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Biomedical subjects

H Ovadia

Publications and source records attributed to H Ovadia.

At least 55 records · Page 3Linked to original sources
PubMed1994

Lipopolysaccharide induces proenkephalin gene expression in rat lymph nodes and adrenal glands.

The proenkephalin gene encodes a family of neuropeptides that was originally identified in brain tissue and adrenal glands. Recently, it was shown that proenkephalin is also expressed in cultured lymphoid cells. To elucidate the physiological significance of this expression, we examined the in vivo expression of proenkephalin in lymphoid tissues. We show here that exposing rats to the endotoxin lipopolysaccharide induces an intense and transient expression of proenkephalin in adrenal glands and lymph nodes. By using combined in situ hybridization and immunohistochemistry on tissue slices, we identified proenkephalin expression in macrophages located within the lymph nodes and in chromaffin cells within the adrenal glands. This in vivo expression of proenkephalin was enhanced by adrenaline. The present observations demonstrate that the immune system is a site of significant expression of proenkephalin and provide a basis for neuroimmune interactions.

Adrenal Glands↗
PubMed1993

Treatment of chronic-relapsing experimental autoimmune encephalomyelitis with the synthetic immunomodulator linomide (quinoline-3-carboxamide).

Linomide is a synthetic immunomodulator that enhances natural killer cell activity and significantly activates several lymphocytic cell subpopulations in both experimental animals and humans. In this study we examined the effect of linomide (80 mg per kg per day in drinking water) on mice with chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE), a T-cell-mediated organ-specific autoimmune disease that resembles human multiple sclerosis. None of the mice (n = 17) that were treated with linomide from day 7 after disease induction developed any clinical or histopathological signs of CR-EAE, as compared to 19 of 20 untreated controls that were severely paralyzed and had extensive demyelinating lesions in the central nervous system. Linomide-treated animals were also resistant to an induced attack by a booster injection with a murine spinal cord homogenate. When administered to mice exhibiting severe clinical signs of paralysis, linomide inhibited both spontaneous and induced relapses. Linomide treatment protected mice from passively induced CR-EAE as well, when given from the day of injection with myelin-basic-protein-specific lymphocytes. Lymphocytes obtained from linomide-treated mice had a reduced in vitro proliferative response to the myelin basic protein and to the tuberculin purified protein derivative, whereas the mitogenic response to concanavalin A was not affected. Natural killer cell and lymphokine-activated killer cell activities were enhanced. These results suggest that linomide regulates autoimmunity in the absence of systemic immunosuppression. Since linomide is very well tolerated in experimental animals and humans, it might be used in the treatment of multiple sclerosis.

Adjuvants, Immunologic↗
PubMed1993

Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide.

Linomide (LS-2616, quinoline-3-carboxamide) is a synthetic immunomodulator that stimulates natural killer cell activity and activates several lymphocytic subpopulations in experimental animals and humans. In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outbred strain of rats (Sabra) by subcutaneous injection of spinal cord homogenate in adjuvant followed by inoculation with Bordetella pertussis. Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide-treated mice (0/41) and Sabra rats (0/15) developed any clinical or pathological signs of experimental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% died from the disease. Lymphocytes obtained from linomide-treated animals had reduced in vitro proliferative responses to guinea pig myelin basic protein, proteolipid protein of the myelin, and tuberculin-purified protein derivative, unlike antigen-independent proliferation which was rather unaffected. Natural killer cell activity (tested by a cytotoxic assay on radiolabeled YAC-1 target cells) was significantly enhanced in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of experimental autoimmune encephalomyelitis in the absence of systemic immunosuppression. Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders.

Adjuvants, Immunologic↗
PubMed1993

Wrist arthrodesis using an embedded iliac crest bone graft.

34 patients treated by the iliac crest bone graft technique for wrist arthrodesis were reviewed. The average age was 45.6 years and the mean follow-up was 45 months. The procedure is performed through a straight ulnar approach and the head of the ulna is removed. A longitudinal trench is created in both distal radius and carpus preserving the anterior, posterior and lateral cortices. A curved trapezoidal monocortical iliac crest bone graft is embedded inside the trench. The position of the arthrodesis automatically follows the curvature of the graft. No fixation device is used. A short-arm cast is applied for 2 to 3 months. All arthrodeses except two fused within 3 months. Pain was completely relieved in 85% of the cases. Pronation and supination returned to normal 5 months post-operatively. Grip strength was increased in 80% of the cases. The carpometacarpal joints remained pain-free even when not fused. Complications were rare: two lesions of the dorsal branch of the ulnar nerve; two cases of delayed union due to errors in technique, and displacement of the graft in one case. Although it is technically demanding, the embedded iliac crest graft wrist arthrodesis improves pronation and supination as a result of resection of the distal radio-ulnar joint, preserves or improves grip strength, and relieves pain.

Arthritis, Rheumatoid↗
PubMed1993

Digitalis-like compounds in the toad Bufo viridis: interactions with plasma proteins.

Digitalis-like compounds (DLC), normal constituents of animal tissues, are possible regulators of the Na+,K(+)-ATPase implicated in water and salt homeostasis. DLC are present in toad (Bufo viridis) tissues. Although DLC highest levels were found in toad skin, it was also detected in plasma and many internal organs. The abundant distribution and the different levels of DLC in various tissues exclude the possibility that toxicity is the only function of these compounds in the toad. The concentration of DLC in toad plasma is 30 microM, out of which 25-30% is bound to plasma proteins. Fractionation of toad plasma proteins on a G-100 Sephadex column followed by the extraction of DLC from the plasma proteins revealed that DLC are bound primarily to proteins of 48,000-53,000 Da. These results establish the existence of bufodienolide-binding protein(s) in animal plasma.

Animals↗
PubMed1993

Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation.

A chronic relapsing form of experimental autoimmune encephalomyelitis (CR-EAE) was induced in SJL/J mice by adoptive transfer of lymph node cells (LNC) sensitized to guinea pig myelin basic protein (GMBP). We examined the efficacy of high dose immunosuppressive regimens (cyclophosphamide [CY] 300 mg/kg or total body irradiation [TBI] 900 cGy) followed by syngeneic bone marrow transplantation (SBMT) in prevention and treatment of already established CR-EAE. Treatment with TBI and SBMT on day 5 after the induction of CR-EAE, just before the onset of clinical signs, completely inhibited the appearance of the paralytic signs. The same treatment, applied 4 d after the clinical onset of the disease, led to a significant regression of the paralytic signs and to a total inhibition of spontaneous relapses during a follow-up period of 2 mo. Challenge of mice with GMBP+CFA 78 d after the passive induction of CR-EAE induced a relapse of the disease 7 d later in almost all of the untreated mice; in contrast, the same challenge given to TBI+SBMT-treated mice caused a delayed relapse (30 d later) in only a minority (3/7) of the challenged mice. In vitro lymphocytic proliferative responses to GMBP and purified protein derivative were significantly lower in TBI/SBMT-treated mice before and after the GMBP challenge, although these mice were fully immunocompetent, as evidenced by their normal lymphocytic proliferation to concanavalin A (ConA) and the FACS analysis of their lymphocytic subpopulations. A similar beneficial therapeutic effect was observed in mice treated with CY followed by SBMT, after the onset of CR-EAE. Our results could support possible clinical applications of similar therapeutic strategies, involving acute immunosuppression followed by stem cell transplantation and retolerization of the reconstituting immune cells in life-threatening neurological and multisystemic autoimmune diseases.

Animals↗
PubMed1992

Chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE): treatment and induction of tolerance, with high dose cyclophosphamide followed by syngeneic bone marrow transplantation.

We examined the effect of acute immunosuppression with high dose cyclophosphamide (CY), followed by syngeneic T-cell-depleted bone marrow transplantation (SBMT) on chronic-relapsing autoimmune encephalomyelitis (CR-EAE) induced in SJL/J mice by immunization with mouse spinal cord homogenate (MSCH) in adjuvant. Treatment of mice on day 9 post immunization, before the appearance of clinical signs of the disease, delayed the onset of paralysis, but did not affect its clinical course. Treatment on day 2-3 after the first clinical signs led to complete regression of the disease. During a period of 3 months, only one of the 15 mice treated after the the onset of CR-EAE relapsed, as compared to a total of 21 relapses in the 15 untreated animals. A rechallenge with MSCH in adjuvant on day 78 after immunization induced a severe relapse in all untreated mice, with 78% mortality; in contrast, only 25% of mice treated with CY and SBMT relapsed when similarly rechallenged. Lymphocytes from mice treated with CY and SBMT showed reduced in vitro proliferative responses to myelin basic protein (GMBP) and PPD, even after the rechallenge with MSCH. Our results show that high dose CY for elimination of immunocompetent lymphocytes, followed by SBMT rescue, suppresses CR-EAE and induces tolerance to the immunizing antigens. These results may encourage attempts to apply a similar therapeutic principle in life-threatening human neurological autoimmune diseases.

Animals↗
PubMed1992

[Mathematical modelling of open-wedge tibial osteotomy and correction tables].

This study analyzes mathematically the orientation of the superior tibial epiphysis in frontal and sagittal planes for knees with genu varum arthrosis. The assessment of the opening is determined mathematically for the osteotomies; this leads to the establishment of tables which can be used in practise during upper tibial osteotomies.

Humans↗
PubMed1991

Expression of alpha-smooth muscle actin in murine bone marrow stromal cells.

Human fibrotic bone marrow (BM) stroma has been shown to contain alpha-smooth muscle actin (alpha-SMA)-positive cells. These closely resemble myofibroblasts that were described in other fibrotic tissues. We studied the expression of alpha-SMA in a series of murine BM-derived stromal cell lines to investigate the cellular origin and functional significance of myofibroblast-like cells in hematopoietic tissues. Although these cell lines differed in their biologic properties, most of them expressed alpha-SMA under certain conditions. Cells expressing alpha-SMA constituted a minor population in post-confluent, growth-arrested cultures. However, the incidence of cells expressing alpha-SMA increased significantly when cultures were transferred to nonconfluent conditions. A similar increase in alpha-SMA-positive cells occurred after a strip of cells was scraped away from the confluent cell layer; the cells of the affected area acquired alpha-SMA-positive contractile phenotype. The relationship between alpha-SMA expression and hematopoietic activity was studied using a cloned cell line of BM origin (14F1.1). The ability of these endothelial-adipocyte cells to support hematopoiesis in vitro was maximal under confluent conditions, whereas their expression of alpha-SMA under such conditions was residual. Moreover, in long-term BM cultures supported by confluent 14F1.1 cells, stromal areas associated with proliferating hematopoietic precursors, known as "cobblestone areas," were devoid of alpha-SMA-positive cells. These observations suggest that the expression of alpha-SMA is reversible and inversely related to hematopoietic activity.

Actins↗
PubMed1991

Regulation of proenkephalin A messenger ribonucleic acid levels in normal B lymphocytes: specific inhibition by glucocorticoid hormones and superinduction by cycloheximide.

Proenkephalin A (PEA) encodes a group of small peptides known to function as neurotransmitters, neuromodulators, and neurohormones in the nervous and neuroendocrine systems. This gene has been shown to be expressed in lymphoid cells, supporting the concept of bidirectional communication between the immune system and the central nervous system. In the present study, we investigated the effect of steroids and the inhibition of protein and RNA syntheses on the regulation of PEA expression in normal rat B cells. The transient expression of PEA messenger (m) RNA levels occurring normally in B cells was markedly inhibited by the presence of either 50 nM prednisolone or dexamethasone, both of which are glucocorticoids; other steroids, such as testosterone or the steroid-inactive metabolite androsterone, were ineffective. In the presence of cycloheximide, a protein synthesis inhibitor, PEA mRNA was superinduced by a factor of 15-fold. Sorting by flow cytometry of cycloheximide-treated cells followed by in situ hybridization analysis revealed that the expression of PEA mRNA was exclusively confined to a small fraction of B cells. These results indicate that the mechanisms regulating PEA gene expression in B cells differ from those previously described in cells of the neuroendocrine and the nervous systems.

Animals↗
PubMed1990

Selective facilitation of putative corticotropin-releasing factor-secreting neurones by interleukin-1.

The activity of single hypothalamic paraventricular nucleus (PVN) neurones was recorded in order to examine the mechanism by which the endogenous pyrogen interleukin-1 (IL-1) increases activity of the hypothalamo-hypophyseal-adrenocortical axis. IL-1 injected intravenously caused a rapid increase in the electrical activity of putative corticotropin-releasing factor (CRF)-secreting neurones located within the PVN. The activity of neighboring, electrophysiologically identified, vasopressin-secreting neurones was not altered by the stimulus, indicating a lack of involvement of this secretagogue of adrenocorticotropic hormone (ACTH) in this response to IL-1. These results support the concept of a rapid and specific activating effect of IL-1 upon hypothalamic CRF secretion as a part of a bidirectional communicating link between immune and central nervous systems.

Animals↗
PubMed1989

Regulated expression of proenkephalin A in normal lymphocytes.

The expression of proenkephalin A (PEA), a neuropeptide-encoding gene, was examined in normal rat lymphocytes. With the use of Northern blot hybridization analysis of total RNA, PEA mRNA was found in normal cells derived from spleen, lymph nodes, and bone marrow. Cell sorting of the two main fractions of B and T cells derived from the spleen revealed that PEA is expressed in normal B cells (sIg+). The expression of PEA mRNA was markedly enhanced after a short incubation (3 h) of cells with LPS or Salmonella typhimurium. This was not the case when these cells were incubated with Con A during the same period of time; whereas, in thymocytes the presence of PEA mRNA was exclusively dependent upon mitogenic stimulus (Con A) and could be detected after 24 h of in vitro incubation. Extracts of cells were also found to contain immune reactive enkephalins, indicating that the PEA mRNA is translated. These results support the concept that neuropeptides, such as enkephalins, have a role in the modulation of the immune response and may participate in the bidirectional communication between the nervous and immune systems.

Animals↗
PubMed1989

Effect of interleukin-1 on adrenocortical activity in intact and hypothalamic deafferentated male rats.

The present study was designed to elucidate the site of action of interleukin 1 (IL-1) modulation of the hypothalamic-hypophyseal-adrenal (HHA) axis. An intraperitoneal injection of recombinant human IL-1 beta (160 U/rat) significantly elevated serum levels of ACTH and corticosterone (CS). In rats with complete mediobasal hypothalamic deafferentation, the HHA response to IL-1 was inhibited. An intracerebroventricular injection of rIL-1 (2 U/rat) caused a marked increase in serum ACTH and CS. These results suggest that IL-1 activates the HHA axis by a direct effect upon the brain, and that intact neural connections between the mediobasal hypothalamus and extrahypothalamic brain regions are essential for IL-1-induced HHA responses.

Adrenocorticotropic Hormone↗
PubMed1989

Evidence for the involvement of the central adrenergic system in interleukin 1-induced adrenocortical response.

The role of central catecholamines in the mediation of adrenocortical activation, induced by interleukin 1 (IL-1), was investigated by measuring ACTH and corticosterone in serum. Adult male rats were injected with either vehicle or the neurotoxin 6-hydroxydopamine (6-OHDA) into the lateral ventricle or the ventral noradrenergic ascending bundle. In vehicle-injected rats, 2 U of IL-1, injected intraventricularly, produced a 5- and 15-fold increase in ACTH and CS, respectively, in serum, 120 min after the injection of IL-1. In contrast, 6-OHDA, injected either intraventricularly or into the ventral noradrenergic ascending bundle, abolished the response to an intracerebral injection of IL-1. In addition, in rats pretreated with the alpha 1-adrenergic antagonist, prazosin, IL-1 failed to activate the adrenocortical axis. In other rats pretreated with the beta-adrenergic antagonist, propranolol, the adrenocortical response did not significantly differ from that of vehicle-pretreated rats. These results suggest that central adrenergic transmission, originating at the ventral noradrenergic ascending bundle and acting through alpha 1-adrenergic receptors, is involved in the adrenocortical response to IL-1.

Adrenal Cortex↗
PubMed1989

Evidence for the involvement of the central adrenergic system in the febrile response induced by interleukin-1 in rats.

We have studied the effect of noradrenaline- and serotonin-depleting agents on the febrile response induced by an intracerebroventricular (i.c.v.) injection of interleukin-1 (IL-1) in rats. Pretreatment with an injection into the lateral ventricle of the catecholamine-depleting agent, 6-hydroxydopamine (6-OHDA), abolished the febrile response induced by IL-1. Injection of 6-OHDA into the ventral noradrenergic ascending bundle (VNAB) did not affect the pyrogenic effect of IL-1. Pretreatment with the serotonin-depleting agent, 5,7-dihydroxytryptamine (5,7-DHT), did not inhibit the febrile response to IL-1. In addition, pretreatment with a beta-adrenergic blocker (propranolol) but not an alpha-adrenergic blocker (yohimbine) attenuated the fever induced by an i.c.v. injection of IL-1. These results suggest that the integrity of the central catecholaminergic system is important in mediating the IL-1-induced fever in rats. The central serotonergic system, as well as noradrenergic neurotransmission at the hypothalamus, do not appear to participate in this endogenous pyrogen-induced febrile response.

5,7-Dihydroxytryptamine↗
PubMed1989

Characterization of opiate binding sites on membranes of rat lymphocytes.

In view of the importance of membrane receptors for the interconnection between the central nervous system and the immune system, we carried out a study to characterize opiate binding sites on membranes of rat lymphocytes. We found that mitogen-activated spleen cells, but not thymocytes, possess specific and displaceable binding sites for [3H]naloxone. The binding was equally effective and intense while using B-cell-depleted spleen cells. The binding showed two sites of saturation, one at 10 nM and the other at concentrations greater than 20 nM of [3H]naloxone. Computer analysis of the binding data obtained with the lowest concentrations of naloxone revealed a unique site with high affinity binding to opiates. Displacement was achieved with morphine sulphate and naloxone but not with opioid peptides. The binding of the antagonist, [3H]naloxone, was profoundly inhibited by the co-presence of 120 mM NaCl and up to 100 microM guanosine 5'-O-(3-thiotriphosphate (GTP gamma S). Other metal ions and cyclic nucleotides were not able to interfere with the specific binding. This specificity for GTP analogues is consistent with the hypothesis that a GTP-binding regulatory protein that couples receptors to adenylate cyclase is involved in the process of binding of opiates to lymphocytes. The existence of binding sites on lymphoid cells, analogous to receptors for agents known to affect brain functions, may be another link between the immune system and the central nervous system.

Animals↗
PubMed1989

Central administration of immunomodulatory factors alters neural activity and adrenocortical secretion.

This study was designed to examine the effects of intracerebroventricular administration of a variety of immunomodulatory factors upon cortical EEG, preoptic area/anterior hypothalamic (POA/AH) multiunit activity (MUA), and corticosterone secretion in conscious, freely moving rats. The substances tested were alpha-interferon (alpha-INF), thymic humoral factor (THF), histamine, and interleukin-1 (IL-1). Saline administration did not alter POA/AH MUA up to 45 min after injection but increased the total time and duration of synchronized EEG periods. alpha-INF and THF were found to significantly reduce POA/AH MUA and increased the amount and duration of synchronized EEG while decreasing basal plasma corticosterone levels. Histamine and IL-1 did not alter POA/AH MUA discharge but decreased EEG synchronization and evoked an increase in plasma corticosterone levels. These results demonstrate that some secretions of the immune system are able to alter EEG discharge and neural activity in an area of the brain known to modulate both immune and neuroendocrine secretory activity. The results also appear to be related to adrenocortical secretory activity, which was altered by the substances tested.

Adrenal Cortex↗