Citations

Objective Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs. Design Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats. Results Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17β-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis. Conclusions PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool.

The surprising ability of thalidomide and its analogs to treat various hematologic malignancies is through the loss of two transcription factors. [Also see Reports by Krönke et al. and Lu et al. ]

BACKGROUNDGeneral internists suffer higher rates of burnout and lower satisfaction with work‐life balance than most specialties, but the impact of inpatient vs outpatient practice location is unclear.METHODSPhysicians in the American Medical Association Physician Masterfile were previously surveyed about burnout, depression, suicidal ideation, quality of life, fatigue, work‐life balance, career plans, and health behaviors. We extracted and compared data for these variables for the 130 internal medicine hospitalists and 448 outpatient general internists who participated. Analyses were adjusted for age, sex, hours worked, and practice setting.RESULTSThere were 52.3% of the hospitalists and 54.5% of the outpatient internists affected by burnout (P = 0.86). High scores on the emotional exhaustion subscale (43.8% vs 48.1%, P = 0.71) and on the depersonalization subscale (42.3% vs 32.7%, P = 0.17) were common but similar in frequency in the 2 groups. Hospitalists were more likely to score low on the personal accomplishment subscale (20.3% vs 9.6%, P = 0.04). There were no differences in symptoms of depression (40.3% for hospitalists vs 40.0% for outpatient internists, P = 0.73) or recent suicidality (9.2% vs 5.8%, P = 0.15). Rates of reported recent work‐home conflict were similar (48.4% vs 41.3%, P = 0.64), but hospitalists were more likely to agree that their work schedule leaves enough time for their personal life and family (50.0% vs 42.0%, P = 0.007).CONCLUSIONSBurnout was common among both hospitalists and outpatient general internists, although hospitalists were more satisfied with work‐life balance. A better understanding of the causes of distress and identification of solutions for all internists is needed. Journal of Hospital Medicine 2014;9:176–181. © 2014 Society of Hospital Medicine

SummaryBackgroundVillous atrophy (VA) with intraepithelial lymphocytosis is the histological hallmark of coeliac disease (CD), but reported rates of mucosal recovery are variable.AimTo determine the impact of age and other demographic variables on the probability of persistent VA on follow‐up biopsy.MethodsWe identified patients with VA on duodenal histology at all 28 Swedish pathology departments during the years spanning 1969–2008. We examined age, gender, calendar period, duration of disease and educational attainment to determine predictors of persistent VA.ResultsOf 7648 patients with CD who underwent follow‐up biopsy, persistent VA was present in 3317 (43%; 95% CI 42–44%). The effect of age on persistent VA varied according to time period; among those biopsied in the years spanning 2000–2008, the prevalence of persistent VA was 31%, and increasing age was associated with increasing rates of persistent VA (17% among those younger than 2 years compared to 56% among those ≥70 years). In contrast, persistent VA did not vary widely by age in earlier years. On multivariate analysis (restricted to the calendar period 2000–2008, 2–5 years after CD diagnosis), persistent VA was more common among males (OR 1.43; 95% CI 1.07–1.90) and less common among patients with higher educational attainment (OR for college degree vs. <2 years of high school 0.52, 95% CI 0.35–0.78).ConclusionsThe prevalence of persistent villous atrophy has changed over time, with greater rates of healing in recent years. Social differences in persistent villous atrophy suggest that access and/or education regarding the gluten‐free diet impact mucosal healing.

Abstract Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.

Abstract Objective Risk scores and accelerated diagnostic protocols can identify chest pain patients with low risk of major adverse cardiac event who could be discharged early from the ED , saving time and costs. We aimed to derive and validate a chest pain score and accelerated diagnostic protocol ( ADP ) that could safely increase the proportion of patients suitable for early discharge. Methods Logistic regression identified statistical predictors for major adverse cardiac events in a derivation cohort. Statistical coefficients were converted to whole numbers to create a score. Clinician feedback was used to improve the clinical plausibility and the usability of the final score (Emergency Department Assessment of Chest pain Score [ EDACS ]). EDACS was combined with electrocardiogram results and troponin results at 0 and 2 h to develop an ADP ( EDACS‐ADP ). The score and EDACS‐ADP were validated and tested for reproducibility in separate cohorts of patients. Results In the derivation ( n = 1974) and validation ( n = 608) cohorts, the EDACS‐ADP classified 42.2% (sensitivity 99.0%, specificity 49.9%) and 51.3% (sensitivity 100.0%, specificity 59.0%) as low risk of major adverse cardiac events, respectively. The intra‐class correlation coefficient for categorisation of patients as low risk was 0.87. Conclusion The EDACS‐ADP identified approximately half of the patients presenting to the ED with possible cardiac chest pain as having low risk of short‐term major adverse cardiac events, with high sensitivity. This is a significant improvement on similar, previously reported protocols. The EDACS‐ADP is reproducible and has the potential to make considerable cost reductions to health systems.

Objective To assess US physicians’ attitudes towards using shared decision-making (SDM) to achieve cost containment. Design Cross-sectional mailed survey. Setting US medical practice. Participants 3897 physicians were randomly selected from the AMA Physician Masterfile. Of these, 2556 completed the survey. Main outcome measures Level of enthusiasm for “Promoting better conversations with patients as a means of lowering healthcare costs”; degree of agreement with “Decision support tools that show costs would be helpful in my practice” and agreement with “should promoting SDM be legislated to control overall healthcare costs”. Results Of 2556 respondents (response rate (RR) 65%), two-thirds (67%) were ‘very enthusiastic’ about promoting SDM as a means of reducing healthcare costs. Most (70%) agreed decision support tools that show costs would be helpful in their practice, but only 24% agreed with legislating SDM to control costs. Compared with physicians with billing-only compensation, respondents with salary compensation were more likely to strongly agree that decision support tools showing costs would be helpful (OR 1.4; 95% CI 1.1 to 1.7). Primary care physicians (vs surgeons, OR 1.4; 95% CI 1.0 to 1.6) expressed more enthusiasm for SDM being legislated as a means to address healthcare costs. Conclusions Most US physicians express enthusiasm about using SDM to help contain costs. They believe decision support tools that show costs would be useful. Few agree that SDM should be legislated as a means to control healthcare costs.