Biomedical subjects
H Cohen
Publications and source records attributed to H Cohen.
Guanidinium derivatives act as high affinity antagonists of Na+ ions in occlusion sites of Na+,K(+)-ATPase.
We have screened various alkyl- and arylguanidinium derivatives as possible competitors of Na+ or Rb+ for the cation sites on renal Na+,K(+)-ATPase. Alkyl-monoguanidinium or alkylbisguanidinium (BisG) compounds (chain lengths of C3 to C10) competitively inhibit the occlusion of Rb+ and Na+ with an order of affinities C10 greater than C8 greater than C6 greater than C4 greater than C3. BisG compounds are approximately twice as effective as the equivalent alkylmonoguanidinium compounds. In media of high ionic strength, affinities of tens of micromolar are observed, e.g. 26 microM for BisG 8. m-(mXBG)- and p-xylylenebisguanidinium were synthesized and were found to compete with Rb+ or Na+ with intrinsic affinities of 7.7 and 8.2 microM, respectively. The hydrophobicity rather than the degree of proximity of the guanidinium groups in all BisG compounds appears to determine the binding affinity. A systematic search has been made of conditions in occlusion assays for which the inhibitor affinities are highest. When the pH is raised from 7.0 to 8.5, a 5-fold increase in affinity is observed, suggesting that the guanidinium derivatives compete with protons at sites of pKa approximately 7.5. Replacing Tris-HCl with choline chloride-containing media raised apparent affinities approximately 2-fold. All guanidinium derivatives stabilize the E1 conformation of fluorescein-labeled Na+,K(+)-ATPase, acting as competitive Na+ analogues. In media containing only 1 mM Tris-HCl, pH 8.55, very high affinities were observed for binding to the fluorescein-labeled enzyme (e.g. 0.08 microM for mXBG). In very low ionic strength medium, the inhibition was still competitive with Rb+ ions. However, there was also evidence for nonspecific adsorption to the membranes. The following findings show that mXBG, a typical guanidinium derivative, behaves as a Na(+)-like antagonist. (a) It inhibits Na+,K(+)-ATPase activity, competing strongly with Na+ but only weakly with K+ ions. (b) It inhibits phosphorylation from ATP, competing with Na+ ions. (c) Like Na+ ions, it blocks phosphorylation from inorganic phosphate. Based on these results, we propose that the guanidinium group binds to a relatively wide vestibule at the cytoplasmic surface; but, unlike Na+ or K+ ions, it cannot pass into a narrower region of the cation transport path within the membrane. Therefore, it blocks the occlusion and active transport of cations. In the future, high affinity guanidinium derivatives may serve the purpose of locating cation-binding domains of the pump protein after being converted to reactive affinity or photoaffinity covalent labels.
Habituation and adaptation of the vestibuloocular reflex: a model of differential control by the vestibulocerebellum.
We habituated the dominant time constant of the horizontal vestibuloocular reflex (VOR) of rhesus and cynomolgus monkeys by repeated testing with steps of velocity about a vertical axis and adapted the gain of the VOR by altering visual input with magnifying and reducing lenses. After baseline values were established, the nodulus and ventral uvula of the vestibulocerebellum were ablated in two monkeys, and the effects of nodulouvulectomy and flocculectomy on VOR gain adaptation and habituation were compared. The VOR time constant decreased with repeated testing, rapidly at first and more slowly thereafter. The gain of the VOR was unaffected. Massed trials were more effective than distributed trials in producing habituation. Regardless of the schedule of testing, the VOR time constant never fell below the time constant of the semicircular canals (approximately 5 s). This finding indicates that only the slow component of the vestibular response, the component produced by velocity storage, was habituated. In agreement with this, the time constant of optokinetic after-nystagmus (OKAN) was habituated concurrently with the VOR. Average values for VOR habituation were obtained on a per session basis for six animals. The VOR gain was adapted by natural head movements in partially habituated monkeys while they wore x 2.2 magnifying or x 0.5 reducing lenses. Adaptation occurred rapidly and reached about +/- 30%, similar to values obtained using forced rotation. VOR gain adaptation did not cause additional habituation of the time constant. When the VOR gain was reduced in animals with a long VOR time constant, there were overshoots in eye velocity that peaked at about 6-8 s after the onset or end of constant-velocity rotation. These overshoots occurred at times when the velocity storage integrator would have been maximally activated by semicircular canal input. Since the activity generated in the canals is not altered by visual adaptation, this finding indicates that the gain element that controls rapid changes in eye velocity in the VOR is separate from that which couples afferent input to velocity storage. Nodulouvulectomy caused a prompt and permanent loss of habituation, returning VOR time constants to initial values. VOR gain adaptation, which is lost after flocculectomy, was unaffected by nodulouvulectomy. Flocculectomy did not alter habituation of the VOR or of OKAN. Using a simplified model of the VOR, the decrease in the duration of vestibular nystagmus due to habituation was related to a decrement in the dominant time constant of the velocity storage integrator (1/h0).(ABSTRACT TRUNCATED AT 400 WORDS)
Prospective evaluation of immediate versus delayed refeeding and prognostic value of endoscopy in patients with upper gastrointestinal hemorrhage.
The effects of immediate vs. delayed refeeding and the prognostic value of endoscopic findings in patients with major upper gastrointestinal hemorrhage were assessed in a prospective randomized study. Entry criteria were clinical evidence of major hemorrhage and endoscopic evidence of a Mallory-Weiss tear or an ulcer with a clean base, flat spot, or clot. Two hundred fifty-eight patients were randomly assigned to groups receiving a regular diet immediately or nothing by mouth for 36 hours, then clear liquids for 12 hours, and a regular diet thereafter. Outcomes in the immediate and delayed refeeding groups were comparable: rebleeding occurred in 4% vs. 5%; urgent intervention, 2% vs. 2%; and deaths, 1% vs. 1%, respectively. Rebleeding occurred in 2 (2%) of 96 patients with cleanbased ulcers, 5 (8%) of 65 with ulcers with spots, 3 (14%) of 21 with ulcers with clots (P = 0.05, 3 x 2 chi2 test), and 1 (2%) of 66 with Mallory-Weiss tears. It is concluded that the time of refeeding does not influence the hospital course of patients with a low risk of recurrent bleeding. Patients with clean-based ulcers or nonbleeding Mallory-Weiss tears may be refed and discharged home immediately after stabilization.
Differential regulation of the rat phosphoenolpyruvate carboxykinase gene expression in several tissues of transgenic mice.
The selective expression of a unique copy gene in several mammalian tissues has been approached by studying the regulatory sequences needed to control expression of the rat phosphoenolpyruvate carboxykinase (PEPCK) gene in transgenic mice. A transgene containing the entire PEPCK gene, including 2.2 kb of the 5'-flanking region and 0.5 kb of the 3'-flanking region, exhibits tissue-specific expression in the liver, kidney, and adipose tissue, as well as the hormonal and developmental regulation inherent to endogenous gene expression. Deletions of the 5'-flanking region of the gene have shown the need for sequences downstream of position -540 of the PEPCK gene for expression in the liver and sequences downstream of position -362 for expression in the kidney. Additional sequences upstream of position -540 (up to -2200) are required for expression in adipose tissue. In addition, the region containing the glucocorticoid-responsive elements of the gene used by the kidney was identified. This same sequence was found to be needed specifically for developmental regulation of gene expression in the kidney and, together with upstream sequences, in the intestine. The apparently distinct sequence requirements in the various tissues indicate that the tissues use different mechanisms for expression of the same gene.
Cholecystokinin and satiety: effect of hypothalamic obesity and gastric bubble insertion.
Cholecystokinin (CCK) is a gut peptide whose proposed effect on satiety is thought to be related to gastric volume and to be signaled through vagal afferent fibers to the medial hypothalamus. To test these hypotheses we infused CCK C-terminal octapeptide (CCK-8) or saline in a random double-blind fashion in three groups of subjects: 17 obese subjects, 6 of whom subsequently received a gastric bubble, and 5 obese subjects whose obesity was due to hypothalamic injury. The number of sandwich canapes eaten after saline or CCK-8 infusion was recorded during three consecutive 10-min eating periods. Each subject served as his/her own control. The prior infusion of CCK-8 significantly decreased the consumption of sandwich canapes in the first eating period in both the control obese subjects and the subjects with obesity due to hypothalamic injury. Insertion of a gastric bubble did not enhance the satiety effect of CCK-8. These studies support the hypothesis that CCK produces satiety in a time-dependent manner that is not enhanced after the insertion of a gastric bubble but is operative in obese subjects with hypothalamic injury.
Vestibular rehabilitation reduces functional disability.
Vertigo caused by vestibular disorder may be successfully treated with a physical therapy program of graded exercises to habituate the patient to the vertiginous stimulus and to increase the range of motion through which the patient can tolerate moving. Performance on daily self-care tasks is an important indicator of the patient's tolerance for head movement and the success of treatment. In this study, self-care skill in subjects with labyrinthine and brainstem lesions before and after receiving vestibular rehabilitation was examined. Subjects improved significantly after physical therapy, demonstrating greater independence in their abilities to care for themselves. These data provide further support for the value of vestibular rehabilitation procedures.
[Prevalence of gallbladder lithiasis in a Uruguayan population].
Ultrasound examinations were carried out in 693 volunteers from the health care personnel of the Hospital de Clinicas of Montevideo, with the aim of studying the prevalence of gallbladder gallstones in Uruguay, the proportion of symptomatic and asymptomatic people and its association to some definite risk factors. The prevalence found was 10.4%, which, according to the sample's size, is representative of the general population with a confidence of 99%. Sixty five per cent of gallstones carriers were asymptomatic. A statistically significant association with the following factors was found: people between 31 and 50 years old, slight obesity, and, for women, to have children. A marked tendency with the following factors was found, though it was not statistically significant: female sex, and a familiar history of mother carrying gallstones. Considering all these factors as a whole, the probability of having gallstones reached 19%. Results are discussed and compared with those of foreign publications. It is concluded that uruguayan people with more possibilities of having gallstones are: women between 31 and 50 years old, obese, with children, and whose mother has or had the same disease.
Botulinum toxin treatment of spasmodic torticollis.
We reviewed the efficacy and adverse effects of repeated botulinum toxin injections into hyperactive neck muscles of 107 successive patients with spasmodic torticollis. They received 510 injection treatments over a median period of 15 months (range 3-42 months). One patient failed to benefit at all, but 101 (95%) patients reported considerable (moderate or excellent) benefit from at least one treatment. On a global subjective response rating, 93% of 429 treatments resulted in some improvement and 76% in moderate or excellent improvement. Pain reduction followed 89% of 190 treatments with moderate or excellent reduction after 66%. Median duration of benefit was 9 weeks. All torticollis types responded equally well and injections into two (or more) involved neck muscles were more effective than injection into a single muscle. The most frequent adverse effect was dysphagia, occurring after 44% of all treatments, but this was severe after only 2%. Antibodies to botulinum toxin were detected in the serum of three out of the five patients in whom loss of treatment efficacy occurred. We conclude that botulinum toxin treatment is the most effective available therapy for spasmodic torticollis and practical advice is provided for anyone wishing to set up the technique.
New drugs on the horizon.
The agents covered in this article are useful in a wide range of illnesses, including infections, cancers, cardiovascular and gastrointestinal diseases, and others. One of the major forces driving the development of new drugs is the use of biotechnology. Biotechnology encompasses the techniques of recombinant DNA and monoclonal antibody technologies to produce protein drugs that have not been previously available in sufficiently pure form or in adequate quantities. As new drugs are developed, the authors hope that intensified efforts will be geared towards the development of unique drugs that offer important therapeutic gains.
The team approach to treatment of the dizzy patient.
This report describes how a rehabilitation team treats dizziness and vestibular disorders. Team members include a nurse, physician, audiologist, physical therapist, occupational therapist, and a research scientist. Although unusual, this multidisciplinary approach, involving a close-knit group of professionals, is of great benefit in the treatment of vestibular and balance disorders.
Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension.
BACKGROUND: To test the prognostic value of plasma renin activity prospectively, we determined the pretreatment renin-sodium profile of 1717 subjects with mild-to-moderate hypertension (mean age, 53 years; 36 percent white; 67 percent men) in a systematic work-site treatment program. METHODS: Renin profiles, obtained by plotting plasma renin activity against the urinary excretion of sodium, were classified as high (12 percent of the subjects), normal (56 percent), and low (32 percent), and there were expected variations according to age, sex, and race. Modified stepped-care treatment for hypertension, prescribed without reference to the renin profile, was similar in the three renin groups. RESULTS: Mean (+/- SD) blood pressure at entry was 151 +/- 19/100 +/- 10 mm Hg in the subjects with a high renin profile, 151 +/- 19/97 +/- 10 mm Hg in those with a normal profile, and 151 +/- 20/96 +/- 11 mm Hg in those with a low profile. During 8.3 years of follow-up, there were 27 myocardial infarctions. As adjusted for age, sex, and race, the incidence of myocardial infarction per 1000 person-years was 14.7 among the subjects with a high renin profile, 5.6 among those with a normal profile, and 2.8 among those with a low profile (rate ratio for high vs. low, 5.3; 95 percent confidence interval, 3.4 to 8.3). The rate of mortality from all causes was 9.3 in the high-profile group, 5.3 in the normal-profile group, and 3.9 in the low-profile group. The independent association of a high renin profile with myocardial infarction (but not with stroke or noncardiovascular events) was affirmed by Cox analyses (rate ratio for high vs. normal plus low, 3.2; 95 percent confidence interval, 1.2 to 8.4) after adjustment for race, sex, age at entry, serum cholesterol level, smoking status, electrocardiographic evidence of left ventricular hypertrophy, blood glucose level, body-mass index, history of cardiovascular disease or treatment, blood pressure, and use of beta-blockers. CONCLUSIONS: In the study population, whose blood pressure before and during treatment was in a narrow range, and after other cardiovascular risk factors had been considered, the renin profile before treatment remained independently associated with the subsequent risk of myocardial infarction.
Lack of effect of granulocyte-macrophage and granulocyte colony-stimulating factors on cultured human endothelial cells.
The hematopoietic growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), enhance the effector functions of mature myeloid cells, including the interaction with vascular endothelium. We examined the direct effect of recombinant human GM-CSF (rhGM-CSF) and recombinant human G-CSF (rhG-CSF) on the growth and function of cultured human umbilical vein endothelial cells (HUVEC). Endothelial cell growth supplement (ECGS) increased the proliferation of passaged and primary cells by 305% +/- 45% (mean +/- SEM, n = 5, P less than .01) over control cells at 4 days; GM-CSF and G-CSF had no effect. Endothelial cell procoagulant activity was increased after 4-hour incubation with recombinant interleukin-1 beta (IL-1 beta) 10 U/mL and recombinant tumor necrosis factor (TNF) 10 U/mL to 1,721% +/- 376% (n = 7, P less than .005) and 247% +/- 71% (n = 4) of control levels, respectively. gamma-Interferon (gamma-IFN) 50 U/mL had no direct effect of its own but was able to prime the response to IL-1 beta. There was no direct or priming effect of GM-CSF (1 ng to 1 microgram/mL) on the expression of procoagulant activity in endothelial cells. GM-CSF and G-CSF (1 ng/mL to 1 microgram/mL) had no effect on the expression of either tissue plasminogen activator (tPA) or plasminogen activator inhibitor-1 (PAI-1) by endothelial cells. The secretion of tPA by endothelial cells was increased, however, after 24-hour incubation with thrombin 4 U/mL (314% +/- 72% of control levels, n = 5, P less than .025). The production of PAI-1 was increased by TNF 200 U/mL (241% +/- 44% of control, n = 3, P less than .005), thrombin 4 U/mL (180% +/- 12% of control, n = 5, P less than .0005) and IL-1 beta 10 U/mL (275% +/- 44% of controls, n = 5, P less than .0005). In four experiments, endothelial cells showed no specific binding of 125I-GM-CSF, whereas peripheral blood (PB) neutrophils demonstrated the presence of 802 +/- 78 high-affinity receptors for GM-CSF. Thus, we found no effect of rhGM-CSF or rhG-CSF on the proliferation activities by these cells. These findings are in accordance with the lack of demonstrable receptors for GM-CSF on cultured HUVEC.
Anesthesia for patients with preeclampsia.
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Visual motion perception from stimulation of the human medial parieto-occipital cortex.
Visual phenomena evoked by direct electrical stimulation of extrastriate cortex were observed in 30 epileptic patients as part of a presurgical investigation. An incremental sequence of low-level bipolar stimulation trains was delivered at medial and lateral pairs of contacts of stereotaxically-implanted multilead intracerebral electrodes in parietal, occipital and posterior temporal regions. Diffusion of stimulus afterdischarges was monitored by electrodes in temporal and frontal lobes and by the non-stimulated contacts of the stimulated electrode. Localized stimulations evoked few visual phenomena. The strongest anatomo-perceptual correlation was found for stimulation in the medial parieto-occipital fissure which evoked visual motion phenomena in all three patients stimulated in that region. The evoked motion perceptions were not associated with eye movements or any particular localization of the epileptic focus. These perceptions were only evoked once outside of the medial PO region at the 61 sites examined. The results suggest that the medial parieto-occipital region is closely linked to the human visual motion processing system.
Helicobacter pylori infection in pernicious anemia: a prospective controlled study.
Although some authors believe that Helicobacter pylori is the etiologic agent in chronic nonspecific gastritis, it has also been suggested that the bacterium colonizes inflamed mucosa as a secondary event. This study documents the prevalence of H. pylori in 28 patients with pernicious anemia and compares the findings with those of a group of 28 age-, race-, and sex-matched asymptomatic control subjects. All subjects underwent endoscopy with biopsy of the gastric antrum and corpus. A sample of serum was obtained before endoscopy for determination of antibodies (immunoglobulin A and immunoglobulin G) to H. pylori. The prevalence of H. pylori (by biopsy) in patients with pernicious anemia was significantly less than that in controls (11% vs. 71%, P less than 0.0001). All patients with pernicious anemia had abnormalities of corpus histology (inflammation and/or atrophy). In addition, 50% of patients with pernicious anemia had a lymphocytic infiltration of the antrum. All controls with H. pylori had gastritis, 50% having active chronic gastritis. Atrophic changes of the corpus were more commonly found in patients with pernicious anemia (75% vs. 7%, P less than 0.0001). Serology and biopsy results correlated poorly in the patients with pernicious anemia: all 5 patients with positive serology results had negative biopsy results, whereas all 3 patients with positive cultures on biopsy had negative serological studies. In conclusion, patients with pernicious anemia are protected from infection with H. pylori, and H. pylori does not passively colonize mucosa inflamed by an unrelated process.
Auditory lateralization for speech in language-impaired children.
The ability of five language-impaired (LI) children and five matched controls, aged 7-10 years, to discriminate natural pairs of consonant-vowel syllables contrasted on place of articulation and voicing, presented to the right or left ear with white noise in the contralateral ear, was investigated. The general pattern of errors indicated that LI children had more difficulty than controls in discriminating place of articulation contrasts only when they were presented to the left ear, as well as a difficulty in discriminating voice contrasts selective to the right ear. The results are discussed in terms of acoustic integration and suggest that bihemispheric dysfunction is a basis for specific language impairment.
Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma.
The NOD mouse is studied as an animal model of human insulin-dependent diabetes mellitus (IDDM). To evaluate the role of IFN gamma in the pathogenesis of the disease, we have studied the effect of anti-IFN gamma mAb on the expression of insulitis and clinical diabetes. Treatment of mice with anti-IFN gamma mAb prevented the induction of early IDDM by cyclophosphamide as well as the adoptive transfer of diabetes by spleen cells from diabetic NOD mice. The protection against induction of diabetes by cyclophosphamide was observed in animals treated with the anti-IFN gamma mAb within 24 h following the first cyclophosphamide injection but not in animals in which mAb treatment was started 7 days later. Transfer of disease was prevented both in adult irradiated and in newborn recipients. The absence of clinical signs in these mice was corroborated by a significant reduction of both the extent and severity of insulitis. Over-expression of Ia antigen on endothelial cells lining the islets was also considerably reduced in mice treated with mAb. These data strongly suggest a role for IFN gamma during the autoimmune process leading to beta cell destruction in diabetes and prompt further investigation of the use of such antibodies in the immunoprevention of IDDM.