Nafamostat mesylate,an apparent soi-disant panacea of sorts,is widely used to anticoagulate patients undergoing hemodialysis or cardiopulmonary bypass,mitigate the inflammatory response in patients diagnosed with acut...Nafamostat mesylate,an apparent soi-disant panacea of sorts,is widely used to anticoagulate patients undergoing hemodialysis or cardiopulmonary bypass,mitigate the inflammatory response in patients diagnosed with acute pancreatitis,and reverse the coagulopathy of patients experiencing the commonly preterminal disseminated intravascular coagulation in the Far East.The serine protease inhibitor nafamostat mesylate exhibits significant neuroprotective effects in the setting of neurovascular ischemia.Nafamostat mesylate generates neuroprotective effects by attenuating the enzymatic activity of serine proteases,neuroinflammatory signaling cascades,and the endoplasmic reticulum stress responses,downregulating excitotoxic transient receptor membrane channel subfamily 7 cationic currents,modulating the activity of intracellular signal transduction pathways,and supporting neuronal survival brain-derived neurotrophic factor/TrkB/ERK1/2/CREB,nuclear factor kappa B.The effects collectively reduce neuronal necrosis and apoptosis and prevent ischemia mediated disruption of blood-brain barrier microarchitecture.Investigational clinical applications of these compounds may mitigate ischemic reperfusion injury in patients undergoing cardiac,hepatic,renal,or intestinal transplant,preventing allograft rejection,and treating solid organ malignancies.Neuroprotective effects mediated by nafamostat mesylate support the wise conduct of randomized prospective controlled trials in Western countries to evaluate the clinical utility of this compound.展开更多
Variability in cardiovascular spectra was first described by Stephan Hales in 1733.Traube and Hering initially noted respirophasic variation of the arterial pressure waveform in 1865 and Sigmund Mayer noted a lower fr...Variability in cardiovascular spectra was first described by Stephan Hales in 1733.Traube and Hering initially noted respirophasic variation of the arterial pressure waveform in 1865 and Sigmund Mayer noted a lower frequency oscillation of the same in anesthetized rabbits in 1876.Very low frequency oscillations were noted by Barcroft and Nisimaru in 1932,likely representing vasogenic autorhythmicity.While the origins of Traube Hering and very low frequency oscillatory variability in cardiovascular spectra are well described,genesis mechanisms and functional significance of Mayer waves remain in controversy.Various theories have posited baroreflex and central supraspinal mechanisms for genesis of Mayer waves.Several studies have demonstrated the persistence of Mayer waves following high cervical transection,indicating a spinal capacity for genesis of these oscillations.We suggest a general tendency for central sympathetic neurons to oscillate at the Mayer wave frequency,the presence of multiple Mayer wave oscillators throughout the brainstem and spinal cord,and possible contemporaneous genesis by baroreflex and vasomotor mechanisms.展开更多
The cervical spine is the most common site of traumatic vertebral column injuries. Respiratory insufficiency constitutes a significant proportion of the morbidity burden and is the most common cause of mortality in th...The cervical spine is the most common site of traumatic vertebral column injuries. Respiratory insufficiency constitutes a significant proportion of the morbidity burden and is the most common cause of mortality in these patients. In seeking to enhance our capacity to treat specifically the respiratory dysfunction following spinal cord injury, investigators have studied the “crossed phrenic phenomenon”, wherein contraction of a hemidiaphragm paralyzed by a complete hemisection of the ipsilateral cervical spinal cord above the phrenic nucleus can be induced by respiratory stressors and recovers spontaneously over time. Strengthening of latent contralateral projections to the phrenic nucleus and sprouting of new descending axons have been proposed as mechanisms contributing to the observed recovery. We have recently demonstrated recovery of spontaneous crossed phrenic activity occurring over minutes to hours in C_1-hemisected unanesthetized decerebrate rats. The specific neurochemical and molecular pathways underlying crossed phrenic activity following injury require further clarification. A thorough understanding of these is necessary in order to develop targeted therapies for respiratory neurorehabilitation following spinal trauma. Animal studies provide preliminary evidence for the utility of neuropharmacological manipulation of serotonergic and adenosinergic pathways, nerve grafts, olfactory ensheathing cells, intraspinal microstimulation and a possible role for dorsal rhizotomy in recovering phrenic activity following spinal cord injury.展开更多
文摘Nafamostat mesylate,an apparent soi-disant panacea of sorts,is widely used to anticoagulate patients undergoing hemodialysis or cardiopulmonary bypass,mitigate the inflammatory response in patients diagnosed with acute pancreatitis,and reverse the coagulopathy of patients experiencing the commonly preterminal disseminated intravascular coagulation in the Far East.The serine protease inhibitor nafamostat mesylate exhibits significant neuroprotective effects in the setting of neurovascular ischemia.Nafamostat mesylate generates neuroprotective effects by attenuating the enzymatic activity of serine proteases,neuroinflammatory signaling cascades,and the endoplasmic reticulum stress responses,downregulating excitotoxic transient receptor membrane channel subfamily 7 cationic currents,modulating the activity of intracellular signal transduction pathways,and supporting neuronal survival brain-derived neurotrophic factor/TrkB/ERK1/2/CREB,nuclear factor kappa B.The effects collectively reduce neuronal necrosis and apoptosis and prevent ischemia mediated disruption of blood-brain barrier microarchitecture.Investigational clinical applications of these compounds may mitigate ischemic reperfusion injury in patients undergoing cardiac,hepatic,renal,or intestinal transplant,preventing allograft rejection,and treating solid organ malignancies.Neuroprotective effects mediated by nafamostat mesylate support the wise conduct of randomized prospective controlled trials in Western countries to evaluate the clinical utility of this compound.
文摘Variability in cardiovascular spectra was first described by Stephan Hales in 1733.Traube and Hering initially noted respirophasic variation of the arterial pressure waveform in 1865 and Sigmund Mayer noted a lower frequency oscillation of the same in anesthetized rabbits in 1876.Very low frequency oscillations were noted by Barcroft and Nisimaru in 1932,likely representing vasogenic autorhythmicity.While the origins of Traube Hering and very low frequency oscillatory variability in cardiovascular spectra are well described,genesis mechanisms and functional significance of Mayer waves remain in controversy.Various theories have posited baroreflex and central supraspinal mechanisms for genesis of Mayer waves.Several studies have demonstrated the persistence of Mayer waves following high cervical transection,indicating a spinal capacity for genesis of these oscillations.We suggest a general tendency for central sympathetic neurons to oscillate at the Mayer wave frequency,the presence of multiple Mayer wave oscillators throughout the brainstem and spinal cord,and possible contemporaneous genesis by baroreflex and vasomotor mechanisms.
基金supported in part by Drexel University College of Medicine
文摘The cervical spine is the most common site of traumatic vertebral column injuries. Respiratory insufficiency constitutes a significant proportion of the morbidity burden and is the most common cause of mortality in these patients. In seeking to enhance our capacity to treat specifically the respiratory dysfunction following spinal cord injury, investigators have studied the “crossed phrenic phenomenon”, wherein contraction of a hemidiaphragm paralyzed by a complete hemisection of the ipsilateral cervical spinal cord above the phrenic nucleus can be induced by respiratory stressors and recovers spontaneously over time. Strengthening of latent contralateral projections to the phrenic nucleus and sprouting of new descending axons have been proposed as mechanisms contributing to the observed recovery. We have recently demonstrated recovery of spontaneous crossed phrenic activity occurring over minutes to hours in C_1-hemisected unanesthetized decerebrate rats. The specific neurochemical and molecular pathways underlying crossed phrenic activity following injury require further clarification. A thorough understanding of these is necessary in order to develop targeted therapies for respiratory neurorehabilitation following spinal trauma. Animal studies provide preliminary evidence for the utility of neuropharmacological manipulation of serotonergic and adenosinergic pathways, nerve grafts, olfactory ensheathing cells, intraspinal microstimulation and a possible role for dorsal rhizotomy in recovering phrenic activity following spinal cord injury.
