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The inherited eye disease retinitis pigmentosa (RP) causes the loss of photoreceptors by a still unknown cell death mechanism. During this degeneration, cyclic guanosine‐3′,5′‐monophosphate (cGMP) levels become elevated, leading to over‐activation of the cGMP‐binding protein cGMP‐dependent protein kinase (PKG). cGMP analogs selectively modified to have inhibitory actions on PKG have aided in impeding photoreceptor death, and one such cGMP analog is Rp‐8‐Br‐PET‐cGMPS. However, cGMP analogs have previously been shown to interact with numerous targets, so to better understand the therapeutic action of Rp‐8‐Br‐PET‐cGMPS, it is necessary to elucidate its target‐selectivity and hence what potential cellular mechanism(s) it may affect within the photoreceptors. Here, we, therefore, applied affinity chromatography together with mass spectrometry to isolate and identify Rp‐8‐Br‐PET‐cGMPS interactors from retinas derived from three different murine RP models (i.e., rd1, rd2, and rd10 mice). Our findings revealed that Rp‐8‐Br‐PET‐cGMPS bound seven known cGMP‐binding proteins, including PKG1β, PDE1β, PDE1c, PDE6α, and PKA1α. Furthermore, an additional 28 proteins were found to be associated with Rp‐8‐Br‐PET‐cGMPS. This latter group included MAPK1/3, which is known to connect with cGMP/PKG in other systems. However, in organotypic retinal cultures, Rp‐8‐Br‐PET‐cGMPS had no effect on photoreceptor MAPK1/3 expression or activity. To summarize, Rp‐8‐Br‐PET‐cGMPS is more target specific compared to regular cGMP. [ABSTRACT FROM AUTHOR]

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs. [ABSTRACT FROM AUTHOR]

Aims To determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582). Methods Details of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8. CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy. Results No adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye. Conclusion The results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor. [ABSTRACT FROM AUTHOR]

Introduction: We established a patient centric navigation model embedded in primary care (PC) to support access to the broad range of health and social resources; the Access to Resources in the Community (ARC) model. Methods: We evaluated the feasibility of ARC using the rapid cycle evaluations of the intervention processes, patient and PC provider surveys, and navigator log data. PC providers enrolled were asked to refer patients in whom they identified a health and/ or social need to the ARC navigator. Results: Participants: 26 family physicians in four practices, and 82 of the 131 patients they referred. ARC was easily integrated in PC practices and was especially valued in the non-inter professional practices. Patient overall satisfaction was very high (89%). Sixty patients completed the post-intervention surveys, and 33 reported accessing one or more service(s). Conclusion: The ARC Model is an innovative approach to reach and support a broad range of patients access needed resources. The Model is feasible and acceptable to PC providers and patients, and has demonstrated potential for improving patients’ access to health and social resources. This study has informed a pragmatic randomized controlled trial to evaluate the ARC navigation to an existing web and telephone navigation service (Ontario 211). [ABSTRACT FROM AUTHOR]

Summary: Background: Sofosbuvir, a prodrug nucleoside inhibitor of hepatitis C virus, has a predominant circulating metabolite that is renally eliminated. Whether sofosbuvir is associated with chronic kidney disease (CKD) progression is not well understood. Methods: We performed a retrospective analysis of patients with estimated glomerular filtration rate (eGFR) 30–89 mL/min/1.73 m2 treated with sofosbuvir in 76 Phase 2/3 registrational trials. We evaluated eGFR at each study visit. Separately, we performed a retrospective analysis of an administrative claims database (IQVIA PharMetrics Plus™) to compare the risk of incident end‐stage renal disease (ESRD) associated with the use of sofosbuvir or non‐sofosbuvir regimens among patients with CKD using propensity score methods. Exposure, CKD status and outcomes were determined using diagnosis and medication claim codes. Cox proportional hazards methods were used to estimate ESRD risk. Results: Among 4642 trial participants with baseline stage 2 CKD (eGFR 60–89 ml/min/1.73 m2) and 682 trial participants with stage 3 CKD (eGFR 30–59 ml/min/1.73 m2) mean (SD) eGFR improved from baseline to 4 weeks post‐treatment (+0.7 [9.3] and +2.6 [8.8] ml/min/1.73 m2, respectively; p < 0.001 each). In the second analysis, among 2042 patients with CKD receiving sofosbuvir‐based regimens compared to 431 receiving non‐sofosbuvir‐based regimens, after adjusting for baseline covariates and weighting based on treatment propensity scores, there was no significant difference in risk of ESRD (adjusted HR = 0.85, 95% CI: 0.51–1.42). Conclusions: Clinical trial participants with CKD did not experience worsening eGFR during sofosbuvir‐based treatment, and sofosbuvir was not associated with an increased risk of ESRD in patients with CKD in a nationally‐representative administrative claims database. [ABSTRACT FROM AUTHOR]

One of the tissues of the central nervous system most affected by diabetes is the retina. Despite a growing understanding of the biochemical processes involved in glucose toxicity, little is known about the physiological consequences of chronic high glucose (HG) on individual neurons and neuronal circuits. Electroretinogram recordings suggest that retinal bipolar cells (BCs), which filter and transmit photoreceptor output to the inner retina, are among the first cells affected by diabetic conditions, and may therefore serve as sensitive early biomarkers for incipient neuronal damage caused in diabetes. Here, we comparatively assessed retinal integrity, calcium responses, and the electrophysiological profiles of specific BC types of mouse and rat organotypic retinal explants after 1 to 3 weeks in tissue culture, under moderate glucose (MG) and HG conditions. While the retinal layers of both rodent species displayed a progressively reduced thickness in culture, BCs retained their electrophysiological profiles and remained morphologically identifiable for up to 2 weeks. Responses to glutamate and endogenous inhibitory responses were routinely observed, indicating that the retinal circuitry remained intact during this period. Significant physiological differences between MG and HG conditions were evident in calcium signals and in the time course of responses to glutamate, but the voltage‐gated current profiles of BCs displayed only minor variations. Overall, rat retina appeared slightly more sensitive to HG levels compared with mouse. In conclusion, electrophysiological analysis of neuronal function in rodent retinal explants is useful for the study of early damage due to HG neurotoxicity. [ABSTRACT FROM AUTHOR]

Acute-on-chronic liver failure (ACLF) is defined by the occurrence of organ failure(s) other than the liver in patients with cirrhosis. Even thoughmortality rates are high, there should no longer be reluctance to admit patients with ACLF in the intensive care unit. The prevalence of multidrug-resistant bacteria is high and broad spectrum antibiotics should be initiated as soon as infection is suspected. In patients with circulatory failure, the assessment of circulatory status is challenging due to the hyperkinetic state and an imbalance between the splanchnic and systemic blood volume. Acute kidney injury is common in patients with ACLF. Acute tubular necrosis should be differentiated from hepatorenal syndrome, which justifies vasoconstrictive agents. Renal replacement therapy and mechanical ventilation should be decided on clinical grounds. Recent trials on extracorporeal liver support failed to demonstrate a survival benefit. Aggressive management may serve as a bridge to transplantation provided patients are likely to survive after transplantation. [ABSTRACT FROM AUTHOR]

The article offers information on the diagnosis and management of acute kidney injury in patients with cirrhosis. It mentions that acute renal failure (ARF) is a common complication in patients with decompensated cirrhosis. It also mentions that the traditional diagnostic criteria of renal failure in these patients were proposed in 19961 and have been refined in subsequent years.

Hepatic artery stenosis ( HAS) is a complication that impacts the results of orthotopic liver transplantation ( OLT). Interventional radiological techniques are important therapeutic options for HAS. The aim of this retrospective study was to evaluate the outcome of repeated radiological treatments in recurring HAS after OLT. Of the 941 patients who underwent OLT at our center from January 1998 to September 2010, 48 (5%) were diagnosed with HAS, 37 (77%) of whom underwent transluminal interventional therapy with the placement of an endovascular stent. Success rate, complications, hepatic artery patency and follow-up were reviewed. After stent placement, artery patency was achieved in all patients. Three patients developed complications, including arterial dissection and hematoma. HAS recurrence was observed in 9 patients (24%), and hepatic artery thrombosis ( HAT) occurred in 4 (11%). Radiological interventions were repeated 10 times in 8 patients without complications. At a median follow-up of 66 months (range 10-158), hepatic artery patency was observed in 35 cases (94.6%). The 5-year rates for graft and patient survival were 82.3% and 87.7%, respectively. Restenosis may occur in one-third of patients after endovascular treatment for thrombosis and HAS, but the long-term outcomes of iterative radiological treatment for HAS indicate a high rate of success. [ABSTRACT FROM AUTHOR]

The well-characterized human teratocarcinoma line Ntera2 (NT2) can be differentiated into mature neurons. We have significantly shortened the time-consuming process for generating postmitotic neurons to approximately 4 weeks by introducing a differentiation protocol for free-floating cell aggregates and a subsequent purification step. Here, we characterize the neurochemical phenotypes of the neurons derived from this cell aggregate method. During differentiation, the NT2 cells lose immunoreactivity for vimentin and nestin filaments, which are characteristic for the immature state of neuronal precursors. Instead, they acquire typical neuronal markers such as β-tubulin type III, microtubule-associated protein 2, and phosphorylated tau, but no astrocyte markers such as glial fibrillary acidic protein. They grow neural processes that express punctate immunoreactivity for synapsin and synaptotagmin suggesting the formation of presynaptic structures. Despite their common clonal origin, neurons cultured for 2–4 weeks in vitro comprise a heterogeneous population expressing several neurotransmitter phenotypes. Approximately 40% of the neurons display glutamatergic markers. A minority of neurons is immunoreactive for serotonin, gamma-amino-butyric acid, and its synthesizing enzyme glutamic acid decarboxylase. We have found no evidence for a dopaminergic phenotype. Subgroups of NT2 neurons respond to the application of nitric oxide donors with the synthesis of cGMP. A major subset shows immunoreactivity to the cholinergic markers choline acetyl-transferase, vesicular acetylcholine transporter, and the non-phosphorylated form of neurofilament H, all indicative of motor neurons. The NT2 system may thus be well suited for research related to motor neuron diseases. [ABSTRACT FROM AUTHOR]

Donor risk is the main obstacle in the development of living-donor liver transplantation in Western countries. The knowledge of a wide and uneven range of donor morbidity has come mainly from various retrospective analyses of complications in the literature. Donor outcomes have not been prospectively analyzed. From 1995, the intra- and postoperative courses of 127 living-donor hepatectomies were prospectively analyzed and recorded. All adverse events were classified and stratified according to the extent of surgery, including 45 left-lateral sectionectomies (LLS); 25 left hepatectomies (LH), and 57 right hepatectomies (RH). There was no donor death. The overall rate of significant complications was 20%, ranging from 8% after LH to 32% after RH. The overall incidences of surgical complications, reoperations, and hospital readmissions were 8%, 3%, and 5%, respectively. However, the prospective accumulation of all adverse events revealed an overall postoperative morbidity of 51%, ranging from 32% after LH to 66% after RH. In conclusion the incidence of postoperative adverse events after living donation is nearly 50% as revealed by prospective screening. These results allow more accurate information for potential donors. This study confirms that right hepatectomy carries three times higher risk of morbidity as compared to left-sided resections, leading to reappraisal of the use of left grafts in adults. [ABSTRACT FROM AUTHOR]

The retinal degeneration (rd)1 mouse displays an inherited retinal degeneration and therefore allows studies of the molecular mechanisms behind the blinding disease retinitis pigmentosa. Activation of the calcium-dependent protease calpain has been suggested to play an important role in cell death in various tissues, but little is known about the expression and activity of calpain during inherited retinal degeneration. Using microarray techniques, transcript levels of cyclic AMP response element-binding protein (CREB)-1, calpastatin and of various calpain genes were analysed in the rd1 mouse compared with its wild-type control. Expression of distinct calpain isoforms and calpastatin was investigated using immunofluorescence and immunoblotting. Gene transcription and protein expression levels were compared with calpain activity using an enzymatic assay that allowed monitoring of calpain activity at the cellular level. We found that CREB-1 and calpastatin expression was reduced in rd1 retinas, whereas calpain activity was substantially increased in rd1 photoreceptors. Calpain activity peaked at postnatal day 13, together with rd1 photoreceptor cell death. Calpain-specific inhibitors decreased calpain activity in situ. These results indicate that activation of calpains correlates with rd1 photoreceptor cell death, which raises the possibility of using calpain inhibitors to prevent or delay photoreceptor degeneration. [ABSTRACT FROM AUTHOR]

In patients with cirrhosis, discrepant findings have been reported on the evolution of pulmonary hemodynamics and gas exchange after liver transplantation. The aim of this study was to evaluate the effects of liver transplantation on pulmonary and systemic hemodynamics and gas exchange in patients transplanted for cirrhosis. Forty-three patients with cirrhosis underwent hemodynamic investigations before and one year after liver transplantation. Mean pulmonary arterial pressures did not significantly change after transplantation (from 17 +/- 4 to 17 +/- 3 mm Hg) whereas pulmonary vascular resistance significantly increased by 62%. Cardiac index significantly decreased by 20%. PaO2 did not change significantly after transplantation (from 88.8 +/- 13.9 to 88.5 +/- 12.1 mm Hg) and PaCO2 significantly increased by 16%. In conclusion, liver transplantation has no effect on pulmonary pressures but normalizes pulmonary vascular resistance in patients with cirrhosis without pulmonary hypertension. Moreover, it has no major effect on gas exchange in patients with cirrhosis without hypoxemia. [ABSTRACT FROM AUTHOR]

Presents a study on the relationship between nasal carriage of Staphylococcus aureus (SA) and the risk of infection in liver transplant recipients. Risk factors associated with liver transplant; Comparison of the characteristics of methicillin-resistant SA carriers and methicillin-susceptible SA carriers; Association between the preoperative carrier status and the occurrence of infection after surgery.

cGMP‐signalling is fundamental to the phototransduction cascade in retinal photoreceptors. Paradoxically, high levels of cGMP lead to photoreceptor loss in hereditary retinal degeneration (RD) caused by a variety of different gene mutations. This makes cGMP‐signalling a prime target for the development of new treatment approaches. The presentation will give details about the development of compounds and drug delivery technology designed for a targeted interference with cGMP‐signalling in photoreceptors. As an example, in vivo treatment data on a liposomal formulation of the inhibitory cGMP analogue DF003/CN03 will be presented. Overall, cGMP analogues may constitute a new class of compounds for RD treatment and, when combined with suitable drug delivery vehicles, they provide a clear perspective for clinical translation, potentially bringing the very first pharmacological treatment to patients suffering from RD. [ABSTRACT FROM AUTHOR]

Describes several cases of autoimmune chronic hepatitis aggravated by the administration of alpha-interferon. Causes of misdiagnosis in the cases; Types of autoimmune chronic hepatitis; Implications in the aggravation of autoimmune chronic hepatitis.

An abstract of the article "cGMP-Prkg1 signaling PDE5 inhibition shelter cochlear hair cells and hearing function" by Marlies Knipper and colleagues, presented at the 6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications that was held in 2013 is presented.

Reports on game ranger Adriaan Louw's discovery of vertebrate fossil bones of the dinosaur Euskelosaurus in the Kruger National Park in South Africa. Circumstances which led to the fossil discovery; Importance of the Kruger Park discovery; Excavation of the site by the National Parks Board and the Council for Geoscience and the South African Society for Amateur Palaeontologists.