SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells

We previously positionally cloned Sorcs1 as a diabetes quantitative trait locus. Sorcs1 belongs to the Vacuolar protein sorting-10 (Vps10) gene family. In yeast, Vps10 transports enzymes from the trans-Golgi network (TGN) to the vacuole. Whole-body Sorcs1 KO mice, when made obese with the leptin^ob mutation (ob/ob), developed diabetes. β Cells from these mice had a severe deficiency of secretory granules (SGs) and insulin. Interestingly, a single secretagogue challenge failed to consistently elicit an insulin secretory dysfunction. However, multiple challenges of the Sorcs1 KO ob/ob islets consistently revealed an insulin secretion defect. The luminal domain of SORCS1 (Lum-Sorcs1), when expressed in a β cell line, acted as a dominant-negative, leading to SG and insulin deficiency. Using syncollin-dsRed5TIMER adenovirus, we found that the loss of Sorcs1 function greatly impairs the rapid replenishment of SGs following secretagogue challenge. Chronic exposure of islets from lean Sorcs1 KO mice to high glucose and palmitate depleted insulin content and evoked an insulin secretion defect. Thus, in metabolically stressed mice, Sorcs1 is important for SG replenishment, and under chronic challenge by insulin secretagogues, loss of Sorcs1 leads to diabetes. Overexpression of full-length SORCS1 led to a 2-fold increase in SG content, suggesting that SORCS1 is sufficient to promote SG biogenesis.     

Reducing potentially inappropriate medications in palliative cancer patients: evidence to support deprescribing approaches

Objectives

Cancer patients who have transitioned from curative intent chemotherapy or radiotherapy to palliative therapy have limited life expectancies. Due to this, medications for primary and secondary prevention or those with no short-term benefit are potentially inappropriate medicines in this patient group. These medications often have potentially harmful profiles, increasing the patient’s adverse drug events, pill burden, and medication costs. This review evaluates the most current evidence to assess the outcomes and potential methods used for identifying and ceasing potentially inappropriate medications (PIMs) in palliative cancer patients.

Methods

A systematic review of the literature was conducted using the databases Ovid MEDLINE, PubMed, EMBASE, IPA, and CINAHL.

Results

Of the 51 articles examined in detail, three studies relating to cancer have been evaluated. In these retrospective and cross-sectional studies, the incidence of PIMs was shown in approximately 20 % of patients, although the studies were inconsistent. In addition, six studies were identified that demonstrated the evidence in other population groups; these studies have been selected to establish the evidence in large-scale retrospective studies, prospective cross-sectional studies, both demonstrating the prevalence of PIMs, as well as the outcomes of ceasing PIMs.

Conclusion

There is evidence that PIMs are commonly prescribed in palliative care patients. There are no studies that have identified the impact of ceasing PIMS in this setting. Published tools and implemented strategies have focused on the elderly populations. Further research is warranted in establishing clear guidelines for the identification of PIMs in palliative cancer patients as well as interventional studies assessing the outcomes of ceasing PIMs in these patients.     

Eficacia y seguridad del interferón pegilado,asociado a la criocirugía en el tratamiento del condiloma acuminado

BackgroundThe continuous recurrences of condylomata acuminata makes it necessary to constantly search for therapeutic alternatives.Patients and methodTo evaluate the therapeutic efficacy and safety of pegylated interferon (IFN p) adjuvant to cryosurgery, an open clinical trial was conducted in condylomata acuminata in 30 patients from the «Hermanos Ameijeiras» hospital, who were randomized to receive 6 weeks (group I) subcutaneous recombinant human interferon alfa 2b (IFN), 3 times per week + biweekly cryosurgery or (group II) subcutaneous IFN p, 1 time per week + biweekly cryosurgery. The main variable was the percentage of recurrence at one year of follow-up. There was also a rigorous control of adverse events.ResultsAt the end of the treatment 12/15 (80%) patients in group I and group II 14/15 (93,3%) were without injuries (p < 0.32). During follow-up, none of the patients who received IFN p + cryosurgery had recurrences; while 2/12 (16.7%) of the patients who received IFN + cryosurgery recurred (p < 0.672). Adverse events were significantly more frequent in group I (fever 13/15, headache 7/15, chills 3/15, and myalgia 2/15) (p < 0.003).ConclusionPegylated interferon with a weekly frequency of administration achieves superior therapeutic effects, a lower percentage of recurrences and adverse reactions than the administration of recombinant human IFN alpha 2b 3 times a week.     

Early propranolol treatment induces lung heme-oxygenase-1, attenuates metabolic dysfunction,and improves survival following experimental sepsis

Introduction

Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis.

Methods

Sprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics.

Results

Seven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged.

Conclusions

These results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.     

Risk Factors for the Presence of Aedes aegypti and Aedes albopictus in Domestic Water-Holding Containers in Areas Impacted by the Nam Theun 2 Hydroelectric Project,Laos

We assessed risk factors for vectors of dengue and chikungunya viruses near a new hydroelectric project, Nam Theun 2, in Laos. Immature stages of Aedes aegypti were found only in sites within 40 km of the urban provincial capital, but Aedes albopictus was found throughout. Aedes aegypti pupae were most common in water storage jars (odds ratio [OR] = 4.72) and tires (OR = 2.99), and Ae. albopictus pupae were associated with tires in 2009 (OR = 10.87) and drums, tires, and jars in 2010 (drums OR = 3.05; tires OR = 3.45, jars OR = 6.59). Compared with water storage vessels, containers used for hygiene, cooking, and drinking were 80% less likely to harbor Ae. albopictus pupae in 2010 (OR = 0.20), and discarded waste was associated with a 3.64 increased odds of infestation. Vector control efforts should focus on source reduction of water storage containers, particularly concrete jars and tires.     

Burkitt lymphoma risk in U.S. solid organ transplant recipients

Case reports of Burkitt lymphoma (BL) in transplant recipients suggest that the risk is markedly elevated. Therefore, we investigated the incidence of BL in 203,557 solid organ recipients in the U.S. Transplant Cancer Match Study (1987–2009) and compared it with the general population using standardized incidence ratios. We also assessed associations with demographic and clinical characteristics, and treatments used to induce therapeutic immunosuppression. BL incidence was 10.8 per 100,000 person‐years, representing 23‐fold (95% confidence interval (CI) 19–28) greater risk than in the general population, and it peaked 3–8 years after the time of transplantation. In adjusted analyses, BL incidence was higher in recipients transplanted when <18 vs. ≥35 years (incidence rate ratio [IRR] 3.49, 95% CI 2.08–5.68) and in those transplanted with a liver (IRR 2.91, 95% CI 1.68–5.09) or heart (IRR 2.39, 95% CI 1.30–4.31) compared with kidney. BL incidence was lower in females than males (IRR 0.45, 95% CI 0.28–0.71), in blacks than whites (IRR 0.33, 95% CI 0.12–0.74), in those with a baseline Epstein‐Barr virus (EBV)‐seropositive versus EBV‐seronegative status (IRR 0.34, 95% CI 0.13–0.93), and in those treated with azathioprine (IRR 0.56, 95% CI 0.34–0.89) or corticosteroids (IRR 0.48, 95% CI 0.29–0.82). Tumors were EBV‐positive in 69% of 32 cases with results. EBV positivity was 90% in those aged <18 years and 59% in those aged 18+ years. In conclusion, BL risk is markedly elevated in transplant recipients, and it is associated with certain demographic and clinical features. EBV was positive in most but not all BL cases with results. Am. J. Hematol. 88:245–250, 2013. © 2012 Wiley Periodicals, Inc.