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.

Ultrasonography in the diagnosis and follow-up of hepatic sinusoidal dilatation.

Hepatic sinusoidal dilatation is a rare complication of oral contraceptive use. A 29-year-old woman who had been taking oral contraceptive pills for eight years was found to have persistently elevated erythrocyte sedimentation rates and alkaline phosphatase levels, hepatomegaly, diffuse hepatic sinusoidal dilatation, and a large nonhomogeneous hyperechogenic lesion in the right hepatic lobe. The abdominal ultrasonogram, liver size, erythrocyte sedimentation rates, and alkaline phosphatase levels reverted to normal within 24 months after discontinuing oral contraceptives. This case should encourage the use of abdominal ultrasonography in detection and follow-up of hepatic sinusoidal dilatation.

Unintentional weight loss. A retrospective analysis of 154 cases.

Unintentional weight loss (UWL) was documented in 154 patients (2.8%) admitted to an internal medicine department during a two-year period. A retrospective analysis of the clinical charts showed that more than one third (36.3%) were found to have a neoplasm, involving preponderantly the gastrointestinal tract. Patients with neoplasia were older and more frequently had abnormal physical findings and significantly lower values of serum albumin as well as higher values of alkaline phosphatase than other patients. Despite extensive investigations, in 36 patients (23.3%) UWL remained unexplained even after prolonged follow-up periods. The remaining 62 patients had a variety of disorders, preponderantly gastrointestinal tract (26 patients) and psychiatric (16 patients) diseases. Endocrinologic disorders such as diabetes mellitus and hyperthyroidism were relatively uncommon (3.8%). Unintentional weight loss is a relatively common problem in clinical practice. Familiarity with the spectrum of disorders associated with UWL as well as selected clinical and laboratory values may help in the initial examination of these patients.

Effect of cimetidine and antacids on gastrointestinal absorption of tetracycline.

In a randomized crossover study, five normal subjects were given 250-mg capsules of tetracycline at weekly intervals with cimetidine 300 mg. sodium bicarbonate 2 gm in water, magnesium-aluminum hydroxide gel 30 ml, or water alone. Gastric pH was monitored by radiotelemetry. Antibiotic bioavailability as measured by area under the serum level-time curve, peak serum level, and urinary elimination was not affected by cimetidine or sodium bicarbonate. Magnesium-aluminum hydroxide gel reduced bioavailability by 90%. The data show that gastric pH does not affect absorption of oral tetracycline and that cimetidine can be used in place of antacids to control gastric acid in patients using tetracycline.

Reduction of serum theophylline levels by terbutaline in children with asthma.

We studied the effect of oral terbutaline on serum theophylline levels in 12 children with asthma. Sustained-release theophylline (10 mg/kg twice a day) was given with placebo or terbutaline (0.075 mg/kg three times a day) in a chronic, randomized, double-blind, crossover design. The trough serum theophylline concentration fell from 13.8 +/- 4.0 to 10.8 +/- 3.6 micrograms/ml and the peak expiratory flow rate increased from 285 +/- 30 to 310 +/- 29 L/min after terbutaline. Further investigation is needed to clarify the mechanism of action by which terbutaline decreases serum theophylline levels.

Effect of nifedipine and theophylline in asthma.

The effect of nifedipine, 10 mg po q.i.d. for 2 weeks, was studied in a randomized, double-blind, crossover trial in nine patients with asthma receiving theophylline. Nifedipine did not significantly affect the mean (+/- SD) morning peak expiratory flow rate (PEFR; 336 +/- 130 L/min for drug vs. 349 +/- 92 L/min for placebo), evening PEFR (393 +/- 69 L/min for drug vs. 367 +/- 66 L/min for placebo), symptom score (27.4% +/- 22.9% for drug vs. 33.8% +/- 26.4% for placebo), or the number of albuterol inhalations per day (5.8 +/- 3.5 for drug vs. 6.2 +/- 4.1 for placebo). Furthermore, there was no change in PEFR 30, 60, or 120 minutes after nifedipine dosing. Nifedipine did not significantly affect the steady-state serum theophylline trough levels (9.1 +/- 2.2 mg/ml for drug vs. 10.2 +/- 1.9 micrograms/ml for placebo) or the theophylline pharmacokinetic parameters, such as the elimination t1/2, peak serum concentration, time to peak, and AUC(0-24). We conclude that nifedipine has little, if any, effect on the clinical status, PEFR, or theophylline serum levels in patients with asthma who receive theophylline.

Correlation of a quinidine-induced platelet-specific antibody with development of thrombocytopenia.

The rapidity by which drug-dependent antiplatelet antibodies can develop is not known, since patients are only studied during or after the episode of thrombocytopenia. This report describes the development of quinidine-induced immune thrombocytopenia in a healthy volunteer during a drug study. The thrombocytopenia developed within two weeks of initiation of quinidine therapy. During the thrombocytopenic episode, but not before receiving the drug, the patient had an IgG antiplatelet antibody that bound to control platelets in the absence of the drug. This antibody was absent when the drug was discontinued and the platelet count rose. The patient's acute serum also induced the release of serotonin from control platelets, and the reaction was enhanced by quinidine. This indicates that drug-dependent antiplatelet antibodies can develop rapidly and supports the hypothesis that quinidine-induced thrombocytopenia is due to a quinidine-dependent platelet-specific IgG.

Hyperammonemia complicating mesenteric vein thrombosis.

Hyperammonemic coma developed in a 69-year-old woman with prolonged symptoms of abdominal pain, dysphagia, and fever. At laparotomy for an acute condition within the abdomen, mesenteric vein thrombosis was found and partial intestinal resection was performed. Following surgery, the patient regained consciousness and blood ammonia levels became normal. Hyperammonemia and coma complicating mesenteric vein thrombosis have not yet been described. Venous shunts are suggested as being responsible for this rare complication.

Lymphoma presenting with adrenal insufficiency. Adrenal enlargement on computed tomographic scanning as a clue to diagnosis.

A 73-year-old woman who presented with primary adrenal insufficiency and enlarged adrenal glands on computed tomographic scanning was ultimately found to have a large-cell lymphoma that had initially involved the adrenals and the stomach. A search of the English language medical literature revealed only seven other cases of lymphoma presenting with hypoadrenalism, none of which involved the stomach. As in this case, in most of those cases adrenal enlargement was documented on computed tomographic scanning. Despite its rare occurrence, lymphoma should be searched for in patients presenting with Addison's disease and enlarged adrenal glands.

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.

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.

Implications of plasma levels of catechols in the evaluation of sympathoadrenomedullary function.

This report summarizes new techniques for examining aspects of sympathoadrenomedullary function. Tracer pharmacokinetic methods are more accurate than measurements of antecubital venous norepinephrine (NE) in assessing sympathoneural responsiveness. During mental challenge (playing a video game), patients with essential hypertension had significantly larger increments of NE spillover into arterial blood than did normotensive control subjects, whereas responses of antecubital venous and even arterial NE did not differ significantly between the groups. The rate of neuronal reuptake of endogenous NE can be measured in vivo using plasma levels of NE and of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG). Regional production of dihydroxyphenylalanine (DOPA) may reflect catecholamine biosynthesis, and DOPA may be an indirectly acting natriuretic neurohormone. Positron emission tomography after injection of positron-emitting fluorodopamine may allow in vivo, noninvasive assessments of regional sympathetic function.

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.

Cadmium uptake by rat red blood cells.

Rat red blood cells were employed to study the uptake of cadmium (109Cd). Suspensions of red blood cells were exposed to Cd concentrations of 0.005-500 microM, which were representative of whole blood concentrations (both bound and free) observed following in vivo Cd administration. Cd uptake was biphasic with an initial rapid phase (less than 1 min) followed by a slower second phase. The rate of Cd uptake at 25 degrees C was one-fourth of that at 37 degrees C. The metabolic inhibitors; sodium fluoride (1 mM), potassium cyanide (1 mM) and carbonyl cyanide-m-chlorophenyl hydrazone (2 microM) and the Na+-K+-ATPase inhibitor, ouabain (1 mM) did not reduce Cd (50 microM) uptake into red blood cells. This suggests that the uptake of Cd into red blood cells was not an active process. Incubation of Cd (10 microM) with an equimolar concentration of Zn did not alter uptake of Cd into red blood cells, but at 5 and 10 times higher concentrations of Zn, Cd uptake was enhanced 5-fold. Mercury at one-tenth and equimolar concentrations of Cd increased Cd uptake by red blood cells 2-fold. N-Ethylmaleimide (0.5-5 mM), which irreversibly inactivates membrane sulfhydryl groups, decreased Cd uptake. The data indicate that Cd uptake into rat red blood cells occurs by passive transport and that alterations of sulfhydryls of red blood cell membrane may modulate the process.

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.

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.

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.

[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.