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Biomedical subjects

D Kaplan

Publications and source records attributed to D Kaplan.

At least 55 records · Page 3Linked to original sources
PubMed1998

Octreotide ameliorates glucose intolerance following acute experimental pancreatitis.

The long-term effects of octreotide, the synthetic analog of the hormone somatostatin, on acute experimental pancreatitis were studied. Acute pancreatitis was induced in rats by intraparenchymal injections of 0.5 ml 5% or 10% sodium taurocholate. Octreotide (10 mg/kg/day, subcutaneously), or saline injections as controls, were started four hours later, and their effects were assessed 30, 60, and 90 days after the induction of pancreatitis. Neither intrapancreatic saline injections nor octreotide administration without the induction of pancreatitis caused any biochemical or histological abnormalities. Taurocholate-induced pancreatitis was followed by remarkable hyperglycemia, which was ameliorated by octreotide. Thirty days after induction of pancreatitis, glucose levels were 269+/-21 mg/100 ml and 153+/-17 mg/100 ml in the control and octreotide treated animals, respectively (P < 0.02). Octreotide administration was associated with increased pH values after 60 and 90 days (P < 0.05 for the 90 days group). The levels of hematocrit, calcium, and amylase were already within the normal ranges after 30 days and were unaffected by octreotide. There were no signs of chronic exocrine insufficiency and all the surviving rats gained weight during the follow-up. However, the relative weights of the pancreases of the octreotide-treated animals were higher than those of the controls 30 days after IOP. Histopathological evaluation demonstrated regeneration of the pancreatic tissue, and increased number and hypertrophy of the islets of Langherhans. There were no significant differences whether the octreotide treatment was given for only 48 or 96 hr. Survival was significantly improved by octreotide; only one octreotide-treated rat (2.5%) with 10% taurocholate-induced pancreatitis died, while six (15%) of the control animals succumbed (P < 0.05). These studies provided data on the sequelae of acute pancreatitis and showed that octreotide may have long-term beneficial effects in this disease.

Acute Disease↗
PubMed1998

Submaximal responses in calcium-triggered exocytosis are explained by differences in the calcium sensitivity of individual secretory vesicles.

A graded response to calcium is the defining feature of calcium-regulated exocytosis. That is, there exist calcium concentrations that elicit submaximal exocytotic responses in which only a fraction of the available population of secretory vesicles fuse. The role of calcium-dependent inactivation in defining the calcium sensitivity of sea urchin egg secretory vesicle exocytosis in vitro was examined. The cessation of fusion in the continued presence of calcium was not due to calcium-dependent inactivation. Rather, the calcium sensitivity of individual vesicles within a population of exocytotic vesicles is heterogeneous. Any specific calcium concentration above threshold triggered subpopulations of vesicles to fuse and the size of the subpopulations was dependent upon the magnitude of the calcium stimulus. The existence of multiple, stable subpopulations of vesicles is consistent with a fusion process that requires the action of an even greater number of calcium ions than the numbers suggested by models based on the assumption of a homogeneous vesicle population.

Animals↗
PubMed1998

The calcium sensitivity of individual secretory vesicles is invariant with the rate of calcium delivery.

Differences in the calcium sensitivity of individual secretory vesicles can explain a defining feature of calcium-regulated exocytosis, a graded response to calcium. The role of the time dependence of calcium delivery in defining the observed differences in the calcium sensitivity of sea urchin egg secretory vesicles in vitro was examined. The calcium sensitivity of individual secretory vesicles (i.e., the distribution of calcium thresholds) is invariant over a range of calcium delivery rates from faster than micromolar per millisecond to slower than micromolar per second. Any specific calcium concentration above threshold triggers subpopulations of vesicles to fuse, and the size of these subpopulations is independent of the time course required to reach that calcium concentration. All evidence supports the hypothesis that the magnitude of the free calcium is the single controlling variable that determines the fraction of vesicles that fuse, and that this fraction is established before the application of calcium. Submaximal responses to calcium cannot be attributed to alterations in the calcium sensitivity of individual secretory vesicles arising from the temporal properties of the calcium delivery. Models that attempt to explain the cessation of fusion using changes in the distribution of calcium thresholds arising from the rate of calcium delivery and/or adaptation are not applicable to this system, and thus cannot be general.

Animals↗
PubMed1997

Antibodies to ribosomal P proteins of Trypanosoma cruzi in Chagas disease possess functional autoreactivity with heart tissue and differ from anti-P autoantibodies in lupus.

Anti-P antibodies present in sera from patients with chronic Chagas heart disease (cChHD) recognize peptide R13, EEEDDDMGFGLFD, which encompasses the C-terminal region of the Trypanosoma cruzi ribosomal P1 and P2 proteins. This peptide shares homology with the C-terminal region (peptide H13 EESDDDMGFGLFD) of the human ribosomal P proteins, which is in turn the target of anti-P autoantibodies in systemic lupus erythematosus (SLE), and with the acidic epitope, AESDE, of the second extracellular loop of the beta1-adrenergic receptor. Anti-P antibodies from chagasic patients showed a marked preference for recombinant parasite ribosomal P proteins and peptides, whereas anti-P autoantibodies from SLE reacted with human and parasite ribosomal P proteins and peptides to the same extent. A semi-quantitative estimation of the binding of cChHD anti-P antibodies to R13 and H13 using biosensor technology indicated that the average affinity constant was about 5 times higher for R13 than for H13. Competitive enzyme immunoassays demonstrated that cChHD anti-P antibodies bind to the acidic portions of peptide H13, as well as to peptide H26R, encompassing the second extracellular loop of the beta1 adrenoreceptor. Anti-P antibodies isolated from cChHD patients exert a positive chronotropic effect in vitro on cardiomyocytes from neonatal rats, which resembles closely that of anti-beta1 receptor antibodies isolated from the same patient. In contrast, SLE anti-P autoantibodies have no functional effect. Our results suggest that the adrenergic-stimulating activity of anti-P antibodies may be implicated in the induction of functional myocardial impairments observed in cChHD.

Amino Acid Sequence↗
PubMed1997

Viral regulation of CD95 expression and apoptosis in T lymphocytes.

T lymphocyte apoptosis has been observed in vivo in association with viral infections. One mechanism known to mediate T cell apoptosis is the CD95 (Fas/APO-1) Ag apoptotic pathway. CD95 is a cell surface protein that is expressed on activated T cells and is capable of relaying an intracellular apoptotic signal upon binding with CD95 ligand. CD95-dependent apoptosis has been shown to be involved in the homeostatic control of peripheral T cell numbers; however, the functional significance of the CD95 apoptotic pathway in the context of viral infections has not been clearly elucidated. We show that exposure to a variety of viral pathogens causes enhanced CD95 expression in naive peripheral blood cell T lymphocytes without leading to enhanced susceptibility to CD95-dependent apoptosis. Productive viral infection was not required for this effect. Furthermore, using a T cell line and the K562 tumor cell line, we demonstrate that cells normally resistant to CD95-mediated killing become susceptible when productively infected with virus in a manner that does not rely on increased CD95 surface expression. These findings demonstrate a regulatory influence of viral infection on CD95 expression and activity and suggest that in addition to having a role in T cell homeostasis, the CD95 apoptotic pathway might also function to eliminate virus-infected T cells.

Adult↗
PubMed1997

Fas ligand deficiency in HIV disease.

Apoptosis is postulated to be involved as an anti-viral immune mechanism by killing infected cells before viral replication has occurred. The Fas-Fas ligand interaction is a powerful regulator of T cell apoptosis and could potentially act as a potent anti-viral immune mechanism against T cell tropic virus such as human immunodeficiency virus (HIV). We investigated the status of Fas ligand in peripheral blood mononuclear cells (PBMCs) obtained from persons infected with HIV. We found that monocytes in freshly isolated PBMCs from healthy individuals possess cell surface Fas ligand. In contrast, monocytes in freshly isolated PBMCs from HIV-infected patients had no detectable Fas ligand on the cell surface. Consistent with these findings of surface expression, Fas ligand activity was deficient in the cells from HIV-infected persons. The effect of replacing Fas ligand activity on HIV production by patients' cells was assessed in an in vitro assay. The addition of a functional anti-Fas antibody to PBMCs from HIV-infected individuals inhibited viral production by greater than 90% without affecting lymphocytic function. These findings suggest the possibility of a new therapeutic modality for the treatment of HIV-infected individuals based on the reconstitution of Fas ligand activity.

Antigens, CD↗
PubMed1997

Two restricted sites on the surface of the nerve growth factor molecule independently determine specific TrkA receptor binding and activation.

Nerve growth factor (NGF) and neurotrophin-3 (NT-3) mediate activities such as survival, differentiation, and proliferation in various subsets of neurons. In this report, we define precisely the residues in human NGF responsible for NGF biological activity and binding specificity to the neurotrophin receptor TrkA. In earlier studies we defined five amino acid residues of NGF which confer NGF-like activity to NT-3 when replacing corresponding residues in the 120-amino acid long NT-3 molecule. Using this gain-of-function strategy we report the further dissection of this functional epitope. We also define another motif separated topographically in the NGF dimer and determined to be independently responsible for NGF specificity. The first of the two motifs determined to elicit NGF specificity is defined by the residues Val-48, Pro-49, and Gln-96, which are situated in the two top beta-loops of NGF. The second motif is represented by residues Pro-5 and Phe-7 situated in the proximal part of the NH2 terminus. Both motifs contain structurally important residues revealing a novel principle, where specificity for neurotrophin ligand-receptor interactions could be determined by variable residues modifying the conformation of the neurotrophin backbone. These findings will enhance further the possibility of mimicking NGF with low molecular weight compounds.

Amino Acid Sequence↗
PubMed1997

The relationship between schizophrenia and irritable bowel syndrome (IBS).

Irritable bowel syndrome (IBS) has been reported in 10-22% of adults. Amongst patients seeking medical attention for IBS 70-90% may have psychiatric co-morbidity, most commonly major depression. In contrast, few studies have looked at the prevalence of IBS in psychiatric patients. To our knowledge, there are no studies assessing the prevalence of IBS in patients with schizophrenia. Using a semistructured clinical interview to study the prevalence of IBS, we compared 47 patients with schizophrenia to an age-matched control group (n = 40) of patients who were seeking treatment in a primary care physicians office for other medical illnesses. IBS was diagnosed according to the criteria of Drossman et al. Nineteen percent (n = 9) of the patients with schizophrenia met criteria for IBS in contrast to 2.5% (n = 1) of the control group (p = 0.012). Schizophrenic patients seldom complain of gastrointestinal symptoms until specifically asked. Therefore, it may be important to inquire about gastrointestinal symptoms prior to initiating pharmacotherapy in order to differentiate side effects from a prior existing condition. Prospective studies should address the question whether remission of psychosis leads to improvement or resolution of IBS.

Adult↗
PubMed1997

NGF and neurotrophin-3 both activate TrkA on sympathetic neurons but differentially regulate survival and neuritogenesis.

In this report we examine the biological and molecular basis of the control of sympathetic neuron differentiation and survival by NGF and neurotrophin-3 (NT-3). NT-3 is as efficient as NGF in mediating neuritogenesis and expression of growth-associated genes in NGF-dependent sympathetic neurons, but it is 20-40-fold less efficient in supporting their survival. Both NT-3 and NGF induce similar sustained, long-term activation of TrkA, while NGF is 10-fold more efficient than NT-3 in mediating acute, short-term TrkA activity. At similar acute levels of TrkA activation, NT-3 still mediates neuronal survival two- to threefold less well than NGF. However, a mutant NT-3 that activates TrkC, but not TrkA, is unable to support sympathetic neuron survival or neuritogenesis, indicating that NT-3-mediated TrkA activation is necessary for both of these responses. On the basis of these data, we suggest that NGF and NT-3 differentially regulate the TrkA receptor both with regard to activation time course and downstream targets, leading to selective regulation of neuritogenesis and survival. Such differential responsiveness to two ligands acting through the same Trk receptor has important implications for neurotrophin function throughout the nervous system.

Animals↗
PubMed1997

Effect of recombinant human erythropoietin on transfusion risk in coronary bypass patients.

BACKGROUND: Patients having a cardiac operation frequently require allogeneic blood transfusions despite surgical blood-conservation techniques. Recombinant human erythropoietin (Epoetin alfa) may augment this conservation by stimulating erythropoiesis. The safety and efficacy of perioperative use of Epoetin alfa to reduce the need of allogeneic transfusion was studied. METHODS: A multicenter double-blind, placebo-controlled, parallel-group study involved 182 patients having coronary artery bypass grafting and randomized to receive Epoetin alfa (300 or 150 IU/kg) or placebo subcutaneously for 5 days before, on the day of, and for 2 days after operation. RESULTS: Perioperative Epoetin alfa resulted in greater increases in baseline to preoperative hemoglobin levels and hematocrit (300 IU/kg) and in presurgery to postsurgical day 1 reticulocyte counts versus placebo (p < or = 0.05). However, there was no significant difference in transfusion requirements. Incidences of adverse events were similar in all study groups. CONCLUSIONS: Lower incidences of allogeneic blood exposure were observed in both Epoetin alfa-treated groups; however, the differences between all treatment groups were not significant. This was probably due to the relatively short 5-day preoperative course of Epoetin alfa therapy. There were no significant differences between the three groups relative to safety. Epoetin alfa was well tolerated in this population.

Antibodies↗
PubMed1997

The protective effect of class III antiarrhythmic agents against calcium overload in cultured myocytes.

Calcium ions have been implicated in the mechanisms of ventricular arrhythmias. Impairment of intercellular coupling by calcium overload is considered to facilitate ventricular fibrillation (VF) and to sup-press its self termination. According to our hypothesis, any compound that decreases intracellular calcium concentration [Ca2+]i during VF can serve as defibrillating drug. In this study, we examined the effect of d-sotalol and tedisamil on calcium overload in cultured, spontaneously beating rat cardiomyocytes. The changes of [Ca2+]i were measured by indo-1 method and the intercellular synchronization by image analysis. The results showed that increase in [Ca2+]o from 1.9 mM to 3.9 mM increased [Ca2+]i from 100 nM to 320 nM and transformed the synchronized cell movement to an asynchronous one. Administration of 5 x 10(-6) M d-sotalol or 10(-6) M tedisamil, decreased the [Ca2+]i to its basic level and restored the synchronized activity. In summary: Our results showed that increase in [Ca2+]i known to cause inhibition of intercellular coupling, that could lead to arrhythmia and fibrillation while d-sotalol or tedisamil prevented this effect. These results support our hypothesis, that class III antiarrhythmic compounds with positive inotropic effect, increase intercellular synchronization, by decreasing free [Ca2+]i, most probably by increasing the Ca2+ uptake by the sarcoplasmic reticulum, and therefore act as a defibrillating compound.

Animals↗
PubMed1997

Incorporation of 2-hydroxyl fatty acids by Acinetobacter calcoaceticus RAG-1 to tailor emulsan structure.

Acinetobacter calcoaceticus RAG-1 was cultured on different chain length saturated 2-hydroxyl fatty acid (2-HOFA) carbon sources as follows: C12:0 (2-OH), C14:0 (2-OH), C16:0 (2-OH) and C18:0 (2-OH). These 2-HOFAs were used as either sole carbon sources or cosubstrates with C14:0 (total 1% w/v) to form new emulsans (EMs) having controlled side chain FA structure and, therefore, unique emulsifier characteristics. EM yields and cell dry weights ranged from 0.6 to 1.8 g/l and 0.9 to 3.9 g/l, respectively, depending on the carbon source(s) and the cultivation conditions. The content of C12:0 (2-OH) EM substituents reached high levels (306 nmol/mg-EM, 64.4 mol% of total FAs) by selectively feeding this FA. Substantial quantities of 2-HOFAs with chain lengths > or = C14-up to 96 nmo1/mg-EM or 15.2 mol% for C16:0 (2-OH)-were also incorporated in EMs by providing the corresponding 2-HOFA carbon source in the medium. By increasing the medium 2-HOFA concentration large increases in EM total FA contents resulted. The EM FA content was as high as 955 nmol/mg-EM or 23 wt% for a culture containing 0.75 g/100 ml C18:0 (2-OH). An important metabolic pathway involved in EM side chain formation from C16:0 (2-OH) and C18:0 (2-OH) involves decarboxylation, oxidation of the alkanol to the corresponding n-1 FA-CoA intermediate and formation of odd chain length substituent side chain linkages by an EM acyl transferase. Addition of the enzyme alkylating agent iodoacetamide to cultures was used to: (i) enhance the incorporation into EMs of both C12:0 (2-OH) and C16:0 (2-OH) substituents; and (ii) increase by 1.3 to 1.8 fold (by wt.) the total EM FA content. Finally, it was concluded that enhanced emulsification activity of EMs is not necessarily achieved by forming products with relatively high 2- and 3-hydroxydodecanoic acid contents.

Acinetobacter calcoaceticus↗
PubMed1997

Activation of trk-A but not trk-B signal transduction pathway inhibits growth of neuroblastoma cells.

In neuroblastoma tumours, the expression of high levels of trk-A mRNA, which encodes the high-affinity nerve growth factor (NGF) receptor, is associated with good prognosis. Constitutive expression of brain-derived neurotrophic factor (BDNF) and variable expression of its receptor trk-B are frequently detected in tumours from patients with a poor prognosis. To evaluate the biological consequences of activation of the trk-A or trk-B signal transduction pathways in neuroblastoma cells, the trk-A or trk-B gene was transfected into the trk negative 15N neuroblastoma cell line. Clones expressing trk-A or trk-B were treated with specific ligands and evaluated for growth and differentiation. Both ligands induced neurite extension. Treatment of the 15N-trk-A clones with NGF inhibited proliferation (80-90% decrease), while treatment of the 15N-trk-B clone with BDNF had no effect (< 10% decrease). NGF-induced growth inhibition was concentration dependent. Such studies indicate that differential trk expression may affect the biology of neuroblastoma tumours and contribute to differences in the clinical course of patients.

Brain-Derived Neurotrophic Factor↗
PubMed1997

Immunization with recombinant Trypanosoma cruzi ribosomal P2beta protein induces changes in the electrocardiogram of immunized mice.

Molecular expression cloning techniques revealed that patients with severe chronic Chagas heart disease showed a strong humoral response against the cloned C-terminal portion of the Trypanosoma cruzi ribosomal P2beta protein, previously named JL5. The main linear epitope of this polypeptide was mapped to the 13 C-terminal amino acid sequence EEEDDDMGFGLFD (named R13), which is almost identical to the mammalian ribosomal P consensus sequence EESDDDMGFGLFD (named H13). Enzyme-linked immunosorbent assay measurements demonstrated that sera from patients with chronic Chagas heart disease presented a very specific anti-P humoral response with high anti-R13, but low H13 antibody levels. We attempted to develop an animal model that would reproduce, at least partially, two features of the human infection: (1) the serological pattern of the anti-P response, and (2) specific cardiac symptoms. To this effect, mice were immunized with T. cruzi P2beta recombinant protein. Immunization reproduced the typical anti-P antibody profile defined for chronic infections, but did not induce cardiac inflammatory lesions. However, it altered significantly the electrocardiograms of immunized mice. It is suggested that this assay represents a functional test for assessing the biological activity of antibodies against T. cruzi ribosomal P protein on cardiac muscle.

Animals↗
PubMed1997

Dyskinesias subside off all medication in a boy with autistic disorder and severe mental retardation.

A boy with autistic disorder and severe mental retardation developed severe dyskinesias, including objective akathisia (probable) and tics, a month after discontinuation of at least two years of treatment with drugs block dopamine receptors. These dyskinesias greatly subsided during a 17-wk. open-label nonblind clinical trial of clomipramine, and returned transiently when the parents abruptly discontinued clomipramine. However, the dyskinesias gradually subsided during two and a half years of follow-up with the boy being off all medication. A few stereotypies remain. We believe this suggests the hypothesis that movement disorders, such as withdrawal and tardive akathisia and tics, occurring in boys with autistic disorder treated with dopamine receptor-blocking drugs may subside months or years after discontinuation of the agents and that clomipramine may facilitate this process. We also hypothesize that some boys with autistic disorder and mental retardation exhibit fewer movement disorders, fewer psychiatric symptoms, and better over-all functioning after they have received no dopamine receptor-blocking drugs for several months, and this improvement continues years after the medication has ceased.

Akathisia, Drug-Induced↗