Vasopressin Receptor Antagonists: From Pivotal Trials to Current Practice

Heart failure is a growing health and economic problem in America, and outcomes continue to remain dismal, particularly for those presenting with acute heart failure syndrome (AHFS). In theory, arginine vasopressin antagonists (VRAs) could be useful in both acute and chronic heart failure, depending on which vasopressin receptor is targeted. Most studies of VRAs in heart failure have focused on V2 receptor antagonism, and to a lesser extent on combined V1a/V2 antagonism, due to the availability of appropriate agents and the unmet need of improving outcomes in AHFS. These agents are particularly attractive as adjunctive or alterative agents in AHFS because of their ability to produce a substantial diuresis without some of the drawbacks intrinsic to loop diuretics. While VRAs have been shown to ameliorate signs and symptoms of congestion when added to standard care, the largest trial of these agents showed no improvement in long-term morbidity, mortality, or hospitalization rates when added to standard care. This article reviews the mechanism of action of VRAs, the relevant clinical trials data, and current recommendations for clinical use, and suggests future directions for study of these agents in patients with heart failure.     

Longer duration of mechanical ventilation was found to be associated with ventilator-associated pneumonia in children aged 1 month to 12 years in India

ObjectivesTo determine primarily (1) the incidence of ventilator-associated pneumonia (VAP) among ventilated patients aged 1 month to 12 years and secondarily (2) the risk factors for VAP and (3) common organisms causing VAP.Study Design and SettingProspective study in a tertiary care center in India. Consecutive ventilated patients aged ≥1 month and ≤12 years and requiring mechanical ventilation (MV) for ≥48 hours were included after written informed parental consent. For the diagnosis of VAP, National Nosocomial Infections Surveillance System criteria of 1996 were used.ResultsIncidence of VAP among patients aged 1 month to 12 years was 36.2% (38/105; 95% confidence interval [CI]: 27, 46). In unconditional logistic regression analysis controlling for the presence of underlying illnesses, risk factor for VAP was >4 days of MV (adjusted odds ratio, 3.76; 95% CI: 1.41, 10.02; P = 0.008). Reintubation within 72 hours of extubation and more than two attendants at the time of recruitment showed increased tendency for the development of VAP but did not reach statistical significance. Endotracheal and endobronchial aspirates were positive for organism in 19.05% (20/105) and 37.14% (39/105) of patients, respectively.ConclusionAlmost one-third of ventilated patients develop VAP. Vigilance for the development of VAP has to be kept on those requiring >4 days of MV. Klebsiella and Staphylococcus aureus were common bacterial isolates in such patients.     

Fifty years of Kawasaki disease–a tribute to Dr Tomisaku Kawasaki

It has been 50 years since the legendary Japanese pediatrician, Dr Tomisaku Kawasaki, published his classic paper in 1967. Little was he to know at that time that this condition would not only be known after his name but would also become the commonest cause of acquired heart disease in children in most of the developed world. The etiology of this condition continues to remain an enigma, and the diagnosis is still based on a set of criteria that are entirely clinical. All pediatricians must be familiar with the various clinical presentations of this disease because delays in diagnosis and treatment can have disastrous consequences.     

Intrahepatic biliary duct branching patterns,cystic duct anomalies,and pancreas divisum in a tertiary referral center: A magnetic resonance cholangiopancreaticographic study

Background

Knowledge about anatomic variations in intrahepatic biliary ducts (IHBD) is relevant for performing biliary drainage and for avoiding bile duct injury during cholecystectomy and liver resections. Low insertion of cystic duct (LICD) is a common anatomic variant. Pancreas divisum is the commonest congenital anomaly of pancreas; it has been causally linked with recurrent acute pancreatitis (RAP).

Methods

Magnetic resonance cholangiopancreaticography (MRCP) images of 500 consecutive patients were reviewed for anatomic variants of IHBD, cystic duct, and pancreatic duct.

Results

Anatomy of IHBD could be evaluated in 458 MRCP’s, of these 301 (65.72 %) had ‘typical’ anatomy. The variant in 157 persons included ‘triple confluence’ in 56 (12.23 %), ‘right posterior segmental duct (RPSD) draining to left hepatic duct (LHD)’ in 64 (14 %), ‘RPSD to common hepatic duct (CHD)’ in 20 (4.4 %), ‘RPSD to cystic duct’ in 2 (0.4 %), ‘accessory duct to CHD’ in 3 (0.7 %), ‘accessory duct to right hepatic duct (RHD)’ in 1 (0.2 %), ‘segment 2 and 3 separately to CHD’ in 1 (0.2 %), and complex variants in 10 (2.2 %). Cystic duct could be evaluated in 338 patients; of these, 15 (4.4 %) had LICD. Patients with RAP had pancreas divisum more often than those without any pancreatic disease, (?/?,10 % and ?/?, 0.8 %; p?=?0.004).

Conclusions

Nearly one third of MRCPs showed atypical IHBD pattern with RPSD draining to LHD being the commonest. LICD was the most common cystic duct variant. Pancreas divisum was more frequent in patients with RAP than in persons without pancreatic disease.

     

Developmental synaptic regulator,TWEAK/Fn14 signaling,is a determinant of synaptic function in models of stroke and neurodegeneration

Identifying molecular mediators of neural circuit development and/or function that contribute to circuit dysfunction when aberrantly reengaged in neurological disorders is of high importance. The role of the TWEAK/Fn14 pathway, which was recently reported to be a microglial/neuronal axis mediating synaptic refinement in experience-dependent visual development, has not been explored in synaptic function within the mature central nervous system. By combining electrophysiological and phosphoproteomic approaches, we show that TWEAK acutely dampens basal synaptic transmission and plasticity through neuronal Fn14 and impacts the phosphorylation state of pre- and postsynaptic proteins in adult mouse hippocampal slices. Importantly, this is relevant in two models featuring synaptic deficits. Blocking TWEAK/Fn14 signaling augments synaptic function in hippocampal slices from amyloid-beta–overexpressing mice. After stroke, genetic or pharmacological inhibition of TWEAK/Fn14 signaling augments basal synaptic transmission and normalizes plasticity. Our data support a glial/neuronal axis that critically modifies synaptic physiology and pathophysiology in different contexts in the mature brain and may be a therapeutic target for improving neurophysiological outcomes.

Neural circuit patterning, refinement, and plasticity are enabled by the dynamic strengthening, weakening, and pruning of chemical synapses in response to circuit activity. However, synapse loss and reduced plasticity are early hallmarks of chronic neurological disorders such as autism, schizophrenia and Alzheimer’s disease (AD) (1–3). It is therefore hypothesized that the underlying molecular mechanisms of pruning, although normally balanced in health, are dysregulated in disease. Particularly interesting is the notion that the mechanisms responsible for the reduction in functional synapses in disease reflect the aberrant reactivation of pathways important for synapse elimination in development. For example, in an AD model, synapse elimination was shown to be mediated by the complement pathway in the hippocampus (HC), reflecting aberrant reactivation of complement-dependent synapse elimination that occurs in the dorsal lateral geniculate nucleus (dLGN) of the thalamus during visual development (4). In such a paradigm, the reactivation of developmental mechanisms enables pathways that can act universally across different ages, circuits, and brain regions. Thus, the mechanisms underlying normal circuit development and their potential reactivation as key contributors to neurological diseases are areas of deep interest.In addition to chronic neurological disorders, circuitry changes also occur in acute ischemic stroke, the second leading cause of death worldwide and a cause of debilitating long-term disability. Interruptions in blood flow that deprive neurons of oxygen and nutrients result in significant cell death, followed by deficits in neurophysiological activity that are associated with poor motor recovery (5). Remarkably, the adult brain can undergo some degree of spontaneous poststroke recovery, apparently by engaging neuroplasticity mechanisms including remapping, synaptogenesis, and synaptic strengthening (5, 6). Despite these adaptations, over half of ischemic stroke patients fail to recover completely and continue to experience persistent long-term disability (7). The underlying signaling pathways that regulate synaptic physiology after stroke are an active topic of investigation.TNF-like weak inducer of apoptosis (TWEAK) protein, originally discovered as a cytokine produced by macrophages (8), signals through its injury-inducible transmembrane receptor, FGF-inducible molecule-14 (Fn14) (9). Consequently, the function of TWEAK/Fn14 signaling was elucidated as a driver of tissue remodeling in contexts of injury and disease in a variety of organ systems (10). Recently, findings have suggested a role for the TWEAK/Fn14 pathway in the central nervous system (CNS). Namely, several compelling observations indicate that TWEAK signaling through Fn14 might be a key molecular modulator of synaptic function in contexts of neurological challenge. TWEAK and Fn14 are up-regulated in the CNS in AD (11, 12, 13 and SI Appendix, Fig. S6A) and after ischemic stroke in humans and mice (14–16). Importantly, TWEAK/Fn14 signaling was also recently shown to be a pathway necessary for synapse maturation during experience-dependent visual development. Light-induced up-regulation of Fn14 in thalamocortical excitatory neurons and corresponding up-regulation of TWEAK in microglia mediate the elimination of weak synapses and strengthening of remaining synapses in the dLGN (17, 18). Indeed, the communication between neurons and supporting microglia has emerged as a key mechanism regulating neuronal circuitry, with microglia deploying their ramified processes to continuously survey and refine synapses in response to neural activity. Interestingly, TWEAK expression has also been shown to be microglia-enriched in the mouse cortex (19), suggesting that it may play a role in multiple brain regions. Thus, like the complement pathway, the TWEAK/Fn14 pathway could be an important regulator of synapse biology in visual development which is re-engaged and acts generally in different ages and brain regions to contribute to pathology.The involvement of TWEAK/Fn14 signaling in synapse physiology or pathophysiology outside of the developing visual system is unknown. We considered it to be a strong candidate modifier of synaptic function in adults given that Fn14 is up-regulated and required for synaptic refinement in experience-dependent visual development, and TWEAK and Fn14 are up-regulated in contexts of neurological injury/disease, suggesting that the TWEAK/Fn14 system is tuned to periods of substantial change in neuronal activity levels or environment (e.g., eye opening, ischemic stroke). We employed HC slices to test the hypothesis that the TWEAK/Fn14 pathway regulates synaptic function in adult mice and in different disease contexts and delineate its mechanism of action. Herein, we reveal that TWEAK, through neuronal Fn14, mediates acute dampening of basal synaptic transmission and synaptic plasticity in hippocampal slices from mature mice. Furthermore, we demonstrate that TWEAK/Fn14 signaling broadly impacts the phosphorylation state of critical synaptic proteins, suggesting a general role in synapse modulation. Finally, we show that pathway deficiency or pharmacological inhibition of TWEAK/Fn14 signaling augments synaptic transmission and plasticity in amyloid-beta (Aβ)–overexpressing mice and post ischemic stroke animals, two model systems featuring synaptic functional deficits. Thus, our results support that TWEAK/Fn14 constitutes a synaptic regulatory pathway with therapeutic potential for CNS disorders in the adult brain.