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To identify the binding domain for diltiazem-like Ca2+ antagonists on L-type Ca2+ channel alpha1 subunits we synthesized the benzazepine [3H]benziazem as a novel photoaffinity probe. [3H]Benziazem reversibly labeled the benzothiazepine (BTZ)-binding domain of partially purified skeletal muscle Ca2+ channels with high affinity (Kd = 12 nM) and photoincorporated into its binding domain with high yield (>66%). Antibody mapping of proteolytic labeled fragments revealed specific labeling of regions associated with transmembrane segments S6 in repeats III and IV. More than 50% of the labeling was found in the tryptic fragment alanine 1023-lysine 1077 containing IIIS6 together with extracellular and intracellular amino acid residues. The remaining labeling was identified in a second site comprising segment S6 in repeat IV and adjacent residues. Unlike for dihydropyridines, no labeling was observed in the connecting IIIS5-IIIS6 linker. The [3H]benziazem photolabeled regions must be in close contact to the drug molecule when bound to the channel. We propose that the determinants for high affinity BTZ binding are located within or in close proximity to segments IIIS6 and/or IVS6. Therefore the binding domain for BTZs, like for the other main classes of Ca2+ antagonists, must be located in close proximity to pore-forming regions of the channel.  相似文献   
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Over a period of 4.5 years, 14 patients with frontoethmoidal meningoencephaloceles were treated. Most patients came from Northern Namibia. Precise delineation of all cranial abnormalities was obtained by modern imaging techniques, and specific patterns of cerebral abnormality were found. The malformation was corrected in a single stage, and significant modifications have been developed to render the procedure simpler and safer. Information from our series favors delayed neural tube closure as the primary pathogenesis of the defect and suggests a common teratogen as the most probable etiological agent. Our experience leads us to advocate early correction of even small defects.  相似文献   
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Obstructive sleep apnea syndrome (OSAS) has been associated with a higher than normal cardiovascular morbidity and mortality. Some OSAS patients lack the sleep-related, nocturnal decrease, or \"dip,\" in blood pressure which is seen in normal individuals. These subjects, called \"non-dippers,\" may be at greater risk for cardiovascular problems. We studied 40 OSAS patients (including 3 women) and 6 control subjects, all identified by polysomnography, for nocturnal blood pressure \"dipping.\" We performed a second nocturnal polysomnogram to determine their apnea and hypopnea indices, (A + H)I, and oxygen saturation levels at the beginning of the study and then initiated 48 hours of ambulatory blood pressure monitoring, with data points collected every 30 minutes. Controls, which included one hypertensive subject, were all dippers. Nineteen OSAS subjects (48% of OSAS individuals) were systolic non-dippers and only 9 of them (22.5%) were diastolic non-dippers. We considered the following clinical variables as potential predictors of non-dipping: age, body mass index, respiratory disturbance index, years of reported loud snoring by bed partners, lowest oxygen saturation during nocturnal sleep, and percentage of sleep time spent with oxygen saturation below 90%. Multiple regression analyses indicated respiratory disturbance index as the only significant variable for systolic (p = 0.04) and diastolic (p = 0.03) blood pressure non-dipping. When we forced the following two nonsignificant variables into the model, they showed a very meager impact: number of years with reported loud snoring (p = 0.4 and p = 0.5, respectively for systolic and diastolic blood pressure non-dipping) and age (p = 0.5 and p = 0.6). The calculated model explained only a low percentage of the variance with an r2 of 0.25 and 0.26 for systolic and diastolic blood pressure non-dipping, respectively. Analysis of hypertension/normotension and dipping/non-dipping failed to show a significant relationship in the studied population. Fifty percent of the normotensive OSAS subjects were non-dippers and 43% of the hypertensive OSAS subjects were also non-dippers. We found a relationship between increasing respiratory disturbance index and increasing average 24-hour systolic blood pressure only when OSAS subjects were non-dippers and hypertensive.  相似文献   
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As spinal motor neurons project to their hindlimb targets, their growth cones avoid particular regions along their pathway. T-cadherin is discretely distributed in the avoided caudal sclerotome and on extrasynaptic muscle surfaces (B. J. Fredette and B. Ranscht (1994) J. Neurosci. 14, 7331-7346), and therefore, the ability of T-cadherin to inhibit neurite growth was tested in vitro. T-cadherin inhibited neurite extension from select neuron populations both as a substratum, and as a soluble recombinant protein. Anti-T-cadherin antibodies neutralized the inhibition. Spinal motor neurons were inhibited only during the stages of axon growth across the sclerotome and muscle innervation. Inhibitory responses corresponded to neuronal T-cadherin expression, suggesting a homophilic binding mechanism. These results suggest that T-cadherin is a negative guidance cue for motor axon projections.  相似文献   
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We determined the nucleotide sequences of Norwalk-like viruses in 10 PCR products from stool or oyster specimens obtained from four outbreaks of gastroenteritis in which shellfish was suspected as the cause in Shizuoka prefecture in Japan between 1987-94. The sequences were determined from nucleotide positions 4561-4852 (292 bp) in the polymerase region. Two types of sequences were detected. One (genotype 1) had 87% sequence homology with the prototype Norwalk virus, and the other (genotype 2) had 59% sequence homology. The sequences from isolates belonging to the same genotype were almost the same regardless of the year of isolation. Because sequences of 2 genotypes were detected in 2 of the 4 outbreaks, nested PCR was performed with genotype-specific primers to detect the presence of 2 genotypes in the same specimen. In 5 of 10 specimens, PCR bands were detected with both genotype-specific primers, indicating the coexistence of 2 genotypes in 1 specimen. We also detected two genotypes of Norwalk-like virus in an oyster from a sample implicated in one of the outbreaks which may provide direct evidence of oysters as the cause of the gastroenteritis.  相似文献   
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In an ongoing survey of the bioactive potential of microorganisms associated with marine invertebrates, the culture media of a sponge-associated bacterial strain of Pseudomonas aeruginosa was found to contain metabolites which inhibit the growth of several Gram-positive microorganisms. A series of diketopiperazines (1-6) including a new natural product (6) and two known phenazine alkaloid antibiotics (7 and 8) were isolated from the culture broth of this bacterium.  相似文献   
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