Miracle-dz/UniFAR-FTUs huggingface dataset:
Hypoxia‐driven Hif2a coordinates mouse liver regeneration by coupling parenchymal growth to vascular expansion

Interaction between sinusoidal endothelial cells and hepatocytes is a prerequisite for liver function. Upon tissue loss, both liver cell populations need to be regenerated. Repopulation occurs in a coordinated pattern, first through the regeneration of parenchyme (hepatocytes), which then produces vascular endothelial growth factor (VEGF) to enable the subsequent angiogenic phase. The signals that instruct hepatocytes to induce timely VEGF remain unidentified. Given that liver is highly vascularized, we reasoned that fluctuations in oxygenation after tissue loss may contribute to the coordination between hepatocyte and sinusoidal endothelial cell proliferation. To prevent drops in oxygen after hepatectomy, mice were pretreated with inositol trispyrophosphate (ITPP), an allosteric effector of hemoglobin causing increased O2 release from heme under hypoxic conditions. ITPP treatment delayed liver weight gain after hepatectomy. Comparison with controls revealed the presence of a hypoxic period around the peak of hepatocyte mitosis. Inhibition of hypoxia led to deficient hepatocyte mitosis, suppressed the regenerative Vegf wave, and abrogated the subsequent reconstruction of the sinusoidal network. These ITPP effects were ongoing with the reduction in hepatocellular hypoxia inducible factor 2a (Hif2a). In contrast, Hif1a was unaffected by ITPP. Hif2a knockdown phenocopied all effects of ITPP, including the mitotic deficiencies, Vegf suppression, and angiogenic failure. Conclusions: Oxygen is a key regulator of liver regeneration. Hypoxia—inherent to the expansion of parenchyme—activates Hif2a to couple hepatocyte mitosis with the angiogenic phase. Hif2a acts as a safeguard to initiate sinusoidal reconstruction only upon successful hepatocyte mitosis, thereby enforcing a timely order onto cell type‐specific regeneration patterns. These findings portray the hypoxia‐driven Hif2a‐Vegf axis as a prime node in coordinating sinusoidal endothelial cell‐hepatocyte crosstalk during liver regeneration. (Hepatology 2016;64:2198‐2209).
Clinical Applicability of an Educational-Behavioural Joint Protection Programme for People with Rheumatoid Arthritis

Joint protection is a major part of rheumatology occupational therapy. Recent research emphasises that an educational-behavioural approach is more effective than current practice in enabling people with rheumatoid arthritis (RA) to increase their use of joint protection and benefit from reduced pain and inflammation and improved function. The aim of this study was to evaluate whether occupational therapists, following a 2-day training course in delivering an educational-behavioural joint protection programme, could enable people with RA to improve use of joint protection significantly and obtain similar results to previous clinical trials. This tested whether it would be feasible to introduce the programme into clinical practice. Three occupational therapists attended a ‘Looking After Your Joints’ training course for leaders. A single-blind crossover trial was conducted. Three centres participated, with each therapist delivering two or three joint protection programmes. Thirty participants with RA attended: 27 women and 3 men, with a mean age of 52.3 years (SD 12.08) and a mean disease duration of 6.76 years (SD 7.02). The primary outcome measure was an observational assessment of use of joint protection, the Joint Protection Behaviour Assessment (JPBA; Hammond and Lincoln 1999b). The median baseline JPBA score for all 30 participants was 15.39% (IQR 11.45–26.82%), which rose significantly to 35% (IQR 25–42.40%) (Z = −3.97; p = 0.0001) at 6 months following the programme. Both participants and therapists expressed positive views of the efficacy of this training approach. Sixteen participants increased use of joint protection by 20% or more. The findings highlight that the 2-day training course facilitated therapists in delivering the programme effectively and they could gain similar behavioural improvements to previous clinical trials.
Patient Disengagement From an HIV Preexposure Prophylaxis Program in a Sexually Transmitted Disease Clinic

Abstract Among 307 patients enrolled in an HIV preexposure prophylaxis (PrEP) program in the Public Health–Seattle & King County STD Clinic, 52 patients (17%) did not fill their PrEP prescription and 40% of those who started PrEP discontinued it at least once within 12 months.
“Project HOPE” for Homeless Individuals with Co-Occurring Mental and Substance Abuse Disorders: Reducing Symptoms, Victimization, and Violence

Homeless individuals with co-occurring mental and substance abuse disorders are at high risk for victimization and violence, frequently cycle between the streets, jails, and emergency rooms, and are difficult to effectively treat because of their multifaceted problems. This study evaluates Project HOPE, an intensive, integrated outreach program for this population. We found that Project HOPE effectively enrolled a highly at-risk, symptomatic group of 69 clients in treatment. However, the majority (62%) of these clients discontinued treatment in less than three months. Those who completed Project HOPE showed remarkable improvement across several domains, including more stable housing, fewer psychiatric and substance abuse problems, and better relationships. In this first study of treatment-related changes in violence and victimization for this population, we found that victimization rates decreased from 67% to 16% and violence rates decreased from 46% to 20% with treatment. Implications for developing programs that better retain clients while effectively improving their symptoms, safety, and functioning are discussed.
Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system

Extrahepatic disease manifestations are common in chronic hepatitis C virus (HCV) infection. The mechanism of HCV‐related lymphoproliferative disorders is not fully understood. Recent studies have found that HCV in peripheral blood mononuclear cells from chronically infected patients is mainly associated with cluster of differentiation 19‐positive (CD19+) B cells. To further elucidate this preferential association of HCV with B cells, we used in vitro cultured virus and uninfected peripheral blood mononuclear cells from healthy blood donors to investigate the necessary serum components that activate the binding of HCV to B cells. First, we found that the active serum components were present not only in HCV carriers but also in HCV recovered patients and HCV‐negative, healthy blood donors and that the serum components were heat‐labile. Second, the preferential binding activity of HCV to B cells could be blocked by anti‐complement C3 antibodies. In experiments with complement‐depleted serum and purified complement proteins, we demonstrated that complement proteins C1, C2, and C3 were required to activate such binding activity. Complement protein C4 was partially involved in this process. Third, using antibodies against cell surface markers, we showed that the binding complex mainly involved CD21 (complement receptor 2), CD19, CD20, and CD81; CD35 (complement receptor 1) was involved but had lower binding activity. Fourth, both anti‐CD21 and anti‐CD35 antibodies could block the binding of patient‐derived HCV to B cells. Fifth, complement also mediated HCV binding to Raji cells, a cultured B‐cell line derived from Burkitt's lymphoma. Conclusion: In chronic HCV infection, the preferential association of HCV with B cells is mediated by the complement system, mainly through complement receptor 2 (CD21), in conjunction with the CD19 and CD81 complex. (Hepatology 2016;64:1900‐1910).
Evaluation of an intervention programme based on empowerment for eldercare nursing staff

Abstract This study evaluated the impact of an intervention programme at individual, worksite, and organizational level, for eldercare nursing staff at 12 eldercare units. The project aimed at empowering auxiliary nurses and nursing assistants, thus promoting good working conditions, health and well-being of eldercare staff, and improving their evaluation of the quality of nursing care. Questionnaire responses from the nursing staff (n=200) before and after an 18-month intervention programme evaluated the effects using ANOVA, repeated measures for the statistical analyses. Although the improvements were limited, the intervention seemed to impact on work conditions and on the perceived quality of nursing rather than on the health and well-being of staff. Work at nursing homes or at home-care was shown to modify the outcome due to different needs and priorities for work unit improvements. Staff turnover and multiple reorganizations are discussed as inhibiting factors for performance as well as for the evaluation of workplace interventions. The sharing of power between occupational groups or organizational levels must be carefully considered. The study emphasizes the importance of involving the middle management in early project planning and decisions.
Costs and outcomes of treatments for excessive alcohol consumption: Making policy decisions with the available data

Aim: To determine which treatments for risky or dependent alcohol consumption provide the best health outcomes for a given expenditure. Methods: Economic evaluation expressing results in cost per unit outcome, from the perspective of the Australian healthcare system. Interventions considered include brief interventions; psychosocial interventions (motivational approaches, cognitive-behavioural approaches and self-guided materials); and pharmacotherapies (acamprosate and naltrexone). Treatment outcomes and standard treatment costs were measured for selected studies, and costs per unit outcome were calculated. Findings: Twenty-nine studies were selected for the analysis. As treatment outcomes were not consistently expressed in a single unit across interventions, two outcomes were used in the analysis: percentage change in alcohol consumption and percentage change in the proportion of abstinent days. Brief interventions provided the best cost per unit outcome, followed by psychosocial interventions, then pharmacotherapies. Conclusions: By using two treatment outcomes instead of one we demonstrated that some treatments for alcohol dependence provide better value for money, but as a result we were unable to complete a formal health economic evaluation. Consistent measurement of alcohol consumption outcomes in research studies would facilitate similar economic evaluations in the future. This work illustrates the difficulties of using research studies with non-comparable outcomes to inform policy on the cost-effectiveness of different treatments.
Pivotal role of glutamine synthetase in ammonia detoxification

Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole‐body muscle‐to‐fat ratio with increased myostatin expression in muscle. Using GS‐knockout/liver and control mice and stepwise increments of enterally infused ammonia, we show that ∼35% of this ammonia is detoxified by hepatic GS and ∼35% by urea‐cycle enzymes, while ∼30% is not cleared by the liver, independent of portal ammonia concentrations ≤2 mmol/L. Using both genetic (GS‐knockout/liver and GS‐knockout/muscle) and pharmacological (methionine sulfoximine and dexamethasone) approaches to modulate GS activity, we further show that detoxification of stepwise increments of intravenously (jugular vein) infused ammonia is almost totally dependent on GS activity. Maximal ammonia‐detoxifying capacity through either the enteral or the intravenous route is ∼160 μmol/hour in control mice. Using stable isotopes, we show that disposal of glutamine‐bound ammonia to urea (through mitochondrial glutaminase and carbamoylphosphate synthetase) depends on the rate of glutamine synthesis and increases from ∼7% in methionine sulfoximine‐treated mice to ∼500% in dexamethasone‐treated mice (control mice, 100%), without difference in total urea synthesis. Conclusions: Hepatic GS contributes to both enteral and systemic ammonia detoxification. Glutamine synthesis in the periphery (including that in pericentral hepatocytes) and glutamine catabolism in (periportal) hepatocytes represents the high‐affinity ammonia‐detoxifying system of the body. The dependence of glutamine‐bound ammonia disposal to urea on the rate of glutamine synthesis suggests that enhancing peripheral glutamine synthesis is a promising strategy to treat hyperammonemia. Because total urea synthesis does not depend on glutamine synthesis, we hypothesize that glutamate dehydrogenase complements mitochondrial ammonia production. (Hepatology 2017;65:281‐293).
TOXIC EPIDERMAL NECROLYSIS IN A PATIEXT WITH PULMONARY ASPERGILLOSIS.

A man aged 85 fell at home and fractured the right femur. He "\̂ 'as admitted to hospital Avhere radiogra]")hy confirmed the fracture and sho"\A'ed the presence of Paget's disease of the pelvis and femur. The latter A\'as pinned t̂ \ o days after and he Avas transfused Avith one pint of blood because the haemoglobin AAas 66%. Eleven days after his fall he developed bilateral coujunetivitis and peeling of the skin of the trunk. The temperature Avas 98° F. The same evening the temperature rose to 102̂ "' F. and examination of the chest revealed a right-sided basal pueumonia. The folloAA'ing da}^ the peeling was more marked and resembled that of extensive scalding of the skin. The patient died tA\̂ o days after the onset of the eruption. The blood urea was 66 mg. per 100 ml. ou admission and 118 mg. per 100 ml. on the day before death. He received an injection of anti-tetanic serum on admission, and injections of atropine and pethidine on the day of operation. An injection of paraldehyde Avas given tAvo days before the onset of" the rash. When the conjunctivitis and peeling had started, he Avas treated Avith sulphacetamide eye drops aud injections of penicillin.
Are proton pump inhibitors a threat for spontaneous bacterial peritonitis and hepatic encephalopathy in cirrhosis? Not so fast

In their recent study, Dam et al. retrospectively analyzed data from three multicenter trials of satavaptan in ascites, to look for associations between proton pump inhibitor (PPI) use and spontaneous bacterial peritonitis (SBP) and hepatic encephalopathy (HE). Although the researchers concluded that PPIs pose a threat of the development of SBP and HE in patients with cirrhosis, the limitations of retrospective analyses should be considered. These trials were designed to address a separate issue and not to assess the effect of PPIs on the development of SBP or HE. Therefore, they cannot account for all potential confounders. In observational epidemiology, summary risk estimates of below 2 are more likely to indicate confounding than causality. Biological plausibility for an association between PPI use and SBP is based on PPIs decreasing gastric acidity, which may promote small intestinal bacterial overgrowth (SIBO) with subsequent bacterial translocation leading to SBP. However, a study of 1,191 patients found no association between PPI use and SIBO. In our recent meta-analysis, we found a statistically significant, but quantitatively small, association between SBP and PPI use. Furthermore, we noted that prospectively conducted studies failed to show any association. Overall, this constituted low-quality evidence as per GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A more recent prospective study by Miozzo et al. with a 5-year follow-up did not report any significant association between PPI use and SBP. Dam et al. found that only 56% of the patents in their retrospective analysis had a valid indication for PPI use. As with all drugs, PPIs should be used in their lowest effective dose and only for appropriate indications—in patients with and without cirrhosis alike. However, based on the evidence presented by Dam et al. it is premature to conclude that PPIs pose a major threat of SBP and HE in patients with cirrhosis. PPI treatment should not be withheld from patients with cirrhosis who have a valid indication for it.
Risk Factors for Incident Herpes Simplex Type 2 Virus Infection Among Women Attending a Sexually Transmitted Disease Clinic

Objectives: To estimate the incidence of herpes simplex type 2 virus (HSV-2) infection, to identify risk factors for its acquisition, and to assess the protective effect of condoms. Study Design: Prospective study of 293 HSV-2 seronegative women, aged 18 to 35 years, attending a sexually transmitted disease clinic in Alabama from 1992 to 1995. Results: Incidence of HSV-2 infection was 20.5 per 100 woman-years [95% confidence interval (CI), 13.1–30.5]. Young women (18–20 years) had a significantly higher risk of incident HSV-2 infection [adjusted hazard ratio (HR), 2.8; 95% CI, 1.3–6.4] than older women. Women diagnosed with prevalent or incident bacterial vaginosis had a higher incidence of HSV-2 infection than those who were not so diagnosed (adjusted HR, 2.4; 95% CI, 1.1–5.6). No significant protective effect was observed for consistent (100%) condom use without breakage and slippage against HSV-2 acquisition (adjusted HR, 0.8; 95% CI, 0.2–2.3). Conclusion: Acquisition of HSV-2 infection among study participants was higher than previous estimates for adult female sexually transmitted disease clinic attendees, and no protective effect for condoms was demonstrated. The high incidence of HSV-2 infection with its potential for adverse health consequences emphasizes the need for better prevention strategies.
Multicentre double-blind study of efficacy and safety of terbinafine 1% cream compared with bifonazole 1% cream in patients with tinea pedis moccasin type

In a multicentre double-blind randomized parallel-group study, 78 patients with myologically proven moccasin-type tinea pedis were treated with terbinafine 1% cream or bifonazole 1% cream applied once daily for 2 weeks. The demographic data of both groups were comparable. Of 40 patients treated with terbinafine, the treatment was effective (i.e. mycological and clinical improvement) in 82.5% compared with 63.2% of 38 patients treated with bifonazole (P=0.05, test of proportion). Both creams were well tolerated. We conclude that topical terbinafine 1% cream is superior to bifonazole 1% cream in the treatment of moccasintype tinea pedis.
Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: A cohort study

The presence of an association between chronic hepatitis B virus (HBV) infection and fatty liver is controversial. We examined the association between HBV infection and the development of nonalcoholic fatty liver disease (NAFLD). We conducted a cohort study of 83,339 participants without NAFLD at baseline who underwent serologic testing for hepatitis B surface antigen (HBsAg) between 2002 and 2006 and were followed annually or biennially until December 2014. NAFLD was defined as the presence of ultrasonographic fatty liver in the absence of excessive alcohol use or other identifiable causes. We used a parametric Cox model to estimate adjusted hazard ratios with 95% confidence intervals of incident NAFLD. During 484,736.1 person‐years of follow‐up, 20,200 incident NAFLD cases were identified. In models adjusted for age, sex, year of visit, smoking status, alcohol intake, regular exercise, education level, and body mass index, the adjusted hazard ratio (95% confidence interval) for incident NAFLD comparing HBsAg‐positive to HBsAg‐negative participants was 0.83 (0.73‐0.94). After introducing HBV infection and confounders (including homeostasis model assessment of insulin resistance and metabolic factors) as time‐dependent exposures, the association between HBV infection and decreased risk of incident NAFLD was attenuated but persisted. These associations were consistently observed across clinically relevant, prespecified subgroups. Conclusion: In this large cohort of apparently healthy Korean adults, HBsAg seropositivity was associated with lower risk of developing NAFLD, indicating a possible effect of HBV infection on the pathogenesis of NAFLD development. (Hepatology 2017;65:828‐835).
Combined analysis of DNA methylation and cell cycle in cancer cells

DNA methylation is a chemical modification of DNA involved in the regulation of gene expression by controlling the access to the DNA sequence. It is the most stable epigenetic mark and is widely studied for its role in major biological processes. Aberrant DNA methylation is observed in various pathologies, such as cancer. Therefore, there is a great interest in analyzing subtle changes in DNA methylation induced by biological processes or upon drug treatments. Here, we developed an improved methodology based on flow cytometry to measure variations of DNA methylation level in melanoma and leukemia cells. The accuracy of DNA methylation quantification was validated with LC-ESI mass spectrometry analysis. The new protocol was used to detect small variations of cytosine methylation occurring in individual cells during their cell cycle and those induced by the demethylating agent 5-aza-2'-deoxycytidine (5AzadC). Kinetic experiments confirmed that inheritance of DNA methylation occurs efficiently in S phase and revealed a short delay between DNA replication and completion of cytosine methylation. In addition, this study suggests that the uncoupling of 5AzadC effects on DNA demethylation and cell proliferation might be related to the duration of the DNA replication phase.
Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein–induced hepatocarcinogenesis

Chronic hepatitis B virus infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a hepatitis B virus protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. Farnesoid X receptor (FXR) is a nuclear receptor with activities in anti‐inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact hepatitis B virus/HBx‐induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a coactivator of FXR. Expression of HBx in vivo enhanced FXR‐responsive gene regulation. HBx also increased the transcriptional activity of FXR in a luciferase reporter gene assay. The HBx–FXR interaction was confirmed by coimmunoprecipitation and glutathione S‐transferase pull‐down assays, and the FXR activation function 1 domain was mapped to bind to the third α helix in the C terminus of HBx. We also found that the C‐terminally truncated variants of HBx, which were found in clinical HCC, were not effective at transactivating FXR. Interestingly, recruitment of the full‐length HBx, but not the C‐terminally truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx‐induced hepatocarcinogenesis. Conclusions: We propose that transactivation of FXR by full‐length HBx may represent a protective mechanism to inhibit HCC and that this inhibition may be compromised upon the appearance of C‐terminally truncated HBx or when the expression and/or activity of FXR is decreased. (Hepatology 2017;65:893‐906)