Search

The aim of this study was to obtain real-world, US, observational data on the effect of baseline resistance-associated substitutions (RASs) on achieving sustained virologic response (SVR) in hepatitis C (HCV) patients treated with direct-acting antiviral (DAA) regimens; the need for long-term follow-up in post-SVR patients. It is uncertain if the presence of RASs limits efficacy to DAAs. Once SVR is achieved, society guidelines recommend long-term surveillance for hepatocellular carcinoma in certain patients. Real-world data are limited on these topics. Adult patients treated with DAAs at community hepatitis clinics between January 2015 and April 2017 were included in this study. Baseline resistance testing was performed before treatment. Per guidelines, post-SVR long-term monitoring was required in patients with F3 to F4 fibrosis before treatment or with elevated ALT levels (>19 U/L females; >30 U/L males). A total of 875 chronic, mostly GT1a (60%) HCV patients were treated with an approved DAA regimen. Average baseline AST and ALT were 75 and 67 U/L, respectively, and 47% had F3 to F4 fibrosis at baseline. SVR was achieved in 863 (98.6%) patients despite a high presence of baseline RASs (61%). Long-term monitoring was required post-SVR in 539 patients (62%). In a real-life, US cohort of HCV-infected patients, nearly all patients achieved SVR with available DAA regimens regardless of baseline RASs. Approximately two-thirds of these patients required long-term follow-up, despite viral eradication.

Epidemiological studies indicate that light-moderate alcohol (ethanol) consumers tend to have reduced risks of cognitive impairment and progression to dementia during aging. Exploring possible mechanisms, we previously found that moderate ethanol preconditioning (MEP, 20-30 mM) of rat brain cultures for several days instigated neuroprotection against β-amyloid peptides. Our biochemical evidence implicated the NMDA receptor (NMDAR) as a potential neuroprotective “sensor”, specifically via synaptic NMDAR signaling. It remains unclear how ethanol modulates the receptor and its downstream targets to engender neuroprotection. Here we confirm with deconvolution microscopy that MEP of rat mixed cerebellar cultures robustly increases synaptic NMDAR localization. Phospho-activation of the non-receptor tyrosine kinases Src and Pyk2, known to be linked to synaptic NMDAR, is also demonstrated. Additionally, the preconditioning enhances levels of an antioxidant protein, peroxiredoxin 2 (Prx2), reported to be downstream of synaptic NMDAR signaling, and NMDAR antagonism with memantine (earlier found to abrogate MEP neuroprotection) blocks the Prx2 elevations. To further link Prx2 with antioxidant-based neuroprotection, we circumvented the ethanol preconditioning-NMDAR pathway by pharmacologically increasing Prx2 with the naturally-occurring cruciferous compound, 3H-1,2-dithiole-3-thione (D3T). Thus, D3T pretreatment elevated Prx2 expression to a similar extent as MEP, while concomitantly preventing β-amyloid neurotoxicity; D3T also protected the cultures from hydrogen peroxide toxicity. The findings support a mechanism that couples synaptic NMDAR signaling, Prx2 expression and augmented antioxidant defenses in ethanol preconditioning-induced neuroprotection. That this mechanism can be emulated by a cruciferous vegetable constituent suggests that such naturally-occurring “neutraceuticals” may be useful in therapy for oxidative stress-related dementias.

The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders., The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization but little is known about the endogenous ligands that engage ErbB4 and the downstream targets. Here the authors describe the existence of a cell-autonomous bidirectional pathway that links NMDA receptor activity with NRG signalling in GABAergic interneurons.

BACKGROUND: Serum amylase and lipase levels are widely used as markers of pancreatic inflammation. However, it would seem that mild elevations of amylase and lipase rarely predict significant pancreatic pathology. Pancreatic imaging tests are expensive. The gold standard, endoscopic retrograde cholangiopancreatography, carries risk of morbidity and mortality.OBJECTIVE: To determine whether extensive investigation of patients with mild, nonspecific abdominal symptoms and mild elevations of amylase and/or lipase results in a significant diagnostic yield.METHODS: Outpatient evaluations were retrospectively analyzed over 12 months. Inclusion criteria were nonspecific abdominal pain, and mild elevations (less than three times the upper limit of normal) of serum amylase or lipase, or both. Exclusion criteria included a history of chronic pancreatitis, elevation of liver tests and acute pain syndromes.RESULTS: Nineteen patients over the study period met the criteria. Of the nineteen patients, 58% had elevation of lipase alone, 21% amylase alone and 21% had elevations of both. In addition, 89.5% of the patients had nonspecific abdominal pain. After imaging with one or more of ultrasound, computed tomography, magnetic resonance cholangiopancreatography, endoscopic ultrasound and endoscopic retrograde cholangiopancreatography, small bowel follow through or hepatobiliary scanning, 78.9% patients were thought to have a normal pancreas. Of the remaining patients, 15.8% had mild or equivocal changes of chronic pancreatitis, and one patient was found to have a pancreatic tail pseudocyst. The average cost of investigation was US$2,255, taking only direct procedural costs into account. No patient was found to have malignancy.CONCLUSIONS: The majority of patients with nonspecific abdominal pain and isolated elevations of amylase and/or lipase (less than three times the upper limit of normal) had no identifiable pancreatic pathology. The diagnostic yield in patients with mild elevations of lipase alone was particularly poor. The cost effectiveness and risk-benefit ratio of extensive investigation of this group of patients warrants further study.

ErbB4 signaling in the central nervous system is implicated in neuropsychiatric disorders and epilepsy. In cortical tissue, ErbB4 associates with excitatory synapses located on inhibitory interneurons. However, biochemical and histological data described herein demonstrate that the vast majority of ErbB4 is extrasynaptic and detergent-soluble. To explore the function of this receptor population, we used unbiased proteomics, in combination with electrophysiological, biochemical, and cell biological techniques, to identify a clinically relevant ErbB4-interacting protein, the GABAA receptor α1 subunit (GABAR α1). We show that ErbB4 and GABAR α1 are robustly coexpressed in hippocampal interneurons, and that ErbB4-null mice have diminished cortical GABAR α1 expression. Moreover, we characterize a Neuregulin-mediated ErbB4 signaling modality, independent of receptor tyrosine kinase activity, that couples ErbB4 to decreased postsynaptic GABAR currents on inhibitory interneurons. Consistent with an evolving understanding of GABAR trafficking, this pathway requires both clathrin-mediated endocytosis and protein kinase C to reduce GABAR inhibitory currents, surface GABAR α1 expression, and colocalization with the inhibitory postsynaptic protein gephyrin. Our results reveal a function of ErbB4, independent of its tyrosine kinase activity, that modulates postsynaptic inhibitory control of hippocampal interneurons and may provide a novel pharmacological target in the treatment of neuropsychiatric disorders and epilepsy.

There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer's disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol "preconditioning" phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20-30 mM ethanol) of rat brain cultures prevents neurodegeneration due to beta-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca(+2)](i) and proinflammatory mediators--e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor --transducer --effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in "effector" heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning-like suppression of ongoing neuroinflammation related to amyloidogenic protein accumulation.

In several epidemiological studies, moderate ethanol consumption has been associated with reduced risks of cognitive decline or Alzheimer's dementia. Of potential relevance is that brain cultures preconditioned with moderate ethanol concentrations are resistant to neurotoxic Alzheimer's amyloid-beta (Abeta) peptides. Using rat cerebellar mixed cultures we investigated whether certain membrane receptors were early 'sensors' in moderate ethanol preconditioning (MEP). In a 6-day MEP protocol (30 mM ethanol), neuroprotection from Abeta25-35 was undiminished by antagonism during the first 3 days of either adenosine A(1) or Galpha(i/o) protein-coupled receptors. However, similar cotreatment with memantine or DL-2-amino-5-phosphono-pentanoic acid (AP-5), antagonists of NMDA receptors (NMDAR), abolished neuroprotection, indicating key early involvement of this ionotropic glutamate receptor. Also in these cultures, directly activating NMDAR using subexcitotoxic NMDA preconditioning prevented Abeta neurotoxicity. By day 2 of MEP, we observed increased levels of NMDAR subunits NR1, NR2B, and NR2C that persisted through day 6. Interestingly, memantine co-exposure blocked elevations in the obligatory NR1 subunit. Furthermore, 2 days of MEP significantly increased two indicators of synaptic NMDAR localization, NR2B phospho-Tyr1472, and post-synaptic density 95 scaffolding protein. The results indicate that ethanol preconditioning-dependent neuroprotection is associated with early increases in NR subunits concomitant with enhancement of synaptic localization and activity of NMDAR.

Since the US Food and Drug Administration banned the use of dietary supplements containing ephedra in February 2004, numerous "ephedra-free" weight-loss products have appeared on the market. Many of these supplements contain compounds such as bitter orange that are similar in structure and action to ephedra. We describe a patient in whom ischemic colitis developed 1 week after initiation of a bitter orange-containing weight-loss supplement. The patient had no other predisposing factors, and discontinuation of the supplement led to immediate improvement and ultimate resolution of her symptoms. Both consumers and health care professionals should be aware of the potential harm that bitter orange-containing dietary supplements can cause and report such adverse events to the US Food and Drug Administration.

We read with great interest the commentary by Boland and Savides ( Gut 2001; 48 :449–50) on our paper “Flexible sigmoidoscopy and the changing distribution of colorectal cancer: implications for screening” ( Gut 2001; 48 :522–5). The authors make several important points about the changing pattern of distribution of colorectal cancer and the possible reasons for the changes we observed. Our data showed an increased percentage of colorectal cancers diagnosed …

Summary Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2 −/− /NPTXR −/− mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2 −/− /NPTXR −/− mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2 −/− /NPTXR −/− mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.