Biomedical subjects
Publications and source records attributed to I Amir.
Schizencephaly rarely presents in the neonatal period. We present the case of a baby girl born with growth retardation and microcephaly who developed seizures on the 3rd day of life. There was no clinical or laboratory evidence of a congenital viral infection but brain imaging revealed widespread calcification and bilateral schizencephaly clefts. By the age of 11 months, she had developed gross psychomotor retardation.
Obsessive-compulsive disorder (OCD) is a severe and disabling anxiety disorder with a marked genetic contribution. Pharmacological data indicated involvement of the serotonergic and dopaminergic systems. We studied the association between OCD and six candidate genes encoding important components of the serotonergic and dopaminergic pathways in 75 biologically unrelated patients and 172 ethnically matched controls (Ashkenazi and non-Ashkenazi Jews). Polymorphisms in the following genes were studied: tryptophan hydroxylase (TPH), serotonin 2A receptor (HTR2A), serotonin 2C receptor (HTR2C), serotonin transporter (5-HTT), dopamine receptor D4 (DRD4), and dopamine transporter (DAT1). The genotypic and allelic distribution of all polymorphisms tested did not show statistically significant differences between patients and controls. Our results suggest that these polymorphisms do not play a major role in the genetic predisposition to OCD, although a minor contribution cannot be ruled out.
Aspirin increases blood alcohol levels after post-prandial alcohol consumption in men. This was attributed to a decrease in first pass metabolism secondary to inhibition of gastric alcohol dehydrogenase. Since accelerated gastric emptying, decreased volume of distribution or delayed elimination could also result in higher blood alcohol levels, we investigated the effect of aspirin (1 g taken with a meal) on these parameters. Aspirin did not change the volume of ethanol distribution or the rate of its elimination. Moreover, it did not have a significant effect on gastric emptying. The half-time of 99Tc-DTPA loss was 65.5+/-5.4 minutes without and 71.3+/-6.5, with aspirin. Despite a trend for slower gastric emptying with aspirin, the alcohol bioavailability increased and was associated with a 39% decrease in the first pass metabolism of alcohol (from 106+/-4 to 65+/-19 mg/kg, p<0.05), consistent with the inhibition of gastric ADH activity. In keeping with this interpretation, the effect of aspirin was virtually absent in women, who have a much smaller first pass metabolism available for inhibition by aspirin.
BACKGROUND: Considering that platelets have been established to be good peripheral markers for the study of catecholaminergic neurons, we have applied an assay to measure the uptake of (3H)-dopamine (DA) into platelet storage granules (PSG). Recently, we reported that Tourette's syndrome (TS) patients (pts) show decreased DA uptake into PSG. METHODS: In the present study, 28 first-degree relatives (3 with chronic motor tics, 3 with transient tics, 6 with obsessive-compulsive behavior, and 16 without symptomatology) belonging to the families of 13 patients, and 14 unrelated healthy controls were studied. RESULTS: Double reciprocal plots were constructed for each subject, and the apparent maximum velocity (Vmax) and Michaelis constant (K(m)) were determined by linear regression analysis (Lineaweaver-Burke plots). The uptake of DA (0.5-5 mumol/L) (mean +/- SEM) by PSG from relatives with symptomatology was similar to the TS patients (symptomatic relatives Vmax 181 +/- 22.2 fmol/mg protein, K(m) (mumol/L) 6.42 +/- 0.29; TS pts Vmax 108 +/- 6.9, K(m) 7.79 +/- 0.64). Relatives without symptomatology on the contrary showed DA affinity characteristics similar to the controls (t test, paired t test, multivariate analysis of variance, and log transformation). CONCLUSIONS: The data presented suggest that TS is hereditary, but they do not distinguish between an autosomal dominant inheritance and a mixed or polygenic model.
The aim of this study of consecutive livebirths between 23 and 30 weeks of gestational age was to determine the changes over time in the relationship between gestational age and the consumption of nursery resources by surviving preterm infants. Three discrete eras, comprising the years 1977-1985, 1986-1990, and 1991-1995, were identified, based on availability of ventilators and changes in perinatal care. The survival rate rose dramatically with each week's increase in gestational age, and increased significantly between successive eras. Overall, consumption of resources for assisted ventilation by survivors increased over time. In infants born before 28 weeks, for each week of decrease in gestational age, survivors averaged an extra 12.9 days of assisted ventilation in 1977-1985, 13.4 days in 1986-1990, and 13.5 days in 1991-1995, while infants born between 28-30 weeks of gestational age needed only an extra 2.3 days, 3.3 days, and 4.6 days of assisted ventilation for each week of decrease in gestational age in successive eras, respectively. There was no indication that improvements in perinatal care over time shortened the duration of assisted ventilation for surviving preterm infants.
The efficacies of four bowel care regimens (bisacodyl suppositories, glycerin suppositories, mineral oil enemas and docusate sodium mini-enemas) were compared in seven subjects with traumatic spinal cord injury. Efficacy was assessed in terms of colonic transit time, bowel evacuation time and subjective responses to a questionnaire. Both docusate sodium mini-enemas and mineral oil enemas decreased total and left-sided colonic transit time. However, docusate sodium mini-enemas were superior to mineral oil enemas in terms of the decrease in bowel evacuation time and symptom reduction. Results in this small group of subjects suggest that docusate sodium mini-enemas may have advantages in the management of bowel evacuation in individuals with spinal cord injury.
Palytoxin, a highly toxic natural product isolated from zoanthids of the genus Palythoa, is accumulated by a wide range of fishes and marine invertebrates used as food in the Indo-Pacific. It is responsible for many incidents of human morbidity and mortality. The toxin is a potent smooth muscle spasmogen. The cause of the contraction of smooth muscle is unclear, but recent work strongly suggests that it is primarily initiated by the release of neurotransmitters from the motor innervation of the smooth muscle. We show here that palytoxin caused the swelling of the muscle cells and some internal organelles of the anococcygeus muscle of the rat, but no substantial structural damage to the tissue. Axons and Schwann cells were also swollen but the most dramatic feature was the depletion of synaptic vesicles from putative release sites in the axons. Some axons were physically damaged following exposure to the toxin, but this was relatively uncommon (< 10% of all axons studied). In the majority of axons there was no damage to nerve terminal membranes, but there was damage to mitochondria. The depletion of vesicles involved all types-clear, dense-cored, large and small. Our observations and pharmacological data gathered elsewhere, provide a neuropathological basis for the spasmogenic activity of palytoxin.
We present two cases of acute nocturnal bruxism occurring as an early side effect of antipsychotic drug treatment. The development of bruxism was coupled with the appearance of neuroleptic-induced akathisia. Both complications were relieved after the beta-adrenergic blocker propranolol was added, suggesting the involvement of the adrenergic and serotonergic central nervous systems, besides the dopaminergic system, in the pathogenesis of bruxism. The positive response of iatrogenic bruxism to propranolol implies that propranolol also deserves a trial for the treatment of noniatrogenic nocturnal bruxism.
We present the case of a 71-year-old female suffering from bipolar affective disorder type 2 and an old lacunar brain infarct who, under the combined treatment of fluoxetine for depression and low dose trazodone for the accompanying insomnia, developed a toxic delirium. The subject presented with mental state changes (confusion and agitation), hyperreflexia, diaphoresis, nausea, vomiting, fever, and a general tonic-clonic seizure which developed soon after an increase in the trazodone dose. One year prior to the above episode, she was hospitalized for a transient episode of agitated confusion while being treated with fluvoxamine for depression, alprazolam and brotazolam for the accompanying anxiety and insomnia. Both episodes subsided spontaneously when treatment was discontinued. This case reports the possible existence of increased vulnerability to hyperserotonergic states in elderly patients suffering from concomitant psychiatric and neurological disorders.
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To investigate the mechanism of the increase in alcohol bioavailability by ranitidine, we determined by nuclear scan the changes in gastric emptying of a 10% ethanol solution (containing 0.3 g ethanol/kg body weight and 300 microCi of technetium-labeled diethylene triamine pentacetic acid) in 8 normal men, before and after treatment with 300 mg ranitidine orally each evening for 1 week. We compared these changes with those of ethanol bioavailability, calculated by integration of the Michaelis-Menten function over the entire alcohol curves after random i.v. and, on a separate day, oral administration of the same ethanol dose, pre- and post-ranitidine. With ranitidine, we found an acceleration of gastric emptying in 7 of 8 subjects, with 20% shortening of the time to 50% emptying (51.8 +/- 4.1 min vs 64.3 +/- 3.4, without ranitidine; P < .001 by paired t test). Despite the disappearance (from the stomach) of most of the dose by the end of the blood alcohol curves, only 83 +/- 4% reached the systemic blood vs 64 +/- 4% without ranitidine (P < .02), most likely because of a shortened exposure of alcohol dehydrogenase to optimal ethanol concentrations. As a result, after oral but not intravenous alcohol administration, ranitidine increased blood alcohol concentrations (29 +/- 4 mg/dl vs 22 +/- 3, without ranitidine; P < .02), with a corresponding decrease in first pass metabolism of ethanol from 107 +/- 16 mg/kg to 47 +/- 16 (P < .01).
Glucocorticoids (GC) are known to inhibit eicosanoid production in various peripheral tissues; however, their role in the regulation of basal and induced prostaglandin (PG) biosynthesis in the brain is still not clear. In the present study we examined the effect of exogenous dexamethasone (dex) or endogenous GC on basal and on bacterial endotoxin (lipopolysaccharide, LPS) induced ex vivo production of PGE2 by the frontal cortex of rat brain. The experimental groups were: 1) intact rats; 2) rats in whom endogenous GC were removed either by surgical or by chemical (metopirone) adrenalectomy (adex); and 3) rats exposed to specific corticosteroid receptor antagonists. In intact rats, the basal rate of PGE2 ex vivo synthesis was about 120 pg/mg protein.hr; dex (0.05-0.5 mg/100 g body wt ip) did not affect this level. Exposure to LPS (50 micrograms, intracerebroventricular) induced a 2-fold increase in PGE2, whereas pretreatment with dex abolished this increase. Bilateral adex or metopirone alone did not change PGE2 synthesis, whereas LPS administration to surgical or chemical adex rats resulted in a 4-fold increase in PGE2 production. Administration (intracerebroventricular) of either one or both of the specific corticosteroid receptor antagonists, RU-28318 (type I) and RU-38486 (type II) did not affect basal PGE2 production. When LPS was given after either one of these antagonists, a slight but significant elevation of PGE2 occurred, as compared to LPS-treated controls. When both antagonists were coadministered, the LPS-induced production of PGE2 was much more pronounced, similar to levels of LPS-treated, adex rats. These results suggest that LPS-induced production of PGE2, but not the basal production, is regulated by either endogenous or exogenous GC, and the inhibitory effect of GC on brain PG synthesis is mediated via both type I and II corticosteroid receptors.
The role of Na + transport systems in the mitogenic signal induced by growth factors was studied, and it was shown that two Na + transport systems contribute to the early increase in cytoplasmic Na + in response to serum growth factors, namely the amiloride-sensitive Na+/H+ antiport and the bumetanide-sensitive Na+/K+/Cl- cotransport. Bumetanide or amiloride, when added separately, inhibited part of the increase in cytoplasmic Na +, as a response to the addition of serum to quiescent BALB/c mouse 3T3 fibroblasts. Each drug also suppressed part of the stimulation of the ouabain-sensitive Rb + influx, which was controlled by intracellular Na +. However, when both drugs were added together with serum growth factors, a complete inhibition of the early increase in [Na +], and subsequently a complete blockage of Na+/K+ pump stimulation was obtained. Amiloride or bumetanide, when added separately, only partially inhibited DNA synthesis induced by serum, 24% and 8% respectively. However, when both drugs were added together, at the time of serum addition to the quiescent cells, cell entry into S-phase was completely inhibited. To investigate the mode of cell-cycle inhibition, analysis was done of the possible role of early Na + fluxes in the mitogenic signal transduced from cell membrane receptors to the nucleus. The effects of the two drugs amiloride and bumetanide on induction of three genes--c-fos, c-myc, and ornithin decarboxylase (ODC)--was measured during cell transition through the G1-phase. Amiloride and bumetanide, when added separately or in combination, did not inhibit the induction of c-fos, c-myc, and ODC mRNAs. These results suggest that stimulation of Na + fluxes by serum growth factors is essential for cell transition into the S-phase of cell cycle, but it plays no apparent role in the growth factor signal transduced from the cell surface to the interior of the cell, as manifested by c-fos, c-myc, and ODC genes induction.
The bumetanide-sensitive transport system performed a net efflux of K+ in serum deprived quiescent cells. The addition of partially purified fibroblast growth factor (FGF) to G0/G1 phase 3T3 fibroblasts induced a transient net influx of K+, carried out by the bumetanide-sensitive transport system for 2-6 minutes. The stimulation of the bumetanide-sensitive K+ influx by FGF was followed by stimulation of the ouabain-sensitive K+ influx. In addition, both the bumetanide-sensitive and the ouabain-sensitive K+ influxes were found to be similarly stimulated when the G0/G1 3T3 cells were treated with insulin. These results suggest that growth factors such as FGF and insulin induce a change in the action of the bumetanide-sensitive transporter from performing net K+ efflux along its concentration gradient to an uphill transport pumping of K+ into the cell. We propose, therefore, that the bumetanide-sensitive transporter contributes to the increase in the intracellular K+ (and probable Na+) stimulated by growth factors such as FGF and insulin in early G1 phase of the cell cycle.
Mouse 3T3 cells transformed by a conditional mutant of Rous sarcoma virus (LA90) can assume either a normal or a transformed phenotype, depending on the temperature of cultivation. These cells (LA90) were arrested at the G0/G1 phase of the cell cycle by starvation for serum growth factors at the nonpermissive temperature (39 degrees C). Release from the G0/G1 phase by serum growth factors resulted in a rapid stimulation of Rb+ influx. To investigate whether the stimulation of Rb+ influx is obligatory for cell proliferation, the cultures were released from the G0/G1 phase by a temperature decrease in the absence of serum. A temperature decrease from 39 to 32 degrees C activated the viral pp60src gene mitogenic activity. Under these conditions, no rapid stimulation of Rb+ influx was observed. These results suggest that the rapid stimulation of Rb+ influx induced by serum growth factors is not an essential signal for cell release from the G0/G1 phase. However, a delayed increase in Rb+ influx concomitant with an increase in the cell content of K+ was observed in the cultures released from the G0/G1 phase by temperature decrease in the absence of serum growth factors. We found that the LA90 cells incubated at the permissive temperature (32 degrees C) secreted a mitogenic activity into the medium. Moreover, the conditioned medium from cultures incubated at 32 degrees C, but not at 39 degrees C, stimulate Rb+ influx in G0/G1 cells. These results indicate that Rous sarcoma virus pp60src induces a slow autocrine secretion of a mitogenic activity. This mitogenic activity slowly modulates the K+ content. Therefore, the slow elevation in cellular content of K+ is proposed to be an obligatory event for proliferation in normal and transformed cells.
Of 82 patients who had obstructing cancer of the left colon, 22% had incurable disease and 36.5% had advanced cancer at presentation. All methods of treatment carried a high morbidity and mortality. The mean survival rate with palliative operations was 8.7 months. Twenty-four poor-risk patients treated with staged operations had a 25% operative mortality and a 20.8% five-year survival rate. Forty primary resections, with or without anastomosis, were followed by a 27.5% operative mortality and by more than a twofold five-year survival rate (47.5%) compared with that of staged resection. These results suggest that delay of cure may reduce the late survival rate and justify primary resection as the operation of choice in selected good-risk patients.
A general formulation of the echo received from a random scatterer ensemble illuminated by a short electromagnetic or sonic signal is developed. It is shown theoretically and confirmed experimentally with ultrasound, that a gradient in scatterer density will return an echo which is partially spatially coherent (i.e. specular). The surface of a random ensemble of uniform scatterers is shown to produce an echo from whose degree of coherence, the scatterer density and cross section can be calculated.
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