Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotran...Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotransmitter glutamate, which binds and activates ionotropic N-methyl-D-aspartate glutamatergic receptors （NMDARs） in the brain. Normally, NMDARs mediate calcium entry into the cell to regulate physiological processes such as synaptic plasticity and memory,展开更多
Peginterferon and ribavirin combination therapy for the treatment of hepatitis C virus （HCV） is well known to be associated with significant adverse effects. Sensorineural hearing loss, that in most cases is unilate...Peginterferon and ribavirin combination therapy for the treatment of hepatitis C virus （HCV） is well known to be associated with significant adverse effects. Sensorineural hearing loss, that in most cases is unilateral, has been reported as a consequence of therapy with both non-pegylabed and pegylated interferon （pegIFN） but is not a well-known adverse effect. We report a 45-year-old Caucasian woman who developed acute sensorineural hearing loss 2 mo after starting therapy with pegIFN-α 2b and ribavirin for the treatment of chronic HCV, genotype la. She did not report the hearing loss to the hepatitis clinic until 1 mo, later whereupon therapy was promptly discontinued. Although her serum alanine aminotransferase （ALT） normalized and her HCV-RNA became undetectable after 12 wk of pegIFN and dbavirin therapy, after discontinuation, her HCV-RNA became detectable with significant elevations of serum ALT. Four months after initial discontinuation, the patient re-commenced pegIFN and ribavirin combination therapy. After 44 of 48 wk of therapy, the patient＇s liver biochemistry has normalized and the HCV-RNA is undetectable. She has not developed worsening of her hearing loss and hearing on the left-side is unaffected. Both patients and physicians should be aware that sensorineural hearing loss may occur with pegIFN therapy. Our experience suggests that re-institution of therapy is not always associated with further hearing impairment.展开更多
Recent advances in understanding of pancreatitis and advances in technology have uncovered the veils of idiopathic pancreatitis to a point where a thorough history and judicious use of diagnostic techniques elucidate ...Recent advances in understanding of pancreatitis and advances in technology have uncovered the veils of idiopathic pancreatitis to a point where a thorough history and judicious use of diagnostic techniques elucidate the cause in over 80% of cases. This review examines the multitude of etiologies of what were once labeled idiopathic pancreatitis and provides the current evidence on each. This review begins with a background review of the current epidemiology of idiopathic pancreatitis prior to discussion of various etiologies. Etiologies of medications,infections,toxins,autoimmune disorders,vascular causes,and anatomic and functional causes are explored in detail. We conclude with management of true idiopathic pancreatitis and a summary of the various etiologic agents. Throughout this review,areas of controversies are highlighted.展开更多
Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have requ...Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation.展开更多
Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor(GABAAR)mediated inhibition is essential for brain functioning;and its imbalance contributes to t...Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor(GABAAR)mediated inhibition is essential for brain functioning;and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental illnesses.Here we identify a novel glutamate-GABAAR interaction mediated by a direct glutamate binding of the GABAAR.In HEK293 cells overexpressing recombinant GABAARs,glutamate and its analog ligands,while producing no current on their own,potentiate GABA-evoked currents.This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at theα+/β−subunit interface of the GABAAR.Moreover,the potentiation does not require the presence of aγsubunit,and in fact,the presence ofγsubunit significantly reduces the potency of the glutamate potentiation.In addition,the glutamate-mediated allosteric potentiation occurs on native GABAARs in rat neurons maintained in culture,as evidenced by the potentiation of GABAAR-mediated inhibitory postsynaptic currents and tonic currents.Most importantly,we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability,including decreased thresholds to noxious stimuli and increased seizure susceptibility.These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAAR.Such a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance(E/I balance),thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.展开更多
文摘Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotransmitter glutamate, which binds and activates ionotropic N-methyl-D-aspartate glutamatergic receptors （NMDARs） in the brain. Normally, NMDARs mediate calcium entry into the cell to regulate physiological processes such as synaptic plasticity and memory,
文摘Peginterferon and ribavirin combination therapy for the treatment of hepatitis C virus （HCV） is well known to be associated with significant adverse effects. Sensorineural hearing loss, that in most cases is unilateral, has been reported as a consequence of therapy with both non-pegylabed and pegylated interferon （pegIFN） but is not a well-known adverse effect. We report a 45-year-old Caucasian woman who developed acute sensorineural hearing loss 2 mo after starting therapy with pegIFN-α 2b and ribavirin for the treatment of chronic HCV, genotype la. She did not report the hearing loss to the hepatitis clinic until 1 mo, later whereupon therapy was promptly discontinued. Although her serum alanine aminotransferase （ALT） normalized and her HCV-RNA became undetectable after 12 wk of pegIFN and dbavirin therapy, after discontinuation, her HCV-RNA became detectable with significant elevations of serum ALT. Four months after initial discontinuation, the patient re-commenced pegIFN and ribavirin combination therapy. After 44 of 48 wk of therapy, the patient＇s liver biochemistry has normalized and the HCV-RNA is undetectable. She has not developed worsening of her hearing loss and hearing on the left-side is unaffected. Both patients and physicians should be aware that sensorineural hearing loss may occur with pegIFN therapy. Our experience suggests that re-institution of therapy is not always associated with further hearing impairment.
文摘Recent advances in understanding of pancreatitis and advances in technology have uncovered the veils of idiopathic pancreatitis to a point where a thorough history and judicious use of diagnostic techniques elucidate the cause in over 80% of cases. This review examines the multitude of etiologies of what were once labeled idiopathic pancreatitis and provides the current evidence on each. This review begins with a background review of the current epidemiology of idiopathic pancreatitis prior to discussion of various etiologies. Etiologies of medications,infections,toxins,autoimmune disorders,vascular causes,and anatomic and functional causes are explored in detail. We conclude with management of true idiopathic pancreatitis and a summary of the various etiologic agents. Throughout this review,areas of controversies are highlighted.
文摘Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation.
基金Canadian Institutes of Health Research(CIHR),Taiwan National Science Council(NSC 102–2320-B-039–038-MY3)Ministry of Science and Technology(MOST 104-2320-B-039-045-MY3,MOST107-2320-B039-060-MY3,MOST 107-2320-B-039-061-MY3,MOST 110-2320-B-039-010-MY3,and MOST 111-2321-B-A49-005-),China Medical University(CMU-107-Z-01,CMU108-MF-14)+4 种基金National Natural Science Foundation of China(82071395,82001158,32170959)Natural Science Foundation of Chongqing(cstc2020jcyj-zdxmX0004 and cstc2021ycjh-bgzxm0186)Science and Technology Research Program of Chongqing Municipal Education Commission(KJZD-K201900403)Innovation Research Group at Institutions of Higher Education in Chongqing(CXQTP19034)CQMU Program for Youth Innovation in Future Medicine(No.W0044).
文摘Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor(GABAAR)mediated inhibition is essential for brain functioning;and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental illnesses.Here we identify a novel glutamate-GABAAR interaction mediated by a direct glutamate binding of the GABAAR.In HEK293 cells overexpressing recombinant GABAARs,glutamate and its analog ligands,while producing no current on their own,potentiate GABA-evoked currents.This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at theα+/β−subunit interface of the GABAAR.Moreover,the potentiation does not require the presence of aγsubunit,and in fact,the presence ofγsubunit significantly reduces the potency of the glutamate potentiation.In addition,the glutamate-mediated allosteric potentiation occurs on native GABAARs in rat neurons maintained in culture,as evidenced by the potentiation of GABAAR-mediated inhibitory postsynaptic currents and tonic currents.Most importantly,we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability,including decreased thresholds to noxious stimuli and increased seizure susceptibility.These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAAR.Such a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance(E/I balance),thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.
