The possible involvement of sema3A and sema4A in the pathogenesis of multiple sclerosis.

BACKGROUND: Immune semaphorins are widely accepted to have functional impact on autoimmune diseases. OBJECTIVES: To assess the status of sema3A and sema4A in the pathogenesis of Multiple Sclerosis (MS). RESULTS: Sema3A expression on (T regulatory cells)Tregs was decreased in MS patients, compared to healthy controls (35.85 ± 16.7% vs 88.27 ± 3.8%; p ≤ 0.001). Serum levels of sema3A were decreased in MS patients 2.95 ± 0.43 vs 18.67 ± 5.7 ng/ml in healthy individuals; p ≤ 0.001. Sema4A serum levels were increased in MS patients compared to healthy individuals (12.99 ± 8.6 vs 5.83 ± 3.91 ng/ml; p ≤ 0.001). Sema3A and sema4A serum levels were found to be in negative/positive correlation with MS disease severity (rs = 0.62, rs = -0.49, respectively). CONCLUSION: We show that sema3A is a regulatory molecule in MS, whereas sema4A is a stimulatory one. Targeting sema3A and sema4A could become a potential therapeutic approach in MS.

[Out-of-hospital resuscitation in Israel 2000].

The aim of the study was to evaluate the impact of pre-hospital cardio-pulmonary resuscitation, performed by mobile intensive cardiac care units of Magen David Adom (MDA) teams in the framework of a national survey conducted in the period February and March 2000. During the survey, MDA performed 539 resuscitations, 485 of which were performed by mobile intensive care units of MDA, and they constitute the study population of the present analysis. The average age of the patients was 70.5 years, and 68% were men. The mean response time of the mobile intensive care units was 10.3 minutes. In 14% of the cases, a bystander initiated basic cardiac life support before the arrival of the MDA team. Upon arrival of the resuscitation team, 242 patients (50%) had asystole, 19% ventricular tachycardia (VT)/ventricular fibrillation (VF), 13% pulseless electrical activity (PEA), and 18% had other severe arrhythmias. One hundred and ninety-nine patients (41%) were transferred alive to the hospital after successful resuscitation. Hospital summaries were obtained for 148 of these patients. The cause of cardiac arrest was cardiac in 64% of the cases and 48% of the patients who reached the hospital had a previous history of heart disease. Fifty-three patients (11%) were discharged alive from the hospital. Patients discharged alive were younger, more promptly resuscitated, 78% had a cardiac cause of death and 38% of them were in ventricular tachycardia/fibrillation when first seen by the resuscitation team. The rate of successful resuscitation to discharge in the sub-group with VT/VF was 21%, and only 4% for patients in asystole, which is in line with other studies. However, the rate of initiation of resuscitation by bystanders is low in Israel. These data may help the medical staff and the health policy providers in Israel.

Fixed-dose combination therapy in the United States, Britain and Israel.

BACKGROUND: Fixed dose combination therapy varies among countries. OBJECTIVE: To compare the list of fixed-dose combination therapies used in the USA, UK and Israel. METHODS: The total list of drugs and FDC drugs were counted manually from a list of generic names. We also counted the number of drugs in four characteristic subgroups: cardiovascular, anti-infective, gastrointestinal, and dermatological. Data for drugs in the USA, UK and Israel were taken from the Physician's Desk Reference (PDR 1997), the British National Formulary (BNF March 1997) and the Monthly Ethical Drug Indexed Compilation (MEDIC July 1997) respectively. RESULTS: The global percentage of FDC drugs in the USA and UK was higher than in Israel (20%, 25% and 15% respectively). A similar trend was found in all subclasses of FDC drugs except for the anti-infective category in which the percentage of FDC drugs was low and similar in all countries. CONCLUSION: The list of FDC drugs varies greatly between the USA, UK and Israel, reflecting the differences in the outcome of debate between the pharmaceutical companies and the regulatory authorities.

Cyclosporin drug-interaction-induced rhabdomyolysis. A report of two cases in lung transplant recipients.

In rare cases the use of cyclosporin in transplant patients can cause myopathic changes. We describe two patients, the recipients of lung transplants, who developed severe reversible rhabdomyolysis associated with cyclosporin drug-drug interaction.

Acute hepatitis A: combination of the relapsing and the cholestatic forms, two rare variants.

Here we present an unusual case of a 23-year-old, otherwise healthy man who had a biphasic form of viral hepatitis A with a combination of two variants, the relapsing and cholestatic forms. One month after resolution of the first phase of acute hepatitis A, he was readmitted with jaundice and intense pruritus. During hospitalization, his serum bilirubin level increased to 50.2 mg/dL, with a slight increase in the other levels of liver enzymes. He was treated with ursodeoxycholic acid and later with corticosteroid therapy, resulting in resolution of symptoms and improvement of his liver function tests after 2 weeks. Medication therapy seems to be justified in markedly symptomatic patients with relapsing hepatitis.

Comparison of ketorolac and diclofenac in the treatment of renal colic.

OBJECTIVE: To compare the efficacy and adverse effects of ketorolac and diclofenac in the treatment of renal colic. METHODS: In a double-blind, randomized clinical trial, 57 patients admitted to the emergency room for renal colic, received either 30 mg of ketorolac or 75 mg of diclofenac i.m. (intramuscularly). Evaluations were performed at 1, 2 h and 6 h after treatment. Pain was assessed by a four-point verbal rating scale (VRS) and a visual analogue scale (VAS). Only patients with at least moderate pain according to the VRS were included. Seventy-five milligrams of pethidine i.m. was given as rescue medicine, if insufficient analgesia was achieved. The adverse effects recorded were sedation, nausea and vomiting. RESULTS: There was no significant difference between ketorolac and diclofenac, with respect to pain level over time, the number of patients requiring rescue medicine, or the level of adverse effects. CONCLUSION: Ketorolac and diclofenac are equally effective in the treatment of renal colic.

MRI imaging of a left atrial mass misinterpreted by transesophageal echocardiography.

Magnetic resonance imaging of the heart was used in a patient with a history of recurrent episodes of transient ischemic attacks in whom a left atrial mass was suspected on transesophageal echocardiography. The use of MRI clarified a diagnosis of a diaphragmatic hernia.

Immediate immunosuppression caused by acute HIV-1 infection: a fulminant multisystemic disease 2 days post infection.

A healthy 19-year-old woman had vaginal intercourse on a single occasion with an HIV-1 positive male from Gambia. Two days later she developed an acute HIV infection presenting as a fulminant multisystem disease that lasted for 35 hospital days and included: immediate immunosuppression with extreme CD4+ lymphocytopenia and combined with CD8+ lymphocytosis, neutropenia and hypogammaglobulinemia; intermittent spiking fever; pneumonitis; hepatitis; changing skin rashes; peripheral neuropathy with myopathy, and panencephalitis. P24 antigen was detected by Western blot on day 23 and seroconversion was detected by ELISA on day 25. Cultured lymphocytes from peripheral blood and cerebrospinal fluid grew HIV-1.

Health resource utilization in ABMT with and without G-CSF in stage III/IV breast cancer patients.

G-CSF has been available since 1991 for use in patients receiving high-dose chemotherapy/ABMT, and while it has been shown to effectively reduce the risk of febrile neutropenia, its cost effectiveness has been open to question. In this small retrospective study, five indicators of the consumption of health care resources were examined in stage III/IV breast cancer patients who received high-dose chemotherapy with ABMT or peripheral stem cell support. The study covered the time periods before and after the availability of G-CSF. The results showed that patients who received G-CSF had reductions in length of hospital stay of 20% (the purged marrow group) and 17% (nonpurged group), compared with similar groups that did not receive the growth factor; the shortest lengths of stay were seen in the peripheral stem cell group, all of whom received G-CSF. Other findings, including number of days the ANC fell below 500, total days of G-CSF use, and total days of antibiotic use, are presented.

Dual regulation by opioids of 3H-norepinephrine release in the human neuroblastoma cell-line SK-N-SH.

Depolarization-evoked 3H-norepinephrine release from SK-N-SH cells was found to be regulated by opioid ligands. Opioids exerted either inhibition or augmentation of 3H-norepinephrine release. Both effects were mediated by opioid receptors. In addition, a nonopioid inhibitory effect of opiates on release was observed. The SK-N-SH cell-line provides a suitable model for studying the various mechanisms underlying the opioid regulatory pathways within single cells.

Role of CRH in glucopenia-induced adrenomedullary activation in rats.

Acute glucoprivation profoundly stimulated hypothalamic-pituitary-adrenocortical (HPA) and adrenomedullary outflows. Whether these responses reflect a single central mechanism regulated by corticotropin-releasing hormone (CRH) has been unclear. This study examined the role of endogenous CRH in HPA and adrenomedullary responses to hypoglycemia in Sprague-Dawley rats, by using anti-CRH immune serum or a CRH antagonist (alpha-helical h/r CRH9-41, and in Lewis rats, a strain characterized by deficient hypothalamic CRH responses during stress. In conscious Sprague-Dawley rats with indwelling arterial and venous cannulas, insulin (0.3 U/kg was injected iv, and responses of serum glucose concentrations and plasma levels of corticotropin (ACTH) and catechols (including epinephrine, EPI; norepinephrine, NE; dihydroxyphenylalanine, DOPA; dihydroxyphenylglycol, DHPG; and dihydroxyphenylacetic acid, DOPAC) were assessed, with or without pretreatment with anti-CRH immune serum (0.5 or 1.0 ml iv or 10 microl icv) or alpha-helical h/r CRH9-41 (130 nmol iv or 13 nmol icv). Responses to insulin (1.0 U/kg iv) were also measured in conscious juvenile Lewis and Fischer 344/N rats. Insulin-induced hypoglycemia markedly increased plasma levels of EPI and ACTH in all groups. Pretreatment iv with 1/0 ml of anti-CRH immune serum blocked the ACTH response to insulin but failed to attenuate the EPI response. alpha-helical h/r CRH9-41, whether given iv or icv, failed to alter ACTH or EPI responses to insulin, although the antagonist did block EPI responses to icv CRH. Hypoglycemia elicited similar increments in ACTH levels in Lewis rats and Fischer 344/N control rats; and although Lewis rats had lower baseline EPI and smaller responses of NE, DHPG, DOPA, and DOPAC levels, the groups did not differ in proportionate increments in EPI levels. The results indicate that the ACTH response to hypoglycemia depends on availability of CRH outside the blood-brain barrier--presumably in the pituitary gland. The findings with icv alpha-helical h/r CRH9-41 can be explained by failure of the antagonist to reach effective concentrations at central sites of action of endogenous CRH, or by mechanisms other than CRH release determining the adrenomedullary response to hypoglycemia. Lewis rats seem to have less adrenomedullary secretion at baseline and smaller responses of NE synthesis and release during hypoglycemia than do Fischer 344/N rats. Neurochemical evidence for differential adrenomedullary and sympathoneural responses during hypoglycemia in all three rat strains is inconsistent with Cannon's view of a functionally unitary sympathoadrenal system. Lewis rats have deficient CRH responses to some stressors but not to others, or else pituitary-adrenomedullary responses in this setting depend on mechanisms other than CRH release in the brain. Both explanations are inconsistent with the doctrine of non-specificity, the main tenet of Selye's stress theory.

Bioequivalence of quinidine in two sustained-release preparations.

The bioequivalence of two sustained-release preparations of quinidine bisulphate from Teva (Israel) and from Astra (Sweden) was assessed in an acute, single-dose randomized cross-over study in seven healthy subjects. There was no significant difference in time to peak, peak serum concentration, area under the concentration time curve from 0 to infinity, and the fraction absorbed between quinidine bisulphate 500 mg from Teva and from Astra. In addition, quinidine bisulphate 250 mg from Teva was compared with the short-acting quinidine sulphate 200 mg. The quinidine bisulphate from Teva had a significantly P less than 0.025) decreased peak serum concentration and an increased time to peak compared with the short-acting quinidine sulphate, although these two drugs are similar for the area under the curve from 0 to infinity. Our pharmaceutical records show that 85% of outpatients receiving quinidine are given the sustained-release quinidine bisulphate. However, only 36% of the outpatients prescribed sustained-release quinidine bisulphate are appropriately prescribed for twice-daily treatment. Thus the quinidine bisulphate from Teva is a sustained-release preparation with bioequivalence to the reference sustained-release preparation and can be administered twice daily.

Effects of clonidine on renal sympathetic nerve activity and norepinephrine spillover.

The antihypertensive action of clonidine (CLO) depends mainly on decreased release of the sympathetic neurotransmitter, norepinephrine (NE), at vascular neuroeffector junctions. The decreased release can be due to stimulation of alpha-2 adrenoceptors or other receptors in the brain or due to stimulation of presynaptic inhibitory alpha-2 adrenoceptors on sympathetic nerve endings. To compare central and peripheral contributions to the depressor action of CLO, renal sympathetic nerve activity (RSNA) and renal spillover of NE (RNEs) were measured at baseline and during reflexive increases in RSNA evoked by nitroprusside-induced hypotension (27, 50 and 105 micrograms/kg/min) before and after CLO treatment in adrenal-demedullated, anesthetized rats. Administration of CLO decreased RSNA by 52 +/- 8% and RNEs by 32 +/- 13% (means +/- S.E.M.). At levels of RSNA less than 50% above control, there were no significant changes in RNEs; above this level of activity RNEs increased, regardless of CLO treatment. CLO treatment did not alter significantly the relationship between increases in RSNA and in RNEs during nitroprusside-induced hypotension. The results suggest that in neurologically intact, anesthetized animals, CLO decreases renal NE release mainly by inhibiting sympathetic outflow, with little if any peripheral presynaptic action.

A clinical and immunologic study of colchicine in asthma.

A double-blind, randomized, crossover chronic study was done to determine the efficacy of colchicine in 10 atopic patients with asthma. A constant dose of sustained-release theophylline and albuterol by inhalation, as needed, was administered. Compared to placebo, colchicine, 0.5 mg twice daily, significantly reduced the mean (+/- SEM) daily clinical score from 2.18 +/- 0.34 to 1.64 +/- 0.32 (p less than 0.05), and the daily number of inhalations of albuterol from 5.89 +/- 1.48 to 4.01 +/- 1.26 (p less than 0.02). Colchicine significantly (p less than 0.05) increased the concanavalin A-induced suppressor cell function from 16.2 +/- 4.6% to 39.0 +/- 10.7%, which was similar to healthy volunteers (41.1 +/- 3.5%). Furthermore, colchicine significantly (p less than 0.05) decreased serum IgE from 248 +/- 63 to 188 +/- 46 IU/ml. Colchicine had no significant effect on pulmonary function tests, the early phase reaction of antigen-induced bronchial inhalation challenge, and immediate skin test responses. Thus, colchicine has immunomodulatory effects that may perhaps have a mild benefit in the treatment of asthma.

Elimination characteristics of intravenously administered rIGF-I in Laron-type dwarfs.

The distribution and elimination characteristics (Ke alpha, Ke beta, t1/2) of an intravenous bolus of biosynthetic IGF-I administered to 10 patients with Laron-type dwarfism (LTD, 3 children and 7 adults) and 6 healthy volunteers (3 children and 3 adults) are reported. The mean (+/- SD) endogenous level of IGF-I in the LTD patients was 5.24 +/- 2.77 nM/l and in the controls 27.2 +/- 9.4 nM/l. In the LTD patients the mean elimination constant (Ke beta) was 0.004 +/- 0.001 min-1 and t1/2 = 2.6 +/- 0.7 h, whereas in the controls, Ke beta was 0.003 +/- 0.009 min-1 and the t1/2 = 4.4 +/- 0.5 h (p less than 0.05). The more rapid elimination of injected IGF-I in the LTD patients is assumed to be due to the absence of the GH-dependent 150 kDa IGF-I binding protein.

Interaction of clonidine and morphine with lidocaine in mice and rats.

Morphine and clonidine both elevated plasma levels of lidocaine to the same extent in mice while slowing lidocaine metabolism to deethylated products. The effects of clonidine on lidocaine disposition were reversed by yohimbine. Mice given morphine, 20 mg/kg sc, or clonidine, 0.2 mg/kg sc, had similar, 30-50%, elevation of plasma lidocaine levels at 15 min after lidocaine, 15 mg/kg iv, when compared to saline-treated animals. Despite similarity of effect on plasma lidocaine, mice treated with morphine were much more susceptible to lethal effects of lidocaine than were mice given clonidine. At iv doses of 22 mg/kg or higher, lidocaine caused death in nearly all morphine-treated mice, while even 32 mg/kg lidocaine caused only 11% mortality after saline or clonidine. Clonidine, 0.5 mg/kg sc, and morphine, 20 mg/kg sc, both raised plasma lidocaine levels in rats, but only morphine depressed respiration, causing hypoxia, hypercapnia, and acidosis and increasing lidocaine lethality. These data suggest that potentiation of lidocaine toxicity by morphine is due primarily to changes in blood gases rather than to elevation in lidocaine levels.

Patterns of plasma levels of catechols in neurogenic orthostatic hypotension.

Patients with neurogenic orthostatic hypotension can have deficits in sympathetic neural function at any of several levels of the sympathetic neuraxis. We determined whether patterns of plasma levels of dopa, norepinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid would distinguish patients with orthostatic hypotension associated with multiple system atrophy, pure autonomic failure, or deficiency of dopamine-beta-hydroxylase. Plasma levels of catechols were normal in most patients with multiple system atrophy, consistent with relatively intact peripheral sympathetic neurons; in contrast, most patients with pure autonomic failure had decreased levels of all four catechols, consistent with degenerative loss of sympathetic nerve endings. Patients with deficiency of dopamine-beta-hydroxylase had increased levels of dopa and dihydroxyphenylacetic acid and markedly decreased levels of norepinephrine and dihydroxyphenylglycol, suggesting compensatory increases in sympathetic nerve activity in the absence of norepinephrine biosynthesis. Subgroups of patients with pure autonomic failure or multiple system atrophy had low levels of norepinephrine with normal levels of dopa, dihydroxyphenylglycol, and dihydroxyphenylacetic acid, consistent with normal catecholamine biosynthesis and decreased postganglionic sympathetic nerve traffic or decreased exocytotic release from sympathetic nerve endings. The results demonstrate the value of examining patterns of plasma levels of catechols to elucidate mechanisms of neurogenic orthostatic hypotension.

Renal sympathetic nerve activity and norepinephrine release in rats.

We examined relationships between changes in directly recorded renal sympathetic nerve activity (RSNA) and renal and total body spillover of norepinephrine into the bloodstream (RNEs and TBNEs, respectively) in anesthetized, adrenal-demedullated rats. Intravenous infusions of nitroprusside (NP) or phenylephrine (PH) produced reflexive, dose-dependent changes in RSNA. High-doses of NP significantly increased RSNA by 90%, RNEs by 155%, and TBNEs by 268%. High doses of PH significantly decreased RSNA by 37%, RNEs by 35%, and TBNEs by 33%. Ganglionic blockade with chlorisondamine decreased RSNA by 65% (P less than 0.05), RNEs by 10%, and TBNEs by 51% (P less than 0.05). There was a significant curvilinear relationship between mean changes in RSNA and mean changes in RNEs (r = 0.99). Simultaneous in vivo measurement of sympathetic nerve traffic and regional release of norepinephrine therefore may be useful in the assessment of presynaptic actions of drugs and hormones and in the evaluation of abnormal sympathetic neurotransmission in disease states.

Plasma levels of catechols during reflexive changes in sympathetic nerve activity.

Relationships between changes in levels of catechols and directly recorded sympathetic nerve activity were examined using simultaneous measurements of renal sympathetic nerve activity and arterial and renal venous concentrations of norepinephrine (NE), dihydroxyphenylalanine (dopa), and dihyroxyphenylglycol (DHPG) during reflexive alterations in renal sympathetic nerve activity in anesthetized, adrenal-demedullated rats. Nitroprusside infusion increased renal sympathetic nerve activity by 90%, arterial levels of dopa by 96%, NE by 326%, and DHPG by 141%. Phenylephrine infusion increased arterial DHPG levels by 81% and decreased renal sympathetic nerve activity by 37% and NE levels by 26%; arterial dopa levels were unchanged. Ganglionic blockade by chlorisondamine (with concomitant phenylephrine infusion to maintain MAP) decreased renal sympathetic nerve activity by 65% and NE concentrations by 37%; arterial dopa concentrations were unchanged, and DHPG concentrations increased by 60%. Proportionate responses of arterial levels of NE were strongly related to proportionate changes in renal sympathetic nerve activity. Clearance of DHPG from arterial plasma was prolonged by phenylephrine-induced hypertension and by nitroprusside-induced hypotension. The results suggest that changes in arterial NE levels reflect changes in sympathetic activity; changes in dopa levels reflect changes in catecholamine biosynthesis; and changes in DHPG levels depend on reuptake of released NE and on hemodynamic factors affecting DHPG clearance.

Skin color, aging, and plasma L-dopa levels.

Although plasma levels of L-dopa are derived substantially from catecholamine-synthesizing tissues, melanocytes--which produce L-dopa as part of the melanin synthetic cascade--also may be a source of circulating L-dopa. We compared plasma L-dopa levels in albino subjects and in Caucasian and Black normal volunteers and patients with essential hypertension. DOPA levels were similar among the subject groups. Among Caucasian normal volunteers, L-dopa levels were negatively correlated with subject age (r = -0.30, P less than 0.05), whereas norepinephrine levels tended to increase with subject age (r = 0.25, 0.05 less than P less than 0.10), so that the L-dopa:norepinephrine ratio was highly negatively correlated with subject age (r = -0.50, P less than 0.01). Skin pigmentation does not contribute importantly to plasma L-dopa levels in humans. In contrast with levels of norepinephrine, L-dopa levels appear to decrease during normal aging.