Miracle-dz/UniFAR-FTUs huggingface dataset:
Overexpression of cholesterol 7α‐hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis

We reported previously that mice overexpressing cytochrome P450 7a1 (Cyp7a1; Cyp7a1‐tg mice) are protected against high fat diet–induced hypercholesterolemia, obesity, and insulin resistance. Here, we investigated the underlying mechanism of bile acid signaling in maintaining cholesterol homeostasis in Cyp7a1‐tg mice. Cyp7a1‐tg mice had two‐fold higher Cyp7a1 activity and bile acid pool than did wild‐type mice. Gallbladder bile acid composition changed from predominantly cholic acid (57%) in wild‐type to chenodeoxycholic acid (54%) in Cyp7a1‐tg mice. Cyp7a1‐tg mice had higher biliary and fecal cholesterol and bile acid secretion rates than did wild‐type mice. Surprisingly, hepatic de novo cholesterol synthesis was markedly induced in Cyp7a1‐tg mice but intestine fractional cholesterol absorption in Cyp7a1‐tg mice remained the same as wild‐type mice despite the presence of increased intestine bile acids. Interestingly, hepatic but not intestinal expression of several cholesterol (adenosine triphosphate–binding cassette G5/G8 [ABCG5/G8], scavenger receptor class B, member 1) and bile acid (ABCB11) transporters were significantly induced in Cyp7a1‐tg mice. Treatment of mouse or human hepatocytes with a farnesoid X receptor (FXR) agonist GW4064 or bile acids induced hepatic Abcg5/g8 expression. A functional FXR binding site was identified in the Abcg5 gene promoter. Study of tissue‐specific Fxr knockout mice demonstrated that loss of the Fxr gene in the liver attenuated bile acid induction of hepatic Abcg5/g8 and gallbladder cholesterol content, suggesting a role of FXR in the regulation of cholesterol transport. Conclusion: This study revealed a new mechanism by which increased Cyp7a1 activity expands the hydrophobic bile acid pool, stimulating hepatic cholesterol synthesis and biliary cholesterol secretion without increasing intestinal cholesterol absorption. This study demonstrated that Cyp7a1 plays a critical role in maintaining cholesterol homeostasis and underscores the importance of bile acid signaling in regulating overall cholesterol homeostasis. (HEPATOLOGY 2011)
Identifying and Assessing the Substance-Exposed Infant

AbstractAs the rate of opioid prescription grows, so does fetal exposure to opioids during pregnancy. With increasing fetal exposure to both prescription and nonprescription drugs, there has been a concurrent increase in identification of Neonatal Withdrawal Syndrome (NWS) and adaptation difficulties after birth. In addition, extended use of opioids, barbiturates, and benzodiazepines in neonatal intensive care has resulted in iatrogenic withdrawal syndromes. There is a lack of evidence to support the use of any one specific evaluation strategy to identify NWS. Clinicians caring for infants must use a multimethod approach to diagnosis, including interview and toxicology screening. Signs of NWS are widely variable, and reflect dysfunction in autonomic regulation, state control, and sensory and motor functioning. Several assessment tools have been developed for assessing severity of withdrawal in term neonates. These tools assist in determining need and duration of pharmacologic therapy and help in titration of these therapies. Considerable variability exists in the pharmacologic and nonpharmacologic approaches to affected babies across settings. An evidence-based protocol for identification, evaluation, and management of NWS should be in place in every nursery. This article provides an overview of identification and assessment considerations for providers who care for babies at risk for or who are experiencing alterations in state, behavior, and responses after prenatal or iatrogenic exposure to agents associated with the spectrum of withdrawal.
Pain and Disability in Chronic Low Back Pain Patients Treated Using Instrumented Fusion

ABSTRACT. Objective: To examine functional status in preoperative and postoperative patients treated with instrumented fusion due to chronic low back pain. Methods: A comparative cross-sectional survey design was applied to compare pain, disability, and work status in preoperative patients and in patients who had surgery one to eight years after surgery. Assessment tools were a visual analog scale and the Oswestry Disability Index. Results: Twenty-five preoperative patients [mean age 45 ± 6.5 years] and 101 postoperative patients [46 ± 8.9 years] participated in the study. The postoperative patients as a group reported significantly less back and hip pain [P < 0.001], less leg pain [P < 0.001], less disability [P < 0.001], less use of analgesics [P < 0.05], and were more frequently employed [P = 0.01] than the group of preoperative patients. Most of the postoperative patients [74 percent] report using less analgesic than before the operation. However, six from the group of postoperative patients reported very severe or worst imaginable pain, and five of them were crippled or bed-bound. Patients who underwent surgery five to eight years ago tended to report less disability as compared to patients who underwent surgery one to two years ago [P < 0.03]. Conclusions: Postoperative patients as a group had substantially less pain intensity and disability one to eight years following instrumented fusion than a comparison group of preoperative patients. Although the same patients were not followed over time, disability may seem to decrease somewhat as a function of time after surgery. However, not all patients who had spinal fusion obtained a favorable result.
Effect of pharmacological therapies for stroke prevention on major gastrointestinal bleeding in patients with atrial fibrillation

Various antiplatelet and anticoagulation options are available for stroke prevention in patients with atrial fibrillation (AF). Currently, it is unclear whether these agents differ in their propensity to cause major gastrointestinal bleeding (MGIB). To our knowledge, no systematic evaluation of MGIB rates from randomised controlled trials (RCTs) of pharmacological stroke prevention in patients with AF has been conducted. Two independent investigators conducted systematic literature searches in MEDLINE and CENTRAL from the earliest possible date through November 2010. To be included, RCTs had to evaluate an adult population with AF or flutter and report data on the incidence of MGIB. Peto’s odds ratios (ORs) with associated 95% confidence intervals (CIs) were calculated for all possible pair‐wise comparisons of pharmacological stroke prevention alternatives. A total of 16 unique trials (n = 42,983) met inclusion criteria. The reported incidence of MGIB in placebo or control arms of identified trials was as high as 1.5%. Upon pair‐wise meta‐analysis of different pharmacological strategies, adjusted‐dose vitamin K antagonists (VKAs) were found to be associated with a higher odds of MGIB compared with placebo/control (OR 3.21, 95% CI 1.32–7.82) and aspirin (or triflusal or indobufen) (OR 1.92, 95% CI 1.08–3.41). The addition of aspirin (or triflusal) to an adjusted‐dose VKA resulted in greater odds of MGIB compared with aspirin alone (OR 4.72, 95% CI 1.35–16.49) and adjusted‐dose VKA alone (OR 2.66, 95% CI 1.05–6.74). While aspirin increased the odds of MBIG by 3.23‐fold compared with placebo/control, this finding did not reach statistical significance. The combination of aspirin and clopidogrel increased patients’ odds of MGIB compared with aspirin alone (OR 1.93, 95% CI 1.46–2.56). Dabigatran was associated with a 30% increased odds of MGIB compared with adjusted‐dose VKA (OR 1.30, 95% CI 1.06–1.59); however, ximelagatran was not. Low‐intensity VKA therapy, alone or in combination with aspirin, was not associated with increased odds of MGIB compared with any (active‐) comparator. The MGIB is a concern for patients with AF receiving pharmacological stroke prevention. Current RCT data suggest that dabigatran and adjusted‐dose VKA therapy are associated with the highest odds of MGIB. Aspirin was not found to increase patients’ odds of MGIB; however, this finding may be the result of type 2 error. Dual therapy resulting from the addition of an antiplatelet agent was typically associated with further increased odds of MGIB compared with monotherapy.
Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis

Autoimmune hepatitis (AIH) typically responds to treatment in 90% of patients. Early prediction of treatment outcome would be advantageous in clinical practice. We evaluated whether parameters at initiation of therapy or changes in these parameters at day 3 and day 7 following corticosteroid initiation predicted treatment failure. Treatment‐naive, jaundiced patients presenting to our tertiary unit between 1999‐2009 were identified and mathematical models of prognosis in liver disease scores calculated at day 0, day 3, and day 7. Overall, 72 patients were identified (48 women, 24 men). Treatment failure occurred in 18% (13/72) of patients. At diagnosis, higher median bilirubin (451 μmol/L versus 262 μmol/L, P = 0.02), INR (1.62 versus 1.33, P = 0.005), model for endstage liver (MELD) score (26 versus 20, P = 0.02), MELD‐sodium (Na) score (27 versus 22, P = 0.03) and United Kingdom endstage liver disease score (UKELD) score (59 versus 57, P = 0.01) significantly correlated with treatment failure. Analysis of area under the receiver operator characteristic curve (AUROC) values at day 7 identified change (Δ) bilirubin (AUROC 0.68), Δ creatinine (0.69), Δ MELD (0.79), Δ MELD‐Na (0.83) and Δ UKELD (0.83) best predicted treatment failure. Specifically, a fall in UKELD of less than 2 points predicted treatment failure with a sensitivity of 85% and specificity of 68%. Of 13 treatment failures, nine required second‐line immunosuppression, three required emergency transplant, and one died of sepsis. In total, four patients died in the treatment failure group compared with one in the responder group (4/13 = 31% versus 1/59 = 1.7%, P = 0.003). Conclusion: Approximately 20% of icteric AIH presentations fail corticosteroid therapy. This is associated with significant mortality and the need for emergency transplantation. Treatment failure is best predicted by change in MELD‐Na and UKELD at day 7. Early identification of nonresponders may allow timely escalation of immunosuppression to prevent clinical deterioration. (HEPATOLOGY 2011;)
Health Professionals' Practices and Attitudes About Miscarriage

Purpose:The purposes of the study were to explore relationships between attitudes, beliefs, and practices of healthcare professionals caring for women and families experiencing miscarriage and to identify gaps and barriers in follow-up services and supports for these women and families. Study Design and Methods:A survey about beliefs, attitudes, and practices regarding women and families experiencing miscarriage and barriers to care was conducted electronically and through distribution in three emergency departments (EDs). There were 174 participants; physicians (n = 50), RNs (n = 63), midwives (n = 38), nurse practitioners (n = 9), and others (n = 4). Results:Participants believed that miscarriage can have high impact on women and families. They provided information to patients about miscarriage and its present and future implications. The most important predictor for mobilization of support by healthcare professionals was confidence. Nurses in EDs reported the least amount of confidence and knowledge to provide women and families with support. Availability and awareness of specific services by professionals and health system issues were identified as barriers to care. Clinical Implications:Education of healthcare professionals, particularly of RNs in EDs, is important to address misconceptions about miscarriage, increase confidence in providing support, and promote effective care. Women and families experiencing miscarriage need privacy and timeliness in care. Interventions such as funded midwifery loss care or a routine telephone follow-up call could improve access to care and help healthcare professionals ensure that families obtain the type and amount of support that they need.
Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice

In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin messenger RNA (mRNA) responsiveness to short and long‐term iron challenge in iron‐depleted Hfe, Tfr2, Hjv, and Bmp6 mutant mice. After 1‐day (acute) iron challenge, Hfe−/− mice showed a smaller hepcidin increase than their wild‐type strain‐matched controls, Bmp6−/− mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21‐day (chronic) iron challenge, Hfe and Tfr2 mutant mice increased hepcidin expression to nearly wild‐type levels, but a blunted increase of hepcidin was seen in Bmp6−/− and Hjv−/− mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (except Bmp6−/− mice) had impaired BMP6 mRNA response to chronic iron loading. Conclusion: TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading. (HEPATOLOGY 2011;)
Randomized trial of lamivudine versus entecavir in entecavir‐treated patients with undetectable hepatitis B virus DNA: Outcome at 2 Years

We aimed to determine the 2‐year outcomes of entecavir followed by lamivudine in patients with undetectable viral load (<12 IU/mL) and normal alanine aminotransferase (ALT) after initial entecavir treatment for at least 6 months. Patients were randomly assigned 1:1 to continue with entecavir or switch to lamivudine. Liver biochemistry and hepatitis B virus (HBV) DNA were determined at weeks 0, 4, 12, 24, 48, 72, and 96. Mutational analysis using line‐probe assay were performed at weeks 0, 24, 48, and 96 and at the time of HBV DNA relapse. There was no elevation of ALT observed in any patients up to 96 weeks. At 96 weeks of follow‐up, 19/25 (76%) patients in the lamivudine arm had persistently undetectable HBV DNA, compared with 25/25 (100%) patients in the entecavir arm. Six patients in the lamivudine arm had HBV DNA >20 IU/mL, occurring at a range of 12 to 96 weeks. Of these, four patients had HBV DNA of less than 100 IU/mL during rebound (three had undetectable HBV DNA after switching back to entecavir), and the remaining two patients had HBV DNA levels of 7,973 and 699 IU/mL. Three patients (12%) had evidence of drug‐resistant mutations, of which two patients had rtM204I mutation and one patient had rtM204V mutation. One of these three patients had previous lamivudine exposure before entecavir treatment and one patient had questionable drug compliance. Conclusion: Sequential therapy using entecavir followed by lamivudine resulted in virological rebound in 24% of patients after 96 weeks. Prior optimal viral suppression with entecavir did not confer any significant advantage in patients who switched to lamivudine. (HEPATOLOGY 2011;)
pyr RNA binding to the Bacillus caldolyticus PyrR attenuation protein – characterization and regulation by uridine and guanosine nucleotides

The PyrR protein regulates expression of pyrimidine biosynthetic (pyr) genes in many bacteria. PyrR binds to specific sites in the 5′ leader RNA of target operons and favors attenuation of transcription. Filter binding and gel mobility assays were used to characterize the binding of PyrR from Bacillus caldolyticus to RNA sequences (binding loops) from the three attenuation regions of the B. caldolyticus pyr operon. Binding of PyrR to the three binding loops and modulation of RNA binding by nucleotides was similar for all three RNAs. The apparent dissociation constants at 0 °C were in the range 0.13–0.87 nm in the absence of effectors; dissociation constants were decreased by three‐ to 12‐fold by uridine nucleotides and increased by 40‐ to 200‐fold by guanosine nucleotides. The binding data suggest that pyr operon expression is regulated by the ratio of intracellular uridine nucleotides to guanosine nucleotides; the effects of nucleoside addition to the growth medium on aspartate transcarbamylase (pyrB) levels in B. subtilis cells in vivo supported this conclusion. Analytical ultracentrifugation established that RNA binds to dimeric PyrR, even though the tetrameric form of unbound PyrR predominates in solution at the concentrations studied.
UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation

Epigenetic changes play significant roles in cancer development. UHRF1, an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene (TSG) silencing in several cancers. In a previous study, we found that UHRF1 promoted gastric cancer (GC) invasion and metastasis. However, the role and underlying mechanism of UHRF1 in GC carcinogenesis remain largely unknown. In the present study, we investigated UHRF1 expression and function in GC proliferation and explored its downstream regulatory mechanism. The results demonstrated that UHRF1 overexpression was an independent and significant predictor of GC prognosis. Downregulation of UHRF1 suppressed GC proliferation and growth in vitro and in vivo, and UHRF1 upregulation showed opposite effects. Furthermore, downregulation of UHRF1 reactivated 7 TSGs, including CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML, via promoter demethylation. These results provide insight into the GC proliferation process, and suggest that targeting UHRF1 represents a new therapeutic approach to block GC development.
Parenchymal expression of CD40 exacerbates adenovirus‐induced hepatitis in mice

The healthy adult human liver expresses low levels of major histocompatibility complex class II (MHC II) and undetectable levels of immune costimulatory molecules. However, high levels of MHC II, CD40, and B7 family molecules are expressed in the activated Kupffer cells and hepatocytes of patients with viral hepatitis. The precise role of these molecules in viral clearance and immune‐mediated liver injury is not well understood. We hypothesized that parenchymal CD40 expression enhances T cell recruitment and effector functions, which may facilitate viral clearance and alleviate liver injury. To test this hypothesis, we generated novel liver‐specific, conditional CD40 transgenic mice, and we challenged them intravenously with a recombinant replication‐deficient adenovirus carrying Cre recombinase (AdCre). Wild‐type mice infected with AdCre developed a relatively mild course of viral hepatitis and recovered spontaneously. CD40 expression in the livers of transgenic animals, however, resulted in CD80 and CD86 expression. The dysregulation of population dynamics and effector functions of intrahepatic lymphocytes (IHLs) resulted in severe lymphocytic infiltration, apoptosis, necroinflammation, and serum alanine aminotransferase elevations in a dose‐dependent fashion. To our surprise, an early expansion and subsequent contraction of IHLs (especially CD8+ and natural killer cells), accompanied by increased granzyme B and interferon‐γ production, did not lead to faster viral clearance in CD40 transgenic mice. Conclusion: Our results demonstrate that hepatic CD40 expression does not accelerate adenoviral clearance but rather exacerbates liver injury. This study unveils a previously unknown deleterious effect of hepatic CD40 on adenovirus‐induced liver inflammation. (Hepatology 2011;)
A test of the revised Frost's ‘rapid manual method’ for the preparation of bone thin sections

A recent publication by Maat et al. (2001) introduces a modification of Frost's earlier ‘rapid manual method’ for ground bone thin section preparations, which uses ‘surface embedding’ with cyanoacrylate for sample protection. This revised method is said to provide a quick, inexpensive system for producing thin sections from archaeological specimens with a finished quality equivalent to more involved and equipment-intensive methods. Our study conducted a test comparing Maat et al.'s method with the standard technique that uses vacuum embedding media. A number of samples were tested, including modern bone samples from the dissecting room as well as archaeological samples in differing states of preservation. The results were highly favourable for a large majority of the specimens. For both modern and archaeological bone, Maat et al.'s revised method produced images of equivalent quality to samples prepared using embedding media. However, poor preservation of the specimens is still an issue, and only relatively dense, intact specimens hold up to the physical demands of the manual grinding procedure. This paper also adds a number of refinements to Maat et al.'s methodology. Future refinement of this technique would greatly facilitate large-scale sampling and encourage more osteological researchers to use histomorphometric analysis of archaeological hard tissues. Copyright © 2006 John Wiley & Sons, Ltd.
Second‐phase hepatitis C virus RNA decline during telaprevir‐based therapy increases with drug effectiveness: Implications for treatment duration

Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase, followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase of decay to treatment effectiveness, whereas the second phase of decay is attributed to the progressive loss of infected cells. Here, we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found the second‐phase slope of viral decline to be strongly correlated with treatment effectiveness and to be roughly four‐fold more rapid than has been reported with interferon‐based therapies. Because telaprevir is not known to increase the death rate of infected cells, our results suggest that the second‐phase slope of viral decline is driven not only by the death of infected cells, but may also involve other mechanisms, such as a treatment‐effectiveness–dependent degradation of intracellular viral RNA. As a result of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. (HEPATOLOGY 2011;)