Showing papers by "Rappaport Faculty of Medicine published in 1997"

Mechanism of 6-hydroxydopamine neurotoxicity

Abstract: The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) has recently been found to be formed endogenously in patients suffering from Parkinson’s disease. In this article, we highlight the latest findings on the biochemical mechanism of 6-OHDA toxicity. 6-OHDA has two ways of action: it easly forms free radicals and it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV. The inhibition of respiratory enzymes by 6-OHDA is reversible and insensitive towards radical scavengers and iron chelators with the exception of desferrioxamine. We conclude that free radicals ate not involved in the interaction between 6-OHDA and the respiratory chain and that the two mechanisms are biochemically independent, although they may act synergistically in vivo.

Activated protein C resistance can be associated with recurrent fetal loss

Abstract: As thrombosis of placental vessels may result in recurrent fetal loss, we analysed 39 consecutive women with recurrent fetal loss of unknown cause for activated protein C resistance. Factor V Leiden (FVL) mutation (19 cases) or APC resistance without FVL (nine cases) were found among these 39 women. Evaluation of 128 pregnancies in 19 patients with factor V Leiden mutation and 56 gestations in nine women with acquired APC resistance, revealed over 50% first-trimester abortions and 17% late abortions. Intra-uterine fetal death occurred in nine out of 19 FVL patients (47%). Only 34 of 184 gestations (18%) in hereditary or acquired APC-resistance women resulted in a live birth, with 11 of the 34 (32%) being premature deliveries. These data suggest that, in some patients with recurrent fetal loss, hereditary and acquired APC resistance are potential causes of vascular placental insufficiency.

Y chromosomes of Jewish priests

Abstract: According the biblical accounts, the Jewish priesthood was established about 3,300 years ago with the appointment of the first Israelite high priest. Designation of Jewish males to the priesthood continues to this day, and is determined by strict patrilineal decent. Accordingly, we sought and found clear differences in the frequency of Y-chromosomes haplotypes between Jewish priests and their lay counterparts. Remarkably, the difference is observable in both Ashkenazi and Sephardic populations, despite the geographical separation of the two communities.

Nocturnal melatonin onset is phase locked to the primary sleep gate

Abstract: In this study, we used the "ultrashort sleep-wake paradigm" (7/13), which measures sleep propensity three times an hour for 29 h, from 0700 to 1200 the next day, on 6 healthy male subjects concomitantly with melatonin plasma level. Melatonin was measured once an hour during the morning and early afternoon of the first day and three times an hour from 1600 to 1000 the following morning. Rectal temperature was measured continuously for four subjects. Subjects underwent the 7/13 paradigm three times, and in all three sessions consistent phase relationships were found between the nocturnal onset of melatonin secretion and opening of the nocturnal sleep gate; also, there was an inverse relationship between melatonin and core body temperature and an almost perfect out-of-phase relationship between sleep propensity and temperature, with the temperature peak falling precisely in the middle of the "forbidden zone" for sleep, i.e., the early evening nadir in sleepiness. On the basis of these phase relationships and previous findings from our laboratory on the effects of exogenous melatonin on the sleep propensity function, we conclude that melatonin participates in sleep-wake regulation in humans.

Improved efficiency Sos recruitment system: expression of the mammalian GAP reduces isolation of Ras GTPase false positives

Abstract: The Sos recruitment system (SRS) is a novel genetic method for detecting protein-protein interactions. The method is based on localizing Sos, a Ras guanyl nucleotide exchange factor (GEF), to the plasma membrane through interaction between two fusion proteins. Mammalian Ras can bypass the requirement for a functional Ras GEF and represents a predictable false positive in this system. This report demonstrates that introduction of mammalian GTPase activating protein (mGAP) reduces the isolation of Ras false positives in SRS screens of mammalian cDNA libraries, thereby significantly enhancing the efficiency of the system.

Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS).

Abstract: J. GEORGE, M. BLANK, M. HOJNIK, E. BAR-MEIR, T. KOIKE*, E. MATSUURA*, M. LORBER†,M. AVIRAM‡ & Y. SHOENFELDResearch Unit of Autoimmune Diseases, Department of Medicine ‘B’, Sheba Medical Centre,Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel, *Department of Medicine II,Hokkaido University School of Medicine, Sapporo, Japan, and † Clinical Immunology Unit and ‡ Lipid Research Laboratories,Rambam Medical Centre and the Bruce Rappaport Faculty of Medicine, Technion, Israel(Accepted for publication 30 January 1997)SUMMARYOx-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleteriousinfluences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate bymacrophages, leading to foam cell formation. APS is characterized by repeated venous and arterialthromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence ofantibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospho-lipids bear structural resemblance to LDL, and several studies have indeed proved that aPL displaycross-reactivity with anti-Ox-LDL antibodies. In this study we assessed the capacity of oxidized andnative forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice.Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinicalpicture resembling APS in humans. Subsequently, the mice were infused with either Ox-LDL, nativeLDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox-LDL werefound to exhibit a significantly more severe form of the disease in comparison with native LDL- andPBS-infused mice, expressed by lower platelet counts (261000/mm

A membrane-fixed, truncated isoform of the human growth hormone receptor

Abstract: Previously, we reported the identification of a new human GH receptor (hGHR) messenger RNA species that encodes a smaller hGHR isoform, termed hGHRtr. Its messenger RNA is expressed in several human tissues and predicts a severely truncated GHR protein that lacks 97.5% of the intracellular domain. Because these two hGHR isoforms, which display similar binding affinity, are coexpressed in several tissues, they may reside side by side and, therefore, interrelate. To further characterize the biological properties of hGHRtr in comparison with hGHR, we generated Chinese hamster ovary (CHO) cell lines stably expressing each of these hGHR isoforms. Cross-linking of [125I]hGH to CHO/hGHRtr cells revealed a majored specific complex with apparent Mr of approximately 100 kDa, which would indicate the hGHRtr to be in molecular mass form of about 80 kDa. When compared with CHO/hGHR, CHO/hGHRtr cells secreted higher amounts of soluble GH-binding protein (GHBP). In contrast to CHO/hGHR cells, CHO/hGHRtr cells did not exhibit any GH-induced receptor down-regulation, and internalization was markedly reduced. Analysis of the constitutive turnover of cellular hGHR and soluble GHBP showed that incubation of CHO/hGHR cells with cycloheximide caused parallel disappearance of hGHR and GHBP. This contrasted with the stability of GHRtr, which showed no decline after cycloheximide treatment for up to 4 h, suggesting that the bulk GHRtr and GHBP may be derived from preformed proteins. Thus, in contrast to hGHR, hGHRtr is fixed at the cell membrane; it undergoes minimal internalization, no down-regulation by hGH, no constitutive turnover for as long as 4 h, but increased capacity to generate a soluble GHBP. Because hGHRtr failed to undergo ligand-induced internalization, the source of the continuous, undisturbed GHBP released into the medium may be from an intracellular storage pool. The relative abundance of these two hGHR isoforms, through regulation of splicing, could be of critical importance in modulating the biological effects of GH.

Alterations in R–R variability associated with experimental motion sickness

Abstract: Motion sickness is a complex integration of responses from multiple physiological systems. Whether the changes that occur during the time course of motion sickness are mediated by the sympathetic or parasympathetic systems is still controversial. The present study evaluates alterations in R-R variability during experimental motion sickness in motion sick and non-motion sick subjects. Ten motion sick subjects and 7 non-motion sick subjects participated in the study. Power spectrum analysis of R-R variation was conducted for all subjects 10 min before a brief vestibular disorientation test (BVDT), for 5-10 min of the test, and 10 min after the test. Subjects were also asked to report their symptoms during the test. The motion sick group showed a significant reduction in the power spectrum density of the R-R interval at the mid and high frequencies during the BVDT test period (BVDT), in comparison with the rest period (Rest). These changes probably indicate a decrease in parasympathetic activity during the time course of motion sickness. The non-motion sick group did not show significant differences at any of the frequencies during BVDT. Power spectrum analysis of the R-R interval provides an objective measure of the autonomic response to experimental motion sickness.

Cyclosporin A in Hyperimmunoglobulin E Syndrome

Abstract: Background The hyperimmunoglobulinemia E syndrome is a serious disorder of an unknown etiology without effective treatment. Cyclosporin A has immunosuppressive properties. Its effect in a patient with hyperimmunoglobulinemia E syndrome was evaluated. Methods We report a 3-year-old boy with severe hyperimmunoglobulinemia E syndrome in whom various therapeutic modalities were ineffective. He was started on cyclosporin A 3 mg/kg/day for 6 months. We examined several humoral and cellular immune functions during the treatment period and monitored his clinical condition. Results Marked improvement in his clinical condition was observed during therapy with cyclosporin A. There was a significant decrease in serum IgE and significant increase in neutrophil chemotactic function. No change in CD40 ligand expression was observed. Cyclosporin A blood level did not exceed 150 ng/mL during the study. Conclusions A small dose of cyclosporin A (3 to 5 mg/kg/day) is beneficial in patients with hyperimmunoglobulinemia E syndrome. It should be considered in severe cases where other therapeutic modalities have failed.

Capsaicin--an Effective Topical Treatment in Pain

Abstract: A number of articles published in the past 5 years have focused on capsaicin a pungent and irritating ingredient found in red hot peppers tbat has safely and successfully been used in the treatment of various painful conditions; e.g. postherpetic neuralgia, painful diabetic neuropathy, painful musculo-skeletal conditions like fibromyalgia and arthritis, hypersensitive bladder disease, postmastectotny pain syndrome, cluster headache, and others. Tbis paper synthesizes data regarding the properties and the clinical use of capsaicin, obtained from Medline searches of original articles and review articles published in tbe past 5 years in North American and European publications.

Severe reversible cardiomyopathy associated with systemic vasculitis in primary Sjogren's syndrome

Abstract: A 40y old woman with primary Sjogren's syndrome developed elevated purpura, peripheral neuropathy, muscular tenderness, abdominal pain, heart failure, and convulsive spells. The hallmarks of this disease were high titers of anti-Ro antibodies and low complement levels in the serum, leukocytoclastic small vessel vasculitis in the cutaneous biopsy specimen, and a life threatening clinical course. Echocardiography revealed left ventricular hypokinesis with low ejection fraction, which is unlike the more common features of cardiomyopathy complicating Sjogren's syndrome. The rapidly deteriorating heart failure and other systemic complications remitted on pulse corticosteroid and cyclophosphamide therapy. The pathogenesis of heart failure, which appeared concurrently with vasculitis and was reversed on immunosuppressive therapy, is explained in the context of the systemic disease. Leukocytoclastic vasculitis might be at the origin of this rare variant of acute, severe but reversible cardiomyopathy in pSS.

Immunohistochemical Localization of Gonadotropin and Gonadal Steroid Receptors in Human Pineal Glands

Abstract: Recently, we demonstrated that melatonin secretion was increased in male patients with GnRH deficiency and decreased to normal levels during testosterone treatment. These data suggested that gonadal steroids modulate melatonin secretion, probably by activating specific receptors in the pineal gland. We used immunohistochemistry to localize gonadotropin (LH and FSH) and gonadal steroid (androgens and estrogens) receptors in human pineal glands. Tissues were obtained at autopsy from 25 males, aged 19–87 yr, and five prepubertal children, aged 0.2–10 yr. Positive staining for all four types of receptors (LH, FSH, androgen, and estrogen) in the pineal parenchymal cells, pinealocytes, was evident in all 30 glands examined. Double staining revealed that nuclear receptors (androgen or estrogen) coexisted with cytoplasmatic receptors (LH or FSH) in the same cells. The results demonstrate the presence of gonadotropin and gonadal steroid receptors in human pinealocytes from infancy to old age.

Fetal pyelectasis in consecutive pregnancies: a possible genetic predisposition

Abstract: Mild fetal pyelectasis is a relatively common finding. The objective of this study was to assess its recurrence rate in subsequent pregnancies. The study comprised 420 women with two consecutive normal uncomplicated pregnancies screened at 15-24 weeks' gestation by ultrasound. Pyelectasis was defined as a fetal pelvis of 4 mm or more in its anterior-posterior dimensions. Of 64 fetuses with pyelectasis, 43 (67%) had a recurrence of this finding in their subsequent pregnancy. Compared with normal fetuses, those with pyelectasis had a relative risk of 6.1 to have a recurrence of this finding in their next pregnancy (95% confidence interval, 4.3-7.5, p < 0.001). These results suggest a predisposition for pyelectusis that may be influenced by genetic and/or environmental factors. More data are needed before an accurate adjustment based on previous results can be made.

Pediatric and Geriatric Tinnitus.

Abstract: The subject of tinnitus in the population extremes-children and the elderly-is ignored by the literature, probably because children do not complain of tinnitus spontaneously, whereas it is only one challenge among other major health problems in the elderly. A short review of the literature on this subject is presented. Presby tinnitus, defined as tinnitus that accompanies the progressive hearing loss of presbycusis is classified as: type 1 (normal aging affecting the cochlea), and type II (preexistent sensorineural hearing loss accompanied by multiple systemic complaints, especially of sensory ones). The incidence of tinnitus in presbycusis is 11%. Like in other age groups, there is no significant gender predilection in the prevalence of tinnitus, but a correlation was demonstrated between the severity of tinnitus and exposure to noise. Hypertension was associated with a lower incidence of tinnitus, as compared to normotension and hypotension. Several treatment modalities of geriatric tinnitus are reviewed: the superiority of the band-noise masker in patients with presbycusis, as compared to electrical promontory stimulation; arnino-oxyacetic in presbycusis and Meniere's disease; zinc supplementation in marginally zinc-deficient elderly patients in improving sensorineural hearing loss and tinnitus; aeration of the middle ear in presbycusis caused by secretory otitis media. Pediatric tinnitus has an incidence of 13% in children who passed an audiometric screening test, and 23-60% in those with hearing loss, 44% in secretory otitis media, but only 3% complain spontaneously because that the child considers tinnitus to be a normal event. There is no significant difference between children with tinnitus and those without in terms of hearing level, age, gender, or etiology of the deafness. Despite the fact that often children do not mention it, tinnitus may incite behavioral problems.

Histochemical properties of upper airway muscles: comparison of dilator and nondilator muscles

Abstract: The upper airway dilator muscles (UADMs) represent a subgroup of muscles in the pharyngeal area which, in addition to their roles in mastication, vocalization, etc., also have an important respiratory function. Failure of these muscles to maintain upper airway patency during sleep is important in the development of the obstructive sleep apnoea syndrome. In the present study, we evaluated the histochemical properties of the UADMs and compared them to those of neighbouring muscles without respiratory functions, and to the diaphragm, to determine whether the UADMs are specifically adapted to their respiratory role. Our results, both in dogs and rats, indicate that the dilator and nondilator upper airway muscles are similar and differ from the diaphragm. In rats, there were significantly less type I fibres (<12% as compared to 42% for the diaphragm) and more type IIb fibres (39-67% as compared to 27% for the diaphragm). A similar pattern was seen in dogs: type I fibres <38% as compared to 46% for the diaphragm, and type IIb fibres, 29-35% as compared to 10% for the diaphragm. These findings suggest that the upper airway dilator muscles are not specifically designed for their respiratory role. They may fail in the presence of increased loads, often encountered in patients with obstructive sleep apnoea, unless appropriate adaptive structural changes take place.

Complications of miniplate osteosynthesis in the treatment of mandibular fractures.

Abstract: Miniplate osteosynthesis with 2.0-mm screws is being increasingly utilized in the treatment of mandibular fractures, midface fractures, zygomatic fractures, orthognathic surgery, and in craniomaxillofacial surgery. It enables better anatomic reduction, better stability of fracture lines, quick recovery and return of function. To examine complications related to its use, data were compiled from the preoperative, immediately postoperative, and 6-months' postsurgery examinations of 143 patients with isolated mandibular fractures. Sixteen of the patients (11.2%) presented with postoperative complications that were related to the miniplate system. The authors' experience and data support the theory that the complication rate is related more to the surgical approach and technique than to the time elapsed between injury and operation.

Orbital Metastasis of Renal Cell Carcinoma Masquerading as Amaurosis Fugax

Abstract: Renal cell carcinoma (RCC) is the most common malignancy involving the kidney. Only rarely does it metastasize to the eye and orbit, sometimes mimicking other lesions. A 70-year-old woman was referred from neurology because of a right orbital lesion, six months after the start of a neurological investigation because of amaurosis fugax. Six months earlier she had complained of transient visual disturbances in her right eye. After excluding cardiovascular abnormalities and coagulopathies as the source of her complaints, she was diagnosed as having a right senile ptosis. A computed tomography scan, done to complete the workout, detected a right orbital mass. The patient was referred to the oculoplastic unit. A biopsy and then a lateral orbitotomy were performed. Histopathological examination proved it to be a metastatic renal cell carcinoma, seven years after the primary tumor had been diagnosed and treated by nephrectomy. The characteristics of metastatic renal cell carcinoma are discussed, in view of the rarity of metastasis to the eye and, in particular, to the orbit, and its tendency to masquerade as other lesions or symptoms. In this case it presented as amaurosis fugax before other signs appeared.

Involvement of the IP3 cascade in the damage to guinea-pig ventricular myocytes induced by cytotoxic T lymphocytes.

Abstract: We have shown previously that the interaction between cytotoxic T lymphocytes (CTL) and ventricular myocytes, an in vitro model for heart transplant rejection, results in electrophysiological and morphological alterations indicative of overload of the intracellular [Ca2+] ([Ca2+]i). Since these deleterious effects cannot be accounted for by increased L-type Ca2+ current (ICa,L), we hypothesize that [Ca2+]i overload due to Ca2+ release from intracellular stores, e.g. sarcoplasmic reticulum (SR), is initiated by CTL-induced activation of the inositol trisphosphate (IP3) cascade. Patch-clamp and fura-2-fluorescence techniques were utilized to record transmembrane potentials and [Ca2+]i from ventricular myocytes bound to peritoneal exudate CTL (PEL). In ventricular myocyte-PEL conjugates (after 60 min), resting potential was reduced (compared with the nonconjugated state) from –80.9 ± 0.7 to –59.9 ± 2.5 mV, action potential amplitude from 139.5 ± 1.4 to 80.6 ± 1.7 mV and action potential duration to 50% repolarization (APD50) from 797 ± 97 to 52 ± 12 ms. The ratio of fluorescence at 340 and 380 nm (R340/380) increased from a control value (in nonconjugated myocytes) of 0.71 ± 0.02 to 2.07 ± 0.03, 30 min after conjugate formation, and exceeded 4.0 at 60 min, before myocyte destruction. Heparin (50 μg/ml), an antagonist of IP3-induced Ca2+ release from SR channels, or U-73122 (2 μM), a phospholipase C (PLC) inhibitor (drugs were included in the pipette solution), prevented PEL-induced morphological and electrophysiological alterations. Accordingly, heparin attenuated the PEL-induced increase in [Ca2+]i; after 60 min of PEL-myocyte interaction, R340/380 was 1.15 ± 0.09 (compared with approximately 4.0 in the absence of heparin). The results indicate that CTL-mediated damage to ventricular myocytes is, at least partially, mediated by PLC activation and IP3-induced Ca2+ release from intracellular stores. Pharmacological targeting of IP3 in heart transplant rejection is thus suggested.

Cigarette smoke induced oxidation of human plasma proteins, lipids, and antioxidants; selective protection by the biothiols dihydrolipoic acid and glutathione.

Abstract: SummaryExposure of human plasma to gas-phase cigarette smoke (CS) causes loss of human plasma antioxidants, protein modification (Frei et al, Biochem J, 1991 277:133–138; Reznick et al, Biochem J, 1992 286: 607–611) and a minimal amount of lipid oxidation. Ascorbic acid was found to prevent CS-induced lipid peroxidation and glutathione (GSH) partially protected against protein modification, as determined by loss of protein -SH groups and by increases in carbonyl content as a measure of protein oxidation. In the present study we demonstrate that dihydrolipoic acid (0.25–1.0 mM) decreases CS-induced protein carbonyls, α-tocopherol loss, and lipid hydroperoxide formation in plasma. In contrast GSH (1 mM) failed to influence CS-induced loss of α-tocopherol, and was 50% as effective as dihydrolipoate in protecting against CS-induced protein carbonyl formation. On the other hand, lipoic acid (oxidized form of dihydrolipoic acid) and oxidized glutathione (GSSG) had minimal effect in protecting against the CS-ind...