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Biomedical subjects

H Schulman

Publications and source records attributed to H Schulman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Nitric oxide: a spatial second messenger.

Fast synaptic transmission by excitatory neurotransmitters endows neural tissue with remarkable computational power but is limited in its ability to adapt with experience. Information in the nervous system can also be distributed beyond the synapse by biogenic amines or neuropeptides released at non-synaptic sites to elicit volume transmission and by the spatial second messenger nitric oxide which can diffuse from a synapse to a volume of surrounding neural tissue. Volume transmission and spatial signaling complement classic point-to-point transmission and may coordinate local activity among groups of neurons and glia. An interesting dialogue exists between these systems. Nitric oxide produced in response to excitation of a neuron by glutamate stimulates exocytosis and release of glutamate and dopamine from nearby neurons. Dopamine in turn can alter the strength of glutamatergic synapses and affect synaptic plasticity.

Animals↗
PubMed1996

Distinct voltage-dependent gating behaviours of a swelling-activated chloride current in human epithelial cells.

1. The swelling-activated chloride current is critical in the homeostatic regulatory volume decrease (RVD) of both excitable and non-excitable cells. Although not activated by voltage, it displays kinetic behaviour similar to voltage-gated Shaker-type potassium currents. We have studied the voltage-dependent properties of this current in single T84 human cell line epithelial cells using whole-cell patch clamp methodology. 2. An external anion permeability sequence of I- > Cl- > methanesulphonate (MeSO3-) was observed for the swelling-activated current. Extracellular application of the chloride channel blocker DIDS (100 microM) resulted in approximately 50% block of the current in a voltage-dependent manner. 3. At positive membrane potentials, the swelling-activated chloride current undergoes time-dependent inactivation. Following such inactivation, recovery of both the inward and outward components of the macroscopic current was found to be voltage dependent. The time constants describing these two individual recovery processes were identical over a range of membrane potentials. In addition, the magnitude of current recovery was directly dependent upon the degree prior inactivation of current at positive voltage. 4. We further observed that the swelling-activated current undergoes a form of steady-state, voltage-dependent inactivation that appears to differ from the inactivation observed at positive potentials. This steady-state inactivation occurred over the physiological voltage range, with a membrane potential at half-maximal inactivation (V1/2) of -72 mV, and differed from the time-dependent inactivation observed at positive membrane potentials, which occurred with a V1/2 of 40 mV. These observations demonstrate two distinct forms of voltage-dependent inactivation, probably reflecting two separate gating processes at the level of the channel. 5. These latter properties are thus anticipated to regulate voltage-dependent chloride efflux under cell swelling conditions and further influence RVD and membrane excitability in cells generating action potentials.

Cell Line↗
PubMed1996

Vertebral pneumatocyst. A case report.

STUDY DESIGN: This study illustrates intraosseous pneumatocyst of the vertebral body, a benign lesion. OBJECTIVES: To review the incidence and location of this benign lesion during a 1-year period. SUMMARY OF BACKGROUND DATA: Intraosseous pneumatocyst is a rare benign condition, commonly seen in iliac bone or sacrum. The etiology of this entity is unclear. Other locations of these lesions are very rare, and only a few isolated cases are reported in the literature. METHODS: In the last year (1994-1995), vertebral pneumatocyst was incidentally found in four patients who underwent computed tomography examination for presumptive discal lesion. Axial computed tomography with 2- and 4-mm slice thickness was performed. RESULTS: The typical computed tomography patterns of intraosseous pneumatocyst involving the cervical, dorsal, or lumbar spine were found. The bony structure and joints were normal. To the best of our knowledge, intraosseous pneumatocyst located in the spinal process has not been reported. CONCLUSIONS: Intraosseous pneumatocyst is a benign lesion. Biopsy and follow-up are unnecessary.

Adult↗
PubMed1996

Nitric oxide modulates synaptic vesicle docking fusion reactions.

Nitric oxide (NO) stimulates calcium-independent neurotransmitter release from synaptosomes. NO-stimulated release was found to be inhibited by Botulinum neurotoxins that inactivate the core complex of synaptic proteins involved in the docking and fusion of synaptic vesicles. In experiments using recombinant proteins, NO donors increased formation of the VAMP/SNAP-25/syntaxin 1a core complex and inhibited the binding of n-sec1 to syntaxin 1a. The combined effects of these activities is predicted to promote vesicle docking/fusion. The sulfhydryl reagent NEM inhibited the binding of n-sec1 to syntaxin 1a, while beta-ME could reverse the NO-enhanced association of VAMP/SNAP-25/syntaxin 1a. These data suggest that post-translational modification of sulfhydryl groups by a nitrogen monoxide (likely to be NO+) alters the synaptic protein interactions that regulate neurotransmitter release and synaptic plasticity.

Animals↗
PubMed1996

Central and peripheral haemodynamic changes in post-term fetuses: correlation with oligohydramnios and abnormal fetal heart rate pattern.

OBJECTIVE: To assess the hypothesis that the occurrence of oligohydramnios and abnormal fetal heart rate (FHR) pattern in post-term fetuses is associated with impaired fetal cardiac function. DESIGN: A cross sectional study was performed on post-term and term fetuses. Fetal tests included a computerised analysis of the FHR, a biophysical profile and Doppler studies of the abdominal aorta, umbilical artery, middle cerebral artery and the fetal heart. Pulsatility index (PI) was calculated from the abdominal aorta, umbilical and middle cerebral artery flow velocity waveforms. Peak velocity, velocity time integral (VTI), E:A ratio, and heart rate (HR) were calculated from the flow velocity waveforms obtained from the aortic and pulmonic outflow, and from the mitral and tricuspid valves. SETTING: Maternal fetal laboratory, Department of Obstetrics. SAMPLE: One hundred and twenty post-term and 42 term fetuses. RESULTS: Only the tricuspid E:A ratio was significantly higher (P < 0.05) in post-term fetuses with a normal amniotic fluid index compared with term fetuses. Post-term fetuses with an abnormal amniotic fluid index had a significantly lower aortic peak velocity (P < 0.01), aortic VTI x HR (P < 0.01), and mitral VTI x HR (P < 0.05) compared with post-term fetuses with a normal amniotic fluid index or compared with term fetuses. Post-term fetuses with reduced FHR variation had a significantly lower aortic peak velocity (P < 0.01), pulmonic peak velocity (P < 0.05), aortic VTI x HR (P < 0.01), pulmonic VTI x HR (P < 0.05) and a significantly lower mitral VTI x HR (P < 0.05) when compared with post-term fetuses with normal FHR variation. Similar results were obtained in comparing fetuses with normal and adverse perinatal outcome. CONCLUSION: The occurrence of oligohydramnios and abnormal FHR pattern in post-term fetuses appears to be associated with impaired fetal cardiac function. This finding should allow further investigations of post-term fetuses.

Adult↗
PubMed1996

Possible aetiology of haemorrhagic shock and encephalopathy syndrome in the Negev area of Israel.

A retrospective study was performed for all patients diagnosed with haemorrhagic shock and encephalopathy syndrome (HSES) over an 11 year period (1984-94). Soroka University Medical Centre is the only medical facility in the southern Negev region of Israel serving a population of about 400,000 residents, consisting primarily of two ethnic populations, Jews and Bedouins. Twenty patients, 17 Bedouin and three Jews, were diagnosed with HSES. The annual incidence of HSES for infants under the age of 1 year was 5:10,000 for Bedouins and 0.6:10,000 for Jews. Patients ranged in age from 6 to 32 weeks and arrived at the hospital late at night or early morning (2:00 am to 11:00 am), during the winter or early spring (November to April). All were healthy before admission, with short prodromal symptoms of upper respiratory tract or gastrointestinal infection noted in 10 cases. Most infants had markedly high body temperature on arrival. A history of overwrapping and/or excessive heating was obtained in four of 20 infants. Bacteriological and virological cultures were negative in all infants. One infant died and neurological sequelae were observed in all survivors. The high prevalence of hyperpyrexia during sleep in the presence of negative microbiological results with no evidence of excessive heating, and the high incidence of HSES among a closed and culturally isolated society known to have a high incidence of congenital malformations, may support previous assumptions that HSES results from hyperpyrexia, originating in most cases from a 'physiological' heat induced trigger, which starts and peaks during the night in previously healthy infants who are genetically susceptible.

Arabs↗
PubMed1996

Surveillance of growth-retarded fetuses with computerized fetal heart rate monitoring combined with Doppler velocimetry of the umbilical and uterine arteries.

OBJECTIVE: To define guidelines for surveillance of growth-retarded fetuses with a computerized fetal heart rate (FHR) monitor and Doppler device. STUDY DESIGN: Eighty-one growth-retarded fetuses with birth weights < 10th percentile and lacking major anomalies were studied. One hundred ninety-two tests (one to six per patient), including computerized FHR monitoring and Doppler studies of the umbilical and uterine arteries, were performed. The relationship between Doppler velocimetry or FHR variation and fetal outcome was examined. RESULTS: Fetuses with an abnormal FHR variation or abnormal Doppler velocimetry had a significantly higher rate of cesarean deliveries for fetal distress and a higher number of admissions to the neonatal intensive care unit (NICU) as compared with fetuses with normal results on both tests. The best distinction was noted when the growth-retarded fetuses were partitioned into four analytic groups based on the presence of normal or abnormal FHR variation or Doppler velocimetry. The group with the poorest results was composed of fetuses with abnormal umbilical flow velocity and reduced FHR variation. These fetuses had significantly lower birth weights (1,250 g) and significantly higher rates of cesarean deliveries for fetal distress (92%) and admission to the NICU (100%). Thirty percent of these fetuses died. CONCLUSION: Fetal surveillance with Doppler and computerized FHR monitoring allows better understanding of the management of fetuses that are small for gestational age.

Adult↗
PubMed1995

A non-selective cation current activated via the multifunctional Ca(2+)-calmodulin-dependent protein kinase in human epithelial cells.

1. Activation of macroscopic membrane currents by intracellular calcium ([Ca2+]i) signalling pathways was examined in human T84 epithelial cells, a model secretory cell line. 2. Elevation of [Ca2+]i by either the calcium ionophore A23187 (1 microM) or the cholinergic agonist carbachol, led to the transient activation of both a chloride and cation current in single voltage clamped cells. The channels underlying the cation conductance were found to be equally permeable to external Na+, K+ and Cs+, but impermeable to the large organic cations tetraethylammonium and N-methyl-D-glucamine (NMDG). These observations indicate that the cation channels are non-selective with respect to monovalent cations. 3. Persistent activation of both the chloride and non-selective cation currents by [Ca2+]i was observed following inhibition of cellular phosphatase activity by the phosphatase inhibitor microcystin LR or the ATP analogue ATP gamma S. This finding strongly suggests the presence of a phosphorylation event in the calcium-dependent activation pathway for both currents. 4. Intracellular dialysis with peptide inhibitors of the multifunctional Ca(2+)-calmodulin-dependent protein kinase (CaM kinase) blocked the activation of both the chloride and cation conductances by elevated [Ca2+]i. Dialysis with an inactive control peptide had no effect on the activation of either current. CaM kinase thus appears to be critically involved in the calcium-dependent activation of both the chloride and cation currents in these cells. 5. Associated with the whole-cell cation conductance were macroscopic tail currents observed at the chloride reversal potential. The distinct kinetic properties of these tail currents were used as a biophysical 'signature' of the whole-cell conductance. 6. In excised, inside-out membrane patches, [Ca2+]i activated single cation channel activity. These channels had a mean conductance of 20 pS, were impermeable to NMDG, and their mean open probability increased at positive membrane potentials. The properties of these single channel events thus closely resemble those reported previously for calcium-activated cation channels in epithelia. 7. Using a novel 'tail current' voltage clamp protocol in excised membrane patches, we observed that ensemble averages of single cation channel events reproduced the behaviour and kinetic properties of the macroscopic tail currents of the calcium-activated cation conductance. This finding provides evidence that the observed single channel events probably underlie the macroscopic cation current recorded from intact cells. 8. The results from this study demonstrate that CaM kinase mediates the calcium-dependent activation of both a chloride and a non-selective cation current in human T84 epithelial cells. Using single channel recordings, we believe we have identified the corresponding whole-cell current for the 20-40 pS calcium-activated cation channel activity reported previously in epithelia and other cell preparations. Physiologically, a calcium-activated inward cation current would allow sodium influx in association with calcium-dependent electrolyte and protein secretion. Thus CaM kinase-dependent activation of cation channels may serve as a co-ordinated influx pathway to balance the efflux and influx of osmotically active solutes as part of an overall cell volume regulatory mechanism.

Amino Acid Sequence↗
PubMed1995

The advantages of using triple-marker screening for chromosomal abnormalities.

OBJECTIVE: Our purpose was to assess the utility of triple-marker serum screening for chromosomal abnormalities. STUDY DESIGN: Our laboratory received 10,605 samples that were between 15 and 22 weeks' gestation for maternal serum screening of chromosomal abnormalities. Triple-marker maternal serum screening consisted of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol in conjunction with maternal age. Women > or = 35 years old were first offered amniocentesis. If they refused amniocentesis, they were offered the screening test. A second-trimester risk for trisomy 21 > or = 1:270 was considered screen positive. Patients were screen positive for trisomy 18 if all three markers were low: alpha-fetoprotein < or = 0.75 multiples of the median, unconjugated estriol < or = 0.60 multiples of the median, and human chorionic gonadotropin < or = 0.55 multiples of the median. RESULTS: The initial screen-positive rate was 8.3% (880 women); amniocentesis was offered to 766 (7.2%). Twelve of 16 ascertained cases of trisomy 21 (75%), two of three cases of trisomy 18 (67%), five cases of 45,X karyotype, and one case each of 45,X/46,XX, 47,XXY, 47,XYY, 46,XX,ins(2)(q21p13p15)mat, and 69,XXX karyotypes were identified in the screen-positive patients. All four known cases of trisomy 21 in the 886 women > or = 35 years old who were screened were detected, with a 21% false-positive rate. Omitting unconjugated estriol from our screening program would have resulted in detecting nine of 16 trisomy 21 and six of 12 other chromosomal abnormalities. The false-positive rate would have remained the same. CONCLUSION: In our sample cohort addition of unconjugated estriol to the screening program resulted in an increased detection rate of chromosomal abnormalities with no change in the false-positive rate. Considering the advancement in screening for chromosomal abnormalities, maternal age alone as an indication for amniocentesis should be reevaluated.

Adolescent↗
PubMed1995

Protein phosphorylation in neuronal plasticity and gene expression.

Protein kinases and phosphatases are intimately involved in several forms of synaptic plasticity. They play a critical role in the initiation of long-term potentiation and long-term depression, as well as in the induction of genes that permit long-term expression of altered synaptic states. Recent findings demonstrate a central role for the cAMP signaling pathway in the persistent phase of long-term potentiation. Genetic approaches have established that the transcription factor CREB is essential for long-term memory.

Animals↗
PubMed1995

Decoding Ca2+ signals to the nucleus by multifunctional CaM kinase.

Multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) is one of the major protein kinases coordinating cellular responses to neurotransmitters and hormones. CaM kinase transduces changes in intracellular free Ca2+ into changes in the phosphorylation state and activity of target proteins involved in neurotransmitter synthesis and release, neuronal plasticity and gene expression. Structure/function analyses of the kinase reveal the kinase is kept inactive in its basal state by a regulatory domain that is displaced by the binding of Ca2+/calmodulin. Once activated by Ca2+/calmodulin, autophosphorylation occurs if a pair of proximate subunits of the decameric kinase have calmodulin bound. The frequency of Ca2+ oscillations or spikes may be decoded by CaM kinase via this autophosphorylation. Calmodulin is essentially trapped by autophosphorylation which converts CaM kinase into a high affinity calmodulin-binding protein. Repetitive stimulation of the kinase may promote recruitment of calmodulin to the kinase so that it becomes increasingly active with each stimulus in a frequency-dependent manner. The association domain at the C-terminal end of CaM kinase contains a variable region that targets isoforms of the kinase to the nucleus or cytoskeleton and assembles the kinase into a decameric structure. Alternative splicing introduces a short nuclear localization signal that targets transfected kinase to the nucleus where it may regulate nuclear functions. The regulatory properties of CaM kinase provide for molecular potentiation of Ca2+ signals and frequency detection whereas its association domain should enable it to decode such Ca2+ fluctuations in the nucleus.

Amino Acid Sequence↗
PubMed1995

Developmental and regional expression of multifunctional Ca2+/calmodulin-dependent protein kinase isoforms in rat brain.

Multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) participates in diverse calcium signaling pathways in neurons. The alpha- and beta-CaM kinase isoforms are neuron-specific and highly abundant in rat brain. The variable domain of CaM kinase is a potential site for the generation of isoform diversity by alternative spicing of its N- and/or C-terminal segments. We used specific PCR primers which span the variable domain of either alpha- or beta-CaM kinase and isolated three new isoforms from rat brain, namely alpha B-, beta e- and beta'e-CaM kinase. alpha beta-CaM kinase contains 11 amino acids, likely inserted by alternative splicing, at the C-terminal segment of the variable domain. This insertion introduces a nuclear localization signal (NLS) that targets alpha B-CaM kinase to the nucleus of transfected cells; alpha-CaM kinase is excluded from the nucleus. The mRNA and the protein corresponding to this isoform are detected only in the diencephalon/midbrain regions. We have also identified two alternatively spliced isoforms of beta-CaM kinase that lack the 24 amino acid sequence at the N-terminal segment of the variable domain. Alternative splicing of these two isoforms occurs with a three base pair shift of the 3'-splice site. Our analysis shows that these new beta-CaM kinase isoforms are expressed primarily in early developmental stages, and we therefore term them beta e - (embryonic) and beta' e-CaM kinase. Recombinant alpha B-, beta e and beta' e-CaM kinase expressed in COS-7 cells exhibit characteristic Ca2+/calmodulin-dependent protein kinase activity and autophosphorylation.

Aging↗
PubMed1995

The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C.

Opioids are some of the most efficacious analgesics used in humans. Prolonged administration of opioids, however, often causes the development of drug tolerance, thus limiting their effectiveness. To explore the molecular basis of those mechanisms that may contribute to opioid tolerance, we have isolated a cDNA for the human mu opioid receptor, the target of such opioid narcotics as morphine, codeine, methadone, and fentanyl. The receptor encoded by this cDNA is 400 amino acids long with 94% sequence similarity to the rat mu opioid receptor. Transient expression of this cDNA in COS-7 cells produced high-affinity binding sites to mu-selective agonists and antagonists. This receptor displays functional coupling to a recently cloned G-protein-activated K+ channel. When both proteins were expressed in Xenopus oocytes, functional desensitization developed upon repeated stimulation of the mu opioid receptor, as observed by a reduction in K+ current induced by the second mu receptor activation relative to that induced by the first. The extent of desensitization was potentiated by both the multifunctional calcium/calmodulin-dependent protein kinase and protein kinase C. These results demonstrate that kinase modulation is a molecular mechanism by which the desensitization of mu receptor signaling may be regulated at the cellular level, suggesting that this cellular mechanism may contribute to opioid tolerance in humans.

Adolescent↗
PubMed1994

An ADP-ribosyltransferase as a potential target for nitric oxide action in hippocampal long-term potentiation.

Recent studies of long-term potentiation (LTP) in the CA1 region of the hippocampus have demonstrated that nitric oxide (NO) may be involved in some forms of LTP and have suggested that postsynaptically generated NO is a candidate to act as a retrograde messenger. However, the molecular target(s) of NO in LTP remain to be elucidated. The present study examined whether either of two potential NO targets, a soluble guanylyl cyclase or an ADP-ribosyltransferase (ADPRT; EC 2.4.2.31) plays a role in LTP. The application of membrane-permeant analogs of cGMP did not produce any long-lasting alterations in synaptic strength. In addition, application of a cGMP-dependent protein kinase inhibitor did not prevent LTP. We found that the CA1 tissue from hippocampus possesses an ADPRT activity that is dramatically stimulated by NO and attenuated by two different inhibitors of mono-ADPRT activity, phylloquinone and nicotinamide. The extracellular application of these same inhibitors prevented LTP. Postsynaptic injection of nicotinamide failed to attenuate LTP, suggesting that the critical site of ADPRT activity resides at a nonpostsynaptic locus. These results suggest that ADP-ribosylation plays a role in LTP and are consistent with the idea that an ADPRT may be a target of NO action.

2-Amino-5-phosphonovalerate↗