In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. ...Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.
Background and Aim: Hepatitis C virus (HCV) infection is associated with impairment in health‐related quality of life (HRQOL). The purpose of this study was to evaluate HRQOL across the HCV disease ...spectrum using preference‐based (utility) and non‐preference‐based (psychometric) methods, adjusting for sociodemographic factors and co‐morbidity.
Methods: Hepatitis C virus patients (n = 751) were recruited from several tertiary care settings in Vancouver, Canada for this observational, cross‐sectional cohort study. Patients completed the Health Utilities Index Mark 2/3, a self‐administered time trade‐off utility instrument, and the Hepatitis Quality of Life Questionnaire (SF‐36 with HCV‐specific items). We examined the association between HRQOL and disease stage using linear regression adjusting for age, education, marital status, income, and co‐morbidities.
Results: Utility scores were low across disease stage and instrument, ranging from 0.51 to 0.80. On the SF‐36, the mean Physical Component Summary score ranged from 37.2 to 49.2 across disease stage, and the Mental Component Summary score ranged from 39.7 to 45.7 (United States norms = 50). In general, patients with viral clearance had the highest scores, and those with late‐stage disease (cirrhosis, liver cancer) had the lowest. Multivariable linear regression showed that the effect of disease stage was modest overall. Increasing age, lower income, unattached marital status, and high comorbidity were strongly associated with impairment in HRQOL.
Conclusions: The effect of stage of disease on HRQOL is modest, although viral clearance is associated with higher HRQOL. HCV patients' HRQOL is strongly associated with concomitant illness and sociodemographic factors.
Background & Aims In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. ...Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage. Methods Control Atp7b +/- and Wilson disease Atp7b -/- rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b -/- rats to test for therapeutic reversal of mitochondrial copper damage. Results In comparison with a normal diet, HCD feeding of Atp7b -/- rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b -/- rats, correlating with severe liver injury. Mitochondria presented with massive structural damage, increased H2 O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage. Conclusions A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.
A nested case-control study, including 830 cases and 992 controls from 7 cohorts, was conducted to evaluate the association of circulating 25-hydroxyvitamin D (25(OH)D), the best indicator of vitamin ...D status, with risk of endometrial cancer. Matching factors included age at blood donation, date of blood donation, and race. Conditional logistic regression was used in the main analysis. The median concentration of 25(OH)D was slightly lower in cases (49.4 nmol/L) than in controls (50.8 nmol/L) (P = 0.08). However, there was no association between 25(OH)D concentration and disease risk, after adjustment for body mass index. Compared with the 50-<75 nmol/L 25(OH)D category, the body mass index-adjusted odds ratios and 95% confidence intervals were 1.08 (95% confidence interval: 0.73, 1.57) for the <25 nmol/L category and 0.90 (95% confidence interval: 0.51, 1.58) for the > or =100 nmol/L category (P(trend) = 0.99). Similarly null results were observed after further adjustment for other known risk factors and in stratified analyses. Although an effect of circulating 25(OH)D at high concentrations cannot be ruled out (the highest category of 25(OH)D was > or =100 nmol/L, and for stratified analyses, > or =75 nmol/L), these results do not support a protective role of vitamin D against endometrial cancer.
BACKGROUND:Endoscopic therapy has been successful in the management of biliary complications after both deceased donor liver transplantation(DDLT) and living donor liver transplantation(LDLT).LDLT is ...thought to be associated with higher rates of biliary complications,but there are few studies comparing the success of endoscopic management of anastomotic strictures between the two groups.This study aims to compare our experience in the endoscopic management of anastomotic strictures in DDLT versus LDLT.METHODS:This is a retrospective database review of all liver transplant patients undergoing endoscopic retrograde cholangiopancreatography(ERCP) after liver transplantation.The frequency of anastomotic stricture and the time to develop and to resolve anastomotic stricture were compared between DDLT and LDLT.The response of anastomotic stricture to endoscopic therapy was also analyzed.RESULTS:A total of 362 patients underwent liver transplantation between 2003 and 2011,with 125 requiring ERCP to manage biliary complications.Thirty-three(9.9%) cases of DDLT and 8(27.6%) of LDLT(P=0.01) were found to have anastomotic stricture.When comparing DDLT and LDLT,there was no difference in the mean time to the development of anastomotic strictures(98±17 vs 172±65 days,P=0.11),likelihood of response to ERCP 22(66.7%) vs 6(75.0%),P=0.69,mean time to the resolution of anastomotic strictures(268±77 vs 125±37 days,P=0.34),and the number of ERCPs required to achieve resolution(3.9±0.4 vs 4.7±0.9,P=0.38).CONCLUSIONS:Endoscopic therapy is effective in the majority of biliary complications relating to liver transplantation.Anastomotic strictures occur more frequently in LDLT compared with DDLT,with equivalent endoscopic treatment response and outcomes for both groups.
Background and Objectives
Concern about diversion of buprenorphine/naloxone (B/N) in the United States may affect prescribing patterns and policy decisions. This study examines addiction treatment ...clinician beliefs and attitudes regarding B/N diversion.
Methods
Participants (n = 369) completed a 34‐item survey in 2010 during two national symposia on opioid dependence. We conducted multivariable regression, examining the relationship of perceived danger from B/N diversion with clinician characteristics and their beliefs about B/N treatment and diversion. We compared causal beliefs about diversion among clinicians with and without B/N treatment experience.
Results
Forty percent of clinicians believed that B/N diversion is a dangerous problem. The belief that B/N diversion increases accidental overdoses in the community was strongly associated with perceived danger from B/N diversion.
Conclusions and Scientific Significance
Attitudes and beliefs, not education level, were associated with clinician's perceived danger from B/N diversion. Clinicians with greater B/N patient experience were more likely to believe treatment access barriers are the major cause of B/N diversion. (Am J Addict 2013;22:574–580)
BACKGROUND: This retrospective study investigated the clinical impact of PVT on the course of patients with HCC who were and were not treated with anticoagulation (AC). METHODS: We retrospectively ...evaluated a cohort of 60 patients diagnosed with HCC and PVT. Nine patients were excluded for lack of follow-up. HCC, PVT diagnosis, and imaging follow-up were performed using contrast-enhanced computed tomography or MRI. Of the 51 patients evaluated, 12 received AC and 39 did not. RESULTS: Forty-two patients were male; mean age was 60.3 years. Mean survival after HCC diagnosis was 32.9 months; after PVT diagnosis, it was 18.4 months. No symptoms directly related to PVT development were reported. AC therapy was initiated for 12 patients and had to be discontinued for 3 patients because of complications. AC was not associated with a difference in PVT progression (49% in non-AC group vs. 50% in AC group). After adjusting for age, HCC type (single vs. multifocal), and Child–Pugh score, AC was associated with an improved survival after HCC diagnosis (adjusted hazard ratio HR = 0.37; 95% confidence interval CI 0.14 to 0.99) and after PVT diagnosis (HR = 0.34; 95% CI 0.13 to 0.88). CONCLUSION: Patients with HCC complicated by PVT in both AC and non-AC groups had a similar rate of progression. Neither group had symptoms attributable to PVT. Possible AC-related complications need to be considered before proceeding with therapy in patients with HCC and PVT. AC may be associated with a survival advantage in patients with HCC and PVT.
Sevoflurane is degraded to compound A (CpA) by carbon dioxide absorbents containing strong base. CpA is nephrotoxic in rats. Patient exposure to CpA is increased with low fresh gas flow rates, use of ...Baralyme, and high sevoflurane concentrations. CpA formation during low-flow and closed circuit sevoflurane anesthesia had no significant renal effects in surgical patients with normal renal function. Preexisting renal insufficiency is a risk factor for postoperative renal dysfunction. Although preexisting renal insufficiency is not affected by high-flow sevoflurane, the effect of low-flow sevoflurane in patients with renal insufficiency is unknown.
After obtaining institutional review board approval, 116 patients with a stable preoperative serum creatinine concentration 1.5 mg/dl or greater were assessable. Patients were randomized to receive either sevoflurane (n = 59, 0.8-2.5 vol%) or isoflurane (n = 57, 0.5-1.4 vol%) at a fresh gas flow rate of 1 l/min or less. Use of opioids was restricted to a minimum, and Baralyme was used to increase CpA exposure. Inspiratory and expiratory CpA concentrations were measured during anesthesia. Renal function (serum creatinine and blood urea nitrogen, urine protein and glucose, creatinine clearance) was measured preoperatively and 24 and 72 h after induction.
Demographic patient data did not differ between groups. Patients received 3.1 +/- 2.4 minimum alveolar concentration-hours sevoflurane or 3.8 +/- 2.6 minimum alveolar concentration-hours isoflurane (mean +/- SD). Durations of low flow were 201.3 +/- 98.0 and 213.6 +/- 83.4 min, respectively. Maximum inspiratory CpA with sevoflurane was 18.9 +/- 7.6 ppm (mean +/- SD), resulting in an average total CpA exposure of 44.0 +/- 30.6 ppm/h. There were no statistically significant changes from baseline to 24- and 72-h values for serum creatinine or blood urea nitrogen, creatinine clearance, urine protein, and glucose, nor were there significant differences between both anesthetics.
There were no statistically significant differences in measured parameters of renal function after low-flow sevoflurane anesthesia compared with isoflurane. These results suggest that low-flow sevoflurane anesthesia is as safe as low-flow isoflurane and does not alter kidney function in patients with preexisting renal disease.
The dose-response relationship between doxorubicin and superabsorbent drug-eluting microspheres has not been established. In this study, we investigated the relationships between dose and delivery ...parameters as they pertain to toxicity and response in surgically resectable hepatocellular carcinoma (HCC).
Twenty-five patients with resectable HCC were randomly assigned and divided into four groups, each receiving either bland, 25 mg, 50 mg or 75 mg of doxorubicin loaded Super Absorbent Polymer microspheres, with 24 patients undergoing surgical resection. Response Evaluation and Criteria in Solid Tumors (RECIST) 1.0 and European Association for the Study of the Liver (EASL)-based volumetric response was performed at one month and surgical resection of the reference tumor was performed at two months. Adverse events were collected at regular intervals.
Fifty-six percent of patients demonstrated complete response according to EASL criteria as opposed to 0% according to RECIST (v1.0) criteria. Residual tumor was identified in all groups (0 mg: 35%±28.5%; 25 mg: 42%±30.4%; 50 mg: 3.6%±3.3%; and 75 mg: 49.29%±32.6%. A total of 112 adverse events of grades 1-3 occurred (average 5.1 per patient), with no grade 4 or 5. No difference was noted between bland embolic and drug-loaded groups. Subset analysis did demonstrate a significantly increased degree of necrosis in the 50 mg-loaded group (p=0.018). Strong correlation existed between arterial phase Computer Tomography EASL-based response and histopathology (r=0.81; p<0.0001). All groups had residual tumor.
Histology correlates strongly with one-month post-procedural imaging and response optimized at 50 mg of loading per vial. Adverse events were a reflection of embolization, with no relationship between loading dose or administered dose of doxorubicin.
Pancreatic infiltration is a rare feature of multiple myeloma. A case of a 74-year-old man presenting with symptomatic biliary obstruction two years after the original diagnosis of myeloma is ...described. Confirmation of pancreatic infiltration with myeloma cells was performed by endoscopic ultrasound-guided fine-needle aspiration. Biliary stenting was performed at endoscopic retrograde cholangiopancreatography. Resolution of the pancreatic mass and the associated biliary stricture was observed after radiation and chemotherapy.
PDF
