average daily duration of nighttime driving (R2 Δ = 0.072, F Change p = 0.013). These results suggest cognitive dispersion may improve prediction of objectively assessed functional changes in older adults without dementia. [ABSTRACT FROM AUTHOR]

The manufacturing industry has witnessed advancements in soft robotics, specifically in robotic grippers for handling fragile or irregular objects. However, challenges remain in balancing shape compliance, structural rigidity, weight, and sensor integration. To address these limitations, a 3D‐printed multimaterial gripper design is proposed. This approach utilizes a single, nearly fully automated 3D printing process to create a universal gripper with almost no assembly work. By processing functional polymer, polymer nanocomposite, and metal wire simultaneously, this technique enables multifunctionality. The gripper achieves different gripping configurations by adjusting joint stiffness through Joule heating of conductive polylactic acid material, ensuring shape conformance. Embedded metal wires, created using an in‐house wire embedding technique, form reliable high‐current‐loading interconnections for the conductive joints acting as the heater. Additionally, an integrated soft sensor printed in thermoplastic polyurethane (TPU) and conductive TPU detects compression levels and discerns handled samples. This study showcases the potential of 3D multimaterial printing for on‐demand fabrication of a smart universal gripper with variable stiffness and integrated sensors, benefiting the automation industry. Overall, this work presents an effective strategy for designing and fabricating integrated multifunctional structures using soft, rigid, and conductive materials, such as polymer, polymer nanocomposite, and metal through multimaterial 3D printing. [ABSTRACT FROM AUTHOR]

Background: Direct‐acting antiviral agents (DAAs) have transformed chronic hepatitis C (CHC) treatment. Continued affordable access to DAAs requires updated cost‐effectiveness analyses (CEA). Utility is a preference‐based measure of health‐related quality of life (HRQoL) used in CEA. This study evaluated the impact of DAAs on utilities for patients with CHC in two clinical settings. Methods: This prospective longitudinal study included patients aged ≥18 years, diagnosed with CHC and scheduled to begin DAA treatment, from two tertiary care hospital clinics and four community clinics in Toronto, Calgary, and Montreal. Patients completed two utility instruments (EQ‐5D‐5L and Health Utilities Index 2/3 (HUI2/3)) before treatment, 6 weeks after treatment initiation, and 12 weeks and 1 year after treatment completion. We measured utilities for all patients, and for hospital‐based and community‐based groups. Results: Between 2017 and 2020, 209 patients (126 hospital‐based, 83 community‐based; average age 53 years; 65% male) were recruited, and 143 completed the 1‐year post‐treatment assessment. Pre‐treatment, utilities were (mean ± standard deviation) 0.77 ± 0.21 (EQ‐5D‐5L), 0.69 ± 0.24 (HUI2) and 0.58 ± 0.34 (HUI3). The mean changes at 1‐year post‐treatment were 0.035, 0.038 and 0.071, respectively. While utilities for hospital‐based patients steadily improved, utilities for the community‐based cohort improved between baseline and 12‐weeks post‐treatment, but decreased thereafter. Discussion: This study suggests that utilities improve after DAA treatment in patients with CHC in a variety of settings. However, community‐based patients may face challenges related to comorbid health and social conditions that are not meaningfully addressed by treatment. Our study is essential for valuing health outcomes in CHC‐related CEA. [ABSTRACT FROM AUTHOR]

In this meta‐analysis, correlations of personality traits and career decision‐making self‐efficacy with self and environmental career exploration were estimated across 71 samples and a pairwise sample of 19,846. Traits included the Big Five personality traits, shyness, locus of control, vocational decision styles, and stress. Many measures of career exploration were based on scores of self and environmental exploration on the Career Exploration Survey. Results varied by characteristics with the largest effects for locus of control, vocational decision style: thinking‐feeling and self‐efficacy. Environmental exploration and self‐exploration were moderately correlated and demonstrated different relations with traits that were consistent with theory. Self‐exploration was related to openness to experience and unrelated to extraversion, while environmental exploration was correlated with extraversion. Both were similarly correlated with conscientiousness such that conscientious individuals were more likely to engage in career exploration. [ABSTRACT FROM AUTHOR]

Summary: Background: Atrial fibrillation (AF) is the most common arrhythmia and its management in cirrhosis can be challenging due to the altered hepatic metabolism of medications and increased risk of bleeding. Aims: To provide a comprehensive overview of the diagnosis, pathophysiology and management of AF in patients with cirrhosis from both a cardiology and a hepatology perspective. Methods: An extensive literature search was performed using the terms 'atrial fibrillation' and 'cirrhosis'. Guideline documents and consensus statements were explored. Results: The prevalence of AF in patients with cirrhosis ranges between 6.6% and 14.2%, while the incidence of new‐onset AF in the post‐operative period after liver transplant ranged between 6.8% and 10.2%. AF in patients with cirrhosis is associated with adverse outcomes in both pre‐transplant and post‐transplant settings, including an increased risk of stroke when compared to the general population. We review the pathogenesis of AF in general and in cirrhosis. This review also provides guidance on the management of AF, including the use of anticoagulation and rate versus rhythm control. In the absence of strict contraindications, all patients with cirrhosis and AF should be anticoagulated. The use of DOACs is preferred over vitamin K antagonists. In patients with a high bleeding risk, a DOAC with an approved antidote may be preferred. Conclusions: Atrial fibrillation is increased in patients with cirrhosis. AF management requires careful consideration of treatment options. Since patients with cirrhosis were excluded from all major randomised clinical trials, dedicated research on the pathophysiology and management of AF in cirrhosis is needed. [ABSTRACT FROM AUTHOR]

Background & Aims: According to pivotal clinical trials, cure rates for sofosbuvir‐based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance‐associated substitutions or clinical risk factors, yet the role of patient‐specific genetic factors has not been well explored. We determined if patient‐specific genetic factors help predict patients likely to fail sofosbuvir treatment in real‐world treatment situations. Methods: We recruited sofosbuvir‐treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case‐control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1‐dependent production of sofosbuvir's active metabolite, interferon‐λ signalling variants expected to impact a patient's immune response to the virus and an HLA variant associated with increased spontaneous and treatment‐induced viral clearance. Results: Three hundred and fifty‐nine sofosbuvir‐treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified CES1 variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR): 5.43; 95% confidence interval (CI): 1.64‐18.01; P =.0057), replicated associations with IFNL4 variants predicted to increase interferon‐λ signalling (eg rs12979860; OR: 2.25; 95% CI: 1.25‐4.06; P =.0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in IL10RB; OR: 1.81; 95% CI: 1.01‐3.24; P =.047). Conclusions: Ultimately, this work demonstrates that patient‐specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner. [ABSTRACT FROM AUTHOR]

Giant clam populations in Singapore are endangered due to historical exploitation, habitat loss, and sediment pollution.Transplanting cultured giant clams onto reefs is a potential conservation strategy. This study examined the growth and survival of three initial size classes (50.0–60.0 mm, 60.1–70.0 mm, >70 mm) of cultured juvenile fluted giant clams, Tridacna squamosa, transplanted to three reef sites under two caging treatments (caged and uncaged).After 145 days, there was no significant difference in clam survival within the size classes and within caging treatments across reef sites, even though environmental conditions varied greatly between sites. However, there was a significant effect of initial size class on T. squamosa survival, with higher survival with increasing size class (50.0–60.0 mm: 11.1%; 60.1–70.0 mm: 34.1%; >70.0 mm: 46.9%).Clams in caged treatments had significantly lower survival (16.7%) than uncaged clams (43.1%), likely due to biofouling atop caged treatments reducing light availability. Growth rates in the caged treatment (2.2 ± SD 1.8 mm month−1) were also lower than those in the uncaged treatment (3.9 ± SD 2.2 mm month−1).By optimizing transplant procedures for Singapore's turbid reef conditions, T. squamosa restocking efforts could play an important role in boosting local population numbers to facilitate natural recovery. [ABSTRACT FROM AUTHOR]

Summary: Background: The World Health Organization (WHO) set a goal to eliminate hepatitis C (HCV) infection globally by 2030, with specific targets to reduce new viral hepatitis infections by 80% and reduce related deaths by 65%. However, an overlooked aspect that may hinder these efforts is the impact other liver diseases could have by continuing to drive liver disease progression and offset the beneficial impact of DAAs on end‐stage liver disease and hepatocellular carcinoma (HCC). In particular, the decrease in HCV prevalence has been countered by a marked increase in the prevalence of metabolic‐associated fatty liver disease (MAFLD). Aims: To review the potential interaction of HCV and MAFLD. Methods: We have reviewed the literature relating to an arrange of interaction of HCV, metabolic dysfunction and MAFLD. Results: In this viewpoint, international experts suggest a holistic and multidisciplinary approach for the management of the growing number of treated HCV patients who achieved SVR, taking into consideration the overlooked impact of MAFLD for reducing morbidity and mortality in people who have had HCV. Conclusions: This will strengthen and improve the continuum of care cascade for patients with liver disease(s) and holds the potential to alleviate the cost burden of disease; and increase quality of life for patients following DAAs treatment. [ABSTRACT FROM AUTHOR]

Summary: Background: Patients with cirrhosis are at risk of developing cirrhotic cardiomyopathy. This syndrome is unique to cirrhosis and is generally defined as subnormal cardiac function in the absence of prior heart disease. There is no systematic or comprehensive review of cirrhotic cardiomyopathy to date. Aims: To comprehensively review the literature on the definition, pathogenic mechanisms, diagnostic criteria, prevalence, management and influence on liver transplantation including reversibility of cirrhotic cardiomyopathy. Methods: Electronic searches of the EMBASE, MEDLINE, EBM Reviews—Cochrane Central Register of Controlled Trials, EBM Reviews—Cochrane Database of Systematic Reviews and Google Scholar databases were conducted. MeSH terms focused on cirrhosis, cardiomyopathy, medication classes and epidemiology. Literature up to August 2020 was reviewed. Results: New diagnostic criteria for the definition of cirrhotic cardiomyopathy have recently been published, consisting of systolic and diastolic dysfunction parameters as assessed by echocardiographic methods. The roles of electrocardiographic disturbances and biomarkers in the definition criteria remain unclear. Pathogenic mechanisms underlying cirrhotic cardiomyopathy are likely related to the inflammatory phenotype of cirrhosis. Prevalence rates of 26%‐81% in cirrhotic patients are reported. Several medical therapies have been proposed, but none with clear evidence of efficacy. The presence of cirrhotic cardiomyopathy complicates the liver transplantation process with a higher risk of adverse cardiovascular events post‐transplant. Complete reversibility of the syndrome after transplantation remains controversial but most studies suggest that it does not occur at least within the first post‐operative year. Conclusions: Cirrhotic cardiomyopathy is a clinically relevant syndrome that affects morbidity and mortality in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Summary: Background: There are limited long‐term data on outcomes of chronic hepatitis B (CHB) in untreated and tenofovir disoproxil fumarate (TDF)‐treated women during pregnancy. Aims: To assess clinical outcomes in a multiethnic cohort of patients during pregnancy and post‐partum in a low HBV endemic region. Methods: Retrospective real‐world study of women with CHB (treated or untreated with TDF) from 2011 to 2019; data including ALT, HBV DNA, HBeAg and liver stiffness measurement were collected during pregnancy and post‐partum. Results: In 341 women (446 pregnancies) followed for a median of 33 months (IQR: 26.7‐39.5) post‐partum, 19% (65/341) received TDF (11 initiated pre‐pregnancy, 53 for mother‐to‐child transmission (MTCT) prevention). During follow‐up, 72/341 had subsequent pregnancy, including 18/53 on TDF for MTCT risk, of whom 7/18 were re‐treated. In all TDF‐treated women, HBV DNA declined but rebounded after TDF withdrawal (median baseline, near birth and early follow‐up levels were 7.2, 3.0 and 5.5 log IU/mL respectively [P < 0.01]). In HBeAg+ patients (65/341) ALT flares were more common (P = 0.03), especially for those who stopped TDF post‐partum, requiring re‐treatment in 21% (11/53). In comparison, 54% (116/215) of untreated women had a post‐partum ALT flare; one with fulminant hepatitis underwent transplant 13 months post‐partum. HBsAg clearance occurred in 2.6% (9/341, 3/9 HBeAg+, 2/9 TDF treated) at median 30 months (IQR: 23‐40) and 37% (24/65) of HBeAg+ patients had HBeAg loss at median 17 months (IQR: 12‐26) post‐partum. Conclusions: Post‐partum ALT flares were common, especially after TDF withdrawal. Overall, 37% achieved HBeAg clearance and 2.9% had HBsAg loss during long‐term follow‐up. [ABSTRACT FROM AUTHOR]

Background & Aims: Cirrhotic cardiomyopathy is a recently recognized entity, but detailed cellular and molecular mechanisms remain unclarified. We aimed to elucidate the role of myosin heavy chain isoform shifts and their relation to calcium transients in the contractile kinetics of cirrhotic rats. Methods: Cirrhosis was induced in male Lewis Brown‐Norway rats by bile duct ligation (BDL). Myosin heavy chain (MHC) isoform distribution was evaluated by gel electrophoresis. Contractile force, Ca2+ transients and cell shortening were studied at varied frequency and extracellular [Ca2+]. T‐tubular integrity was analysed by power spectrum analysis of images of myocytes stained with di‐8‐ANEPPS. Results: Compared with sham controls, the phenotypes of cirrhotic rats were as follows: (a) alpha‐myosin heavy chain shifted to beta‐MHC isoform; (b) mild loss of T‐tubular integrity in myocytes; (c) a reduced maximum and rate of rise of the Ca2+ transient (max F/Fo); (d) a reduction in both the rate of rise and fall of contraction; (e) decreased maximal force‐generating capacity; (f) loss of the inotropic effect of increased stimulus frequency; (g) unchanged sensitivity of force development to varied extracellular [Ca2+] and (h) increased spontaneous diastolic sarcomere length fluctuations. Conclusion: Cardiomyocytes and ventricular trabeculae in a cirrhotic rat model showed features of typical heart failure including systolic and diastolic prolongation, impaired force‐frequency relation and decreased force‐generating capacity. Impaired myosin isoform shift and calcium transients are important contributory mechanisms underlying the pathogenesis of the heart failure phenotype seen in cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatitis C virus (HCV) has high genetic diversity with six major genotypes (GT) GT1‐6 and global distribution. HCV GT5 and 6 are rare with < 10 million people infected worldwide. Data on direct‐acting antiviral use in these rare HCV genotypes are limited. The study aimed to evaluate the efficacy and safety of glecaprevir/pibrentasvir (G/P) in a pooled analysis of phase 2/3 trials in HCV GT5 or 6‐infected patients without cirrhosis or with compensated cirrhosis. Methods: Patients with chronic HCV GT5 or 6 infection received oral G/P (300 mg/120 mg) once daily for 8 or 12 weeks. The primary efficacy endpoint was sustained virological response at post‐treatment week 12 (SVR12) in the intention‐to‐treat population. Results: One hundred eighty‐one patients were evaluated; 56 with HCV GT5 and 125 with HCV GT6. The majority were treatment‐naïve (88%) and non‐cirrhotic (85%). Overall SVR12 rate with 8‐ or 12‐week G/P treatment was 98% (178/181). Eight‐week treatment with G/P yielded SVR12 rates of 95% (21/22) in HCV GT5‐ and 99% (69/70) in HCV GT6‐infected non‐cirrhotic patients. Eight‐ and 12‐week treatment of patients with compensated cirrhosis achieved SVR12 rates of 100% (10/10) and 94% (17/18) respectively. The G/P regimen was well‐tolerated; 3% (6/181) Grade 3 or higher adverse events, and no serious adverse events were attributed to G/P or led to study drug discontinuation. Conclusions: This integrated dataset demonstrates a high SVR12 rate following 8‐week G/P treatment in patients with HCV GT5 (96%) or GT6 (99%) infection without cirrhosis or with compensated cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Tenofovir disoproxil fumarate (TDF) is a first‐line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well‐described cohort of CHB patients. Methods: Hepatitis B e antigen (HBeAg)‐negative and HBeAg‐positive patients from two randomised, double‐blind trials (ClinicalTrials.gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open‐label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety and tolerability. Results: Of 641 randomised and treated patients, 585 (91%) entered the open‐label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg‐negative patients and 78/80 (98%) of HBeAg‐positive patients with available data achieved hepatitis B virus (HBV) DNA < 69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal‐ or bone‐related adverse events. Conclusions: Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance. [ABSTRACT FROM AUTHOR]

Background: Numerous pathologies of pregnancy originate from placental dysfunction. It is essential to understand the functions of key genes in the placenta in order to discern the etiology of placental pathologies. A paucity of animal models that allow conditional and inducible expression of a target gene in the placenta is a major limitation for studying placental development and function. Results: To study the platelet‐derived growth factor receptor alpha (PDGFRα)‐directed and tamoxifen‐induced Cre recombinase expression in the placenta, PDGFRα‐CreER mice were crossed with mT/mG dual‐fluorescent reporter mice. The expression of endogenous membrane‐localized enhanced green fluorescent protein (mEGFP) and/or dTomato in the placenta was examined to identify PDGFRα promoter‐directed Cre expression. Pregnant PDGFRα‐CreER;mT/mG mice were treated with tamoxifen at various gestational ages. Upon tamoxifen treatment, reporter protein mEGFP was observed in the junctional zone (JZ) and chorionic plate (CP). Furthermore, a single dose of tamoxifen was sufficient to induce the recombination. Conclusions: PDGFRα‐CreER expression is restricted to the JZ and CP of mouse placentas. PDGFRα‐CreER mice provide a useful tool to conditionally knock out or overexpress a target gene in these regions of the mouse placenta. Key Findings: Inducible PDGFRα‐directed Cre expression trophoblasts cells.A single tamoxifen treatment is sufficient to induce the recombination.Valuable tool to temporary knockout or over‐express a target gene in the placenta.Do not require sophisticated system and suitable for ordinary laboratory setting. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine how dental student self-assessment and faculty assessment of operative preparations compared for conventional visual assessment versus assessment of scanned digital 3D models. In 2016, all third-year students in the Class of 2018 (N=35) at Harvard School of Dental Medicine performed preclinical exams of Class II amalgam preparations (C2AP) and Class III composite preparations (C3CP) and completed self-assessment forms; in 2017, all third-year students in the Class of 2019 (N=34) performed the same exams. Afterwards, the prepared typodont teeth were digitally scanned. Students self-assessed their preparations digitally, and four faculty members graded the preparations conventionally and digitally. The results showed that, overall, the students assessed their preparations higher than the faculty assessments. The mean student-faculty gaps for C2AP and C3CP in the conventional assessments were 11% and 5%, respectively. The mean digital student-faculty gap for C2AP and C3CP were 8% and 2%, respectively. In the conventional assessments, preclinical performance was negatively correlated with the student-faculty gap (r=-0.47, p<0.001). The correlations were not statistically significant with the digital assessments (p=0.39, p=0.26). Students in the bottom quartile significantly improved their self-assessment accuracy using digital self-assessments over conventional assessments (C2AP 10% vs. 17% and C3CP 3% vs. 10%, respectively). These results suggest that digital assessments offered a significant learning opportunity for students to critically self-assess themselves in operative preclinical dentistry. The lower performing students benefitted the most, improving their assessment ability to the level of the rest of the class. [ABSTRACT FROM AUTHOR]

Background Hypodontia compromises appearance and function and is challenging to manage clinically. Objectives To assess the impact of implant retained crowns on quality of life of patients and to determine clinical performance of implant retained crowns in these patients. Methods In a 24-month prospective observation study, patients with non-syndromic mild hypodontia manifested with missing teeth in the anterior maxilla were included. Pre-treatment screening included a clinical and radiographic examination and completion of an OHIP-20. Narrow neck SLActive TiZr implants (Roxolid®, Straumann AG, Switzerland) were provided and restored with single unit crowns. Implant stability was recorded at time of placement and abutment connection. Standardized radiographs were recorded at time of surgery, abutment connection and 12- and 24-month follow-up visits, and distance between implant shoulder and first bone contact was measured. Oral health-related quality of life was calculated using OHIP-20 scores at 12- and 24-month visits compared with pre-treatment scores. Pink ( PES) and white ( WES) aesthetic scores were used to objectively assess aesthetic outcome of treatment. Results Twenty implants were placed in 12 patients (seven females, five males; mean [ SD] age 19.33 [2.37] years). There was a significant improvement in oral health-related quality of life following treatment ( P = 0.026), and the effect size of this change was 1.17 indicating a large clinically meaningful change. Mean PES and WES scores were high, indicated a satisfactory aesthetic outcome at 24 months. Crestal bone-level changes were considered small. Conclusion Favourable clinical outcomes were observed. Implant retained crowns had a large and clinically meaningful impact on quality of life of patients with hypodontia. [ABSTRACT FROM AUTHOR]

Introduction Neuromodulation, including spinal cord stimulation and peripheral nerve field stimulation, has been used with success in treating several painful conditions. The FDA approved the use of neuromodulation for a few indications. We review evidence for neuromodulation in treating some important painful conditions that are not currently FDA approved. Methods This review included an online web search for only clinical trials testing the efficacy of neuromodulation in treating coronary artery disease, peripheral vascular disease ( PVD), headache, and peripheral field stimulation. Results Our systematic literature search found 10, 6, and 3 controlled studies relating to coronary artery disease, PVD, and headache, respectively. Our review also included 5 noncontrolled studies relating to peripheral field stimulation, as no controlled studies had been completed. Conclusion This review article shows compelling evidence based on clinical trials that neuromodulation can be of benefit for patients with serious painful conditions that are not currently approved by the FDA. [ABSTRACT FROM AUTHOR]

Background & Aims The need for further histological subclassification of cirrhosis has been increasingly recognized because of the heterogeneity of severity within cirrhosis. We sought to identify evidence in the literature regarding the histological subclassification of cirrhosis using the Laennec stage. Methods We conducted a systematic review and meta-analysis by searching databases, including MEDLINE, EMBASE and the COCHRANE library, for relevant studies. Results Of 208 studies identified, 16 were eligible according to the inclusion criteria. With higher grades of the Laennec stage, clinical stages of cirrhosis and Child-Pugh scores/Model for end-stage liver disease scores increased ( P < 0.05). Higher Laennec stages were statistically associated with the development of liver-related events, such as liver-related death, liver cancer progression and variceal haemorrhage, as well as higher hepatic venous pressure gradients and higher liver stiffness values ( P < 0.05). Two open-labelled studies showed the usefulness of the Laennec system with regard to the evaluation of whether antifibrotic treatments were effective. The mean kappa value was 0.81 (range 0.61-0.87) for inter-observer agreement. Conclusions Based on this systematic review and meta-analysis, histological subclassification of cirrhosis using the Laennec system is useful to better predict prognosis and complications of portal hypertension. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum ( ER) is responsible for protein folding, modification, and trafficking. Accumulation of unfolded or misfolded proteins represents the condition of ER stress and triggers the unfolded protein response ( UPR), a key mechanism linking supply of excess nutrients to insulin resistance and type 2 diabetes in obesity. The ER harbors proteins that participate in protein folding including protein disulfide isomerases ( PDIs). Changes in PDI activity are associated with protein misfolding and ER stress. Here, we show that thioredoxin-interacting protein (Txnip), a member of the arrestin protein superfamily and one of the most strongly induced proteins in diabetic patients, regulates PDI activity and UPR signaling. We found that Txnip binds to PDIs and increases their enzymatic activity. Genetic deletion of Txnip in cells and mice led to increased protein ubiquitination and splicing of the UPR regulated transcription factor X-box-binding protein 1 (Xbp1s) at baseline as well as under ER stress. Our results reveal Txnip as a novel direct regulator of PDI activity and a feedback mechanism of UPR signaling to decrease ER stress. [ABSTRACT FROM AUTHOR]

Objective The physiology of the weight-reduced (WR) state suggests that pharmacologic agents affecting energy homeostasis may have greater efficacy in WR individuals. Our aim was to establish a protocol that allows for evaluation of efficacy of weight maintenance agents and to assess the effectiveness of AZD2820, a novel melanocortin 4 receptor (MC4R) agonist in such a paradigm. Methods MC4R agonist was administered in stratified doses to mice who were either fed high-fat diet ad libitum (AL) throughout the study; or stabilized at a 20% reduced body weight (BW), administered the drug for 4 weeks, and thereafter released from caloric restriction while continuing to receive the drug (WR). Results After release of WR mice to AL feeding, the high-dose group (53.4 nmol/day) regained 12.4% less BW than their vehicle-treated controls since the beginning of drug treatment. In WR mice, 10.8 nmol/day of the agonist was sufficient to maintain these animals at 95.1% of initial BW versus 53.4 nmol/day required to maintain the BW of AL animals (94.5%). Conclusions In the WR state, the MC4R agonist was comparably efficacious to a five-fold higher dose in the AL state. This protocol provides a model for evaluating the mechanisms and quantitative efficacy of weight-maintenance strategies and agents. [ABSTRACT FROM AUTHOR]

Antiviral therapy for chronic hepatitis C has dramatically changed with the advent of triple therapy incorporating direct-acting antivirals (DAAs) such as the protease inhibitors (PI) boceprevir and telaprevir. Such triple-therapy is associated with a new spectrum of side-effects which can hamper quality of life. These may lead to dosage reduction and sometimes discontinuation of therapy. This review presents practical tips to help manage adverse effects appropriately and efficiently. The main adverse effects causing discontinuation of therapy are varied. Although the most common adverse effects are the 'flu'-like symptoms of fatigue, myalgia, fever and lassitude, these are usually easily managed and do not lead to treatment discontinuation. Cytopaenia, particularly anaemia, has emerged as perhaps the most troublesome side-effect. Cirrhotic patients are especially prone to moderate or severe anaemia with boceprevir and telaprevir triple-therapy regimens. Aggressive ribavirin dosage reductions, erythropoietin and blood transfusions are effective for managing anaemia. Skin rash can be controlled with moisturization and corticosteroid ointment. Rarely, dermatology consultation is required for further management. Anal discomfort, with or without diarrhoea, sometimes responds to barrier creams and haemorrhoidal ointments. Dysgeusia is treated by sipping water frequently, oral ointments and mouth washes to maintain salivary flow and oral hygiene. Successful adherence to treatment can be enhanced by a strong support network for the patient, including specially-trained hepatitis nurses and a multidisciplinary team incorporating pharmacists, counsellors and social workers. [ABSTRACT FROM AUTHOR]

Fluid dynamics and heat transfer of flow through periodic open-cellular microlattice structures are characterized for varying superficial flow orientations and flow rates to investigate heat transfer and pressure loss anisotropy. For given Reynolds number, friction factor is lowest when flow is aligned with the largest straight-through passages in the microlattice. A maximum friction factor, over twice the optimally aligned friction factor, exists for flow orientations between π/8 and π/4 rad off the optimal alignment, with little variation in friction factor for π/8 and π/4 rad. Heat transfer is maximized at π/4 rad off axis from the largest straight-through passages; however, less angular variation occurs in Nusselt number than in friction factor. Empirical correlations involving superellipses yield analytical equations describing Nusselt number dependence on flow angle and Reynolds number. This work enables selection of optimal flow orientations and optimal cellular architecture in convective heat transfer implementations of microlattice materials for lightweight and multifunctional applications. © 2012 American Institute of Chemical Engineers AIChE J, 59: 622-629, 2013 [ABSTRACT FROM AUTHOR]

Background & Aims Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events ( SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. Methods Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 μg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non- SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non- SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. Results Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE ( SAE or non- SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non- SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. Conclusion This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs. [ABSTRACT FROM AUTHOR]

Summary Invasive fungal infections (IFIs) are associated with high morbidity and mortality in immunocompromised patients. Although Aspergillus spp. remain an important cause of IFI, other moulds such as Fusarium spp., dematiaceous fungi and Mucorales have become increasingly prevalent among this patient population. Diagnosis and treatment of invasive mould infections remain a challenge. Because of the poor prognosis associated with IFIs, understanding the activity, efficacy and limitations of the available drugs is critical to select the appropriate antifungal agent on an individualised basis. [ABSTRACT FROM AUTHOR]

1. There is evidence that different aetiologies of heart failure, especially ischaemic vs dilated cardiomyopathy (ICM and DCM, respectively), may influence the prognosis of patients with this disease. Patients with ICM have a worse prognosis than those with DCM; the mechanisms underlying this difference have not yet been clarified. The aim of the present study was to investigate whether there are changes in myofibrillar function depending on the aetiology of human heart failure. 2. Ca-dependent tension (DT) and actomyosin ATPase acitivity (MYO) in Triton X-skinned fibre preparations of the left ventricular myocardium from patients with heart failure due to ICM ( n = 5) and DCM ( n = 5) were measured. Tension-dependent ATP consumption was calculated by the ratio of DT and MYO ('tension cost'). Non-failing myocardium (NF) from donor hearts, which could not be transplanted because of technical reasons, was evaluated as a control. 3. Although DT was reduced, the myofibrillar Ca sensitivity of DT and MYO, as well as tension cost, were increased in preparations from ICM and DCM myocardium compared with NF. The Ca sensitivity of DT and MYO was significantly increased in ICM compared with DCM preparations, resulting in more economic cross-bridge cycling in ICM than in DCM. 4. In conclusion, ICM is associated with an increased Ca sensitivity of myofibrillar tension and ATPase activity accompanied by decreased tension cost compared with DCM. Thus, the worse prognosis associated with ICM does not seem to be due to differences in myofibrillar function. [ABSTRACT FROM AUTHOR]

Ascites is a frequent complication of cirrhosis and portal hypertension, because of the increase of the sinusoidal hydrostatic pressure. Cirrhosis accounts for over 75% of episodes of ascites. Cirrhotic patients with ascites have marked alterations in the splanchnic and systemic haemodynamics, causing central hypovolaemia and arterial hypotension with consequent activation of the vasoconstrictor systems, renin–angiotensin and sympathetic systems, and with increased renal sodium re-absorption. One of the most serious complications in cirrhotic patients with ascites is the occurrence of refractoriness, that is the inability to resolve ascites by the standard medical treatment with low sodium diet and diuretic doses up to 160 mg/day of furosemide and 400 mg/day of spironolactone. Many patients with refractory ascites also have a chronic renal insufficiency that is called hepatorenal syndrome type-2. In these patients ascites may be treated with periodic paracentesis or with transjugular intrahepatic portosystemic shunt. However, only liver transplantation may improve the survival of such patients. [ABSTRACT FROM AUTHOR]

Aim The purpose of this study was to determine if our previously developed muscle model could be used to predict forces of the quadriceps femoris and triceps surae muscles of children with spastic diplegic cerebral palsy (CP). Method Twenty-two children with CP (12 males, 10 females; mean age 10y, SD 2y, range 7–13y; Gross Motor Function Classification System levels II and III) participated. A physiologically based mathematical model with four free parameters is presented. Results For individuals with CP, the model predicted well the force profile throughout each contraction and both peak force and force–time integral responses to a wide range of stimulation frequencies (5–100Hz) and different stimulation patterns (constant-, variable-, and doublet-frequency trains) both for nonfatigued and fatigued muscles. Interpretation The significance of this work is the insight the model can provide into the physiology of muscle in CP. Additionally, the model can potentially be applied clinically to design optimal electrical stimulation patterns for interventions to address impairments in strength and function in individuals with CP, such as functional electrical stimulation-assisted cycling. [ABSTRACT FROM AUTHOR]

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by loss of the muscle atonia of REM sleep, with release of complex and violent behaviors that are often attempted dream-enactments. This study reviewed the literature on RBD with regard to potentially lethal behavior. A total of 39–41 clinical cases of RBD associated with potentially lethal behaviors to self and/or others were found, involving a child and adults of all age groups, that manifested as choking/headlock ( n = 22–24), defenestration/near-defenestration ( n = 7), and diving from bed ( n = 10). A total of 80.8% ( n = 21) were males; 19.2% ( n = 5) were females; mean age was 65.6 ± (SD) 13.8 years (range: 27–81 years, and a child). (Gender/age data were not listed in the remaining cases.) An etiologic association of RBD with a neurologic disorder (or with pharmacotherapy of psychiatric disorders, n = 4) was present in 21–23 patients. Thus, RBD carries well-documented, potential forensic consequences during RBD episodes that could possibly have been misinterpreted as suicidal or homicidal behavior. [ABSTRACT FROM AUTHOR]

The two main goals of hepatitis B therapy are durable viral suppression and avoidance of antiviral resistance. Recent treatment guidelines now recognize the importance of these treatment endpoints in the prevention of end-stage liver disease and hepatocellular carcinoma rather then other surrogate markers such as HBeAg seroconversion and serum alanine aminotransferase normalization, especially in patients who acquired hepatitis B virus infection early in life. A variety of therapeutic options are now available for the treatment of chronic hepatitis B infection, including four nucleos/tide analogues (i.e lamivudine, adefovir, entecavir and telbivudine), along with standard and pegylated interferon. Newer oral nucleos/tide analogues that include tenofovir, emtricitabine and clevudine are soon likely to be approved worldwide. Given the wide array of choices and the complex nature of chronic hepatitis B infection, selection of the appropriate therapeutic agent can be challenging for clinicians. Effective treatment decisions require an understanding of the natural history of hepatitis B and knowledge of its life cycle and molecular biology. This review includes the range of treatment options and criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients positive for the HBeAg. [ABSTRACT FROM AUTHOR]

Background and Aims: We examined birth cohort and calendar period trends in hepatocellular carcinoma (HCC) incidence in Canada (1976–2000). We also projected HCC incidence rates through 2015. Patients and methods: Data were obtained from the Canadian Cancer Registry on all cases of HCC diagnosed among persons aged 20 years and older in Canada from 1976 to 2000 and was used to describe trends in HCC incidence rates. Results: We found that age-adjusted HCC incidence rates increased faster in males compared with females, 3.4% per year [95% confidence interval (CI): 3.0–3.8%] vs 2.2% per year (95% CI: 1.5–2.8%). An increasing birth cohort trend accelerated among males around the 1940 birth cohort and decelerated among females around the 1935 birth cohort. For calendar period trends, the increasing HCC risk was relatively constant over time among males whereas there was an acceleration in HCC risk around 1988 among females. Age-adjusted HCC incidence rates were projected to increase 73% in males and 28% in females from 1996 to 2015. Conclusions: Our results suggest that HCC incidence rates will continue to increase in Canada during the next decade as persons born in more recent birth cohorts, who face a relatively greater risk for HCC, age. [ABSTRACT FROM AUTHOR]

Background/Aims: Cytokines such as tumour necrosis factor (TNF-α) contribute to the pathogenesis of cirrhotic cardiomyopathy. Nuclear factor-κB (NF-κB) is crucial for cytokine regulation, and induces cardiac dysfunction in several heart disease models. We aimed to elucidate possible NF-κB involvement in cirrhotic cardiomyopathy. Methods: Rats were bile duct ligated (BDL) to produce cirrhosis; controls received sham operation. Animals were studied 4 weeks later. Two NF-κB inhibitors were used: pyrrolidine dithiocarbamate (PDTC) and Bay 11-7082. Four groups were studied in most protocols: sham control, sham+PDTC, BDL and BDL+PDTC. Additional contractility studies were performed with Bay 11-7082. Myocardial NF-κB and TNF-α expression was measured by Western blot and ELISA. The contractility of isolated cardiomyocytes was observed under direct microscopy. Results: Nuclear factor-κB and TNF-α levels were increased in cirrhotic hearts compared with controls. PDTC significantly reduced NF-κB activity and TNF-α expression in cirrhotic hearts; controls were unaffected. Cirrhotic cardiomyocytes showed decreased systolic and diatolic velocity compared with sham controls. Both PDTC and Bay 11-7082 restored contractile function in cirrhotic cardiomyocytes, but did not affect controls. Conclusions: Inhibition of the increased NF-κB activity in cirrhotic hearts was associated with improvement of attenuated cardiomyocyte contractility. NF-κB, via effects on cytokine expression, may contribute to the pathogenesis of cirrhotic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Understanding muscle fatigue properties at different muscle lengths is essential to improve electrical stimulation applications in which impaired muscle is activated to produce function or to serve as an orthotic assist. This study examined the effects of muscle length on fatigue in human quadriceps muscle. Twelve healthy subjects were tested at short and long muscle lengths (15 degrees and 90 degrees of knee flexion, respectively) before and after a fatigue-producing protocol using low-, high-, and variable-frequency testing trains. Greater fatigue was observed at the longer muscle length, supporting the notion that fatigue is largely dependent upon metabolic factors. Fatigue, however, was characterized by greater attenuation of low- than high-frequency responses (i.e., low-frequency fatigue, LFF) at the long length. This observation, accompanied by the fact that variable-frequency trains produced greater augmentations in force production than comparable low-frequency trains at the longer length, suggests that excitation-contraction coupling impairment is also a contributing factor to fatigue and plays a greater role at the more fatigue-susceptible longer muscle length. [ABSTRACT FROM AUTHOR]

Background and Aims: Alterations in the Doppler hepatic vein (HV) waveform are associated with cirrhosis and portal hypertension. We prospectively evaluated the correlation between the extent of abnormal Doppler HV waveforms expressed as damping index (DI) and the hepatic venous pressure gradient (HVPG) and response to propranolol in patients with cirrhosis. Material and Methods: In 76 patients with cirrhosis (69 men and seven women), both DI of Doppler HV waveform and HVPG were measured, and the relationship between them was analysed. DI was calculated by the minimum velocity/maximum velocity of the HV waveform. An HVPG>12 mmHg was defined as severe portal hypertension. In a subgroup of 19 patients receiving propranolol, changes in both DI and HVPG were evaluated after propranolol administration for 3 months. One author (S. K. B.) performed all DI of Doppler HV waveform studies. Results: Abnormal HV waveforms were seen in 66 of 76 patients (86.8%). DI significantly correlated with the grade of HVPG, i.e. with higher HVPG increased DI was observed ( P<0.01). By logistic regression analysis, DI>0.6 was significantly more likely to be severe portal hypertension (odds ratio: 14.19, 95% confidence interval: 4.07–49.55). Receiver-operating characteristic curve according to the value of 0.6 of DI showed a sensitivity of 75.9% and a specificity of 81.8% for the presence of severe portal hypertension. In 19 patients of the propranolol subgroup, change of DI following propranolol treatment also significantly correlated with that of HVPG ( P<0.01). Conclusions: Damping index of the HV waveform by Doppler ultrasonography might be a non-invasive supplementary tool in evaluating the severity of portal hypertension and in responding to propranolol in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

We have previously developed and tested a muscle model that predicts the effect of stimulation frequency on muscle force responses. The aim of this study was to enhance our isometric mathematical model to predict muscle forces in response to stimulation trains with a wide range of frequencies and intensities for the quadriceps femoris muscles of individuals with spinal cord injuries. Isometric forces were obtained experimentally from 10 individuals with spinal cord injuries (time after injury, 1.5-8 years) and then compared to forces predicted by the model. Our model predicted accurately the force-time integrals (FTI) and peak forces (PF) for stimulation trains of a wide range of frequencies (12.5-80 HZ) and intensities (150-600-mus pulse duration), and two different stimulation patterns (constant-frequency trains and doublet-frequency trains). The accurate predictions of our model indicate that our model, which now incorporates the effects of stimulation frequency, intensity, and pattern on muscle forces, can be used to design optimal customized stimulation strategies for spinal cord-injured patients. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus (HBV) and hepatitis C virus (HCV) share similar transmission routes; thus, coinfection is frequent. The consequences of acute HBV infection in patients with chronic hepatitis C are unknown. Methods: We describe a 47-year-old male with chronic hepatitis C who acquired HBV and then spontaneously and apparently completely cleared HCV but developed chronic hepatitis B. Five serum samples collected over 14 months and lymphoid cells obtained after acquiring HBV were tested for HCV and HBV by both standard assays and ultra-sensitive polymerase chain reaction/nucleic acid hybridization (PCR/NAH) (sensitivity ∼2 IU/ml). Results: After superinfection with HBV, HBV surface antigen-positive chronic hepatitis developed with readily detectable HBV DNA. All sera collected after acquisition of HBV, which tested negative for HCV RNA by standard laboratory assay, were positive for HCV genomes when analysed by PCR/NAH. Peripheral lymphoid cells carried HBV DNA and covalently closed circular DNA, but were negative for HCV. Conclusions: This is the first reported case of profound suppression of chronic hepatitis C after superinfection with HBV and establishment of chronic hepatitis B. It is hypothesized that HBV infection precipitated generalized and/or virus-specific cellular immune responses that profoundly suppressed HCV replication and yet failed to inhibit progression to chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Most studies examining the effect of electrical stimulation pattern on the force response of muscle have been done in able-bodied persons. The purpose of this study was to examine the electrically elicited force responses of the paralyzed quadriceps femoris muscles of persons with spinal cord injuries (SCI) to see whether stimulation patterns that increase the force response in non-paralyzed muscle will do so in paralyzed muscle. Thirteen subjects ranging in age from 11 to 24 years old with motor-complete SCI were studied. Isometric muscle performance was tested using 6-pulse constant-frequency trains (CFTs), variable-frequency trains (VFTs), and doublet-frequency trains (DFTs) delivered at mean frequencies of 10, 20, 33, 50, and 100 H Z. In the non-fatigued and fatigued condition, the VFT and DFT peak forces were greater than the CFT peak forces at 10 H Z. In addition, in the fatigued condition the 20-H Z VFT peak forces were greater than the CFT peak forces, and there was a trend for the DFT peak forces to be greater than the CFT peak forces. In the non-fatigued condition, the 33-H Z and 50-H Z DFT force-time integrals were greater than both the CFT and VFT force-time integrals. In the fatigued condition, there was no significant effect of train-type on the force-time integrals. These results differ from those previously reported from studies using able-bodied persons and indicate that findings from studies of the electrically elicited force responses of the muscles of able-bodied persons do not apply to the paralyzed muscles of persons with SCI. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

Cardiac contractility in cirrhosis is normal at baseline but hyporesponsive to stimuli, a phenomenon known as 'cirrhotic cardiomyopathy'. The pathogenesis remains unclear. Endocannabinoids are vasoactive, but have not previously been examined in the cirrhotic heart. We therefore aimed to systematically clarify a possible role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy. Cirrhosis was induced in Sprague-Dawley rats by bile duct ligation; controls underwent a sham operation. At 4 weeks after operation, isolated left ventricular papillary muscle contractility was studied. Dose-response curve for a beta-adrenergic agonist isoproterenol was constructed in the presence and absence of a CB-1 antagonist AM251 (1 microM). Cirrhotic muscles had a blunted response to isoproterenol, which was completely restored by AM251. Dose-response curves to anandamide, and CB-1 and CB-2 protein and mRNA expression in Western blot and reverse transcriptase-polymerase chain reaction experiments were not significantly different between cirrhotic and sham muscles. Force-frequency relationship studies were performed in cirrhotic and normal muscles. At higher frequencies, anandamide reuptake blockers (VDM11 and AM404) significantly enhanced muscle relaxation in cirrhotic muscles, but not in controls. This effect was completely blocked by AM251 and pertussis toxin, whereas tetrodotoxin partially reversed it. Taken together, these results indicate a pathogenic role for increased local (neuronal) production of endocannabinoids, mediated by a G(i)-protein-dependent CB-1-responsive pathway in cirrhotic cardiomyopathy. The increased tachycardia-stress-induced release of endocannabinoids may help explain why contractility is normal at baseline but attenuated with stress. [ABSTRACT FROM AUTHOR]

Chatur N, Ramji A, Bain VG, Ma MM, Marotta PJ, Ghent CN, Lilly LB, Heathcote EJ, Deschenes M, Lee SS, Steinbrecher UP, Yoshida EM. Transplant immunosuppressive agents in non-transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus. Liver International 2005: DOI: 10.1111/j.1478-3231.2005.01107.x © Blackwell Munksgaard 2005 Conventional treatment of autoimmune hepatitis consists of either prednisone alone or in combination with azathioprine. Ten to 20% of patients do not respond to or are intolerant of this treatment. Novel drug treatments include immunosuppressive drugs such as tacrolimus (TAC), mycophenolate mofetil (MMF), methotrexate and cyclosporine. We describe a multi-centre Canadian experience with MMF and TAC. To study a multi-centre patient population who had failed conventional therapy and were treated with non-conventional medical therapy for autoimmune hepatitis and document response. Members of the Canadian Association for the Study of Liver (CASL) obtained MMF from Hoffmann-La Roche Ltd, as part of a compassionate release program, were contacted for standardized data on patients with AIH who received MMF or TAC. Response definitions based on aminotransferase changes were: Complete response (CR)-sustained normalization, partial response (PR)-improvement by greater than 50%, non-response (NR)-less than 50% improvement and relapse (RP)-initial CR or PR followed by an increase in aminotransferases. A total of 16 patients were identified: six in Ontario, one in Quebec, five in Alberta and four in British Columbia. Three were treated with TAC, eleven with MMF and two with combination MMF and TAC. CR was observed in 50%, PR in 12.5%, RP in 25% and NR occurred in 12.5%. The CR for MMF without TAC was approximately 64%. MMF is effective and well tolerated by patients with autoimmune hepatitis who do not respond to, or are intolerant of, conventional immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) genotype 4 is predominantly found in the Middle East and North Africa. Because most of the large randomized controlled trials of antiviral therapy for chronic hepatitis C were conducted in North America and Europe, little is known about management of patients with this particular genotype. Based on the available data, sustained virological response rates to interferon-based therapies appear to be intermediate between the relatively resistant HCV genotype 1 and the readily responsive genotypes 2 and 3. Several large prospective studies of pegylated interferon plus ribavirin combination therapy, the current gold-standard treatment, have recently been completed and will be reviewed.© 2004 Blackwell Publishing Asia Pty Ltd [ABSTRACT FROM AUTHOR]

We sought to identify all genes in the Candida albicans genome database whose deduced proteins would likely be soluble secreted proteins (the secretome). While certain C. albicans secretory proteins have been studied in detail, more data on the entire secretome is needed. One approach to rapidly predict the functions of an entire proteome is to utilize genomic database information and prediction algorithms. Thus, we used a set of prediction algorithms to computationally define a potential C. albicans secretome. We first assembled a validation set of 47 C. albicans proteins that are known to be secreted and 47 that are known not to be secreted. The presence or absence of an N-terminal signal peptide was correctly predicted by SignalP version 2.0 in 47 of 47 known secreted proteins and in 47 of 47 known non-secreted proteins. When all 6165 C. albicans ORFs from CandidaDB were analysed with SignalP, 495 ORFs were predicted to encode proteins with N-terminal signal peptides. In the set of 495 deduced proteins with N-terminal signal peptides, 350 were predicted to have no transmembrane domains (or a single transmembrane domain at the extreme N-terminus) and 300 of these were predicted not to be GPI-anchored. TargetP was used to eliminate proteins with mitochondrial targeting signals, and the final computationally-predicted C. albicans secretome was estimated to consist of up to 283 ORFs. The C. albicans secretome database is available at Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Background: Liver transplantation for inherited metabolic disorders aims to save the patient's life when the disorder is expected to progress to organ failure, and to cure the underlying metabolic defect. Methods: We retrospectively analyzed 146 pediatric liver transplants (28 metabolic; 118 non-metabolic) performed between 1986 and 2000. Results: Twenty-eight transplants were performed in 24 children with metabolic disease (8 females; 16 males; age range 3 months to 17 yr). Indications included α-1-antitrypsin deficiency (n = 8), two cases each of hyperoxaluria type 1, Wilson's disease, hereditary tyrosinemia type I, citrullinemia, methylmalonic acidemia, and one case each of propionic acidemia, Crigler–Najjar syndrome type I , neonatal hemachromatosis, hemophilia B, Niemann–Pick disease type B, and cystic fibrosis. Eighteen transplants were whole organ grafts and 10 were lobar or segmental. Auxiliary liver transplants were performed in two patients and three received combined liver-kidney transplants. There were three deaths from sepsis, two from chronic rejection, and one from fulminant hepatitis. Seven of 10 patients currently of school age are within 1 yr of expected grade and three who had pretransplant developmental delay have remained in special education. Actuarial survival rates at 5 and 10 yr are 78% and 68%, respectively, with mean follow-up in excess of 5 yr. These results compare favorably to 100 pediatric patients transplanted for non-metabolic etiologies (65% and 61%, respectively) (p= NS). Conclusions: Pediatric liver transplantation for metabolic disorders results in excellent clinical and biochemical outcome with long survival and excellent quality of life for most recipients. [ABSTRACT FROM AUTHOR]

Summary. Combination interferon-alpha (IFN-alpha) and ribavirin treatment has become standard therapy for patients with chronic hepatitis C and elevated transaminase levels (> 1.5 x upper limit of normal). No previous study has specifically examined the efficacy of this treatment in patients with normal transaminase values. In this pilot study, we treated 19 patients, with normal or near-normal ALT values on at least three occasions, and histologically mild disease, with :induction IFN-alpha 2b. 5 mega units daily for 4 weeks, then 3 mega units thrice weekly for 44 week, plus concomitant ribavirin 1000 mg or 1200 mg daily for 48 weeks. Nine of the 19 (47%) showed sustained virological response, defined as undetectable HCV-RNA at 24 weeks alter the end of treatment. No ALT flares were observed in any patient. We conclude that combination induction IFN-alpha and ribavirin therapy may be effective in patients with normal-ALT, and appears not to induce flares of ALT activity. Controlled trials of this treatment in this subgroup of patients with hepatitis C are warranted. [ABSTRACT FROM AUTHOR]