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Biomedical subjects

S Handa

Publications and source records attributed to S Handa.

At least 109 records · Page 6Linked to original sources
PubMed1997

Pathogenesis of the neurotoxicity caused by anti-GD2 antibody therapy.

After treatment of melanomas with anti-GD2 monoclonal antibody (MAb) (14G2a), some patients develop sensorimotor demyelinating polyneuropathy with and without the syndrome of inappropriate antidiuretic hormone (SIADH). To clarify what causes the neurotoxicity of anti-GD2 MAb, we investigated the immunohistochemical localization of GD2 in the human nervous system. Anti-GD2 MAb (14G2a) reacted with the myelin sheaths in the peripheral nerves as well as with the pituicyte cytoplasm in the posterior lobe of the pituitary gland. We assume that the binding of anti-GD2 MAb to peripheral nerve myelin and the pituicytes in the posterior pituitary causes sensorimotor demyelinating neuropathy and SIADH.

Animals↗
PubMed1997

Close association of Guillain-Barré syndrome with antibodies to minor monosialogangliosides GM1b and GM1 alpha.

Cumulative evidence supports the theory that anti-ganglioside antibodies function in the development of Guillain-Barré syndrome (GBS). Some patients have developed GBS after the administration of monosialoganglioside extracted from bovine brain. To clarify the pathogenesis of GBS associated with and without administration of the monosialoganglioside fraction, we investigated serum antibodies to the minor monosialogangliosides GM1b and GM1 alpha in patients with GBS and in control patients. GM1b and GM1 alpha were recognized specifically by the IgG antibody from the GBS patients. Twelve of 20 GBS patients who had high IgG anti-GM1b antibody titers had a preceding gastrointestinal infection. To evaluate the hypothesis that GM1b could be an immunogen, we determined whether a GM1b epitope was present in Campylobacter jejuni isolated from a patient with GBS associated with anti-GM1b antibody. Immunostaining with the monoclonal anti-GM1b antibody indicated that the lipopolysaccharide of the C. jejuni strain has the GM1b epitope. We speculate that an injection of bovine GM1 fraction that contains GM1b, as well as infection by an agent that bears the GM1b epitope, induces production of the anti-GM1b antibody which functions in the development of GBS in some patients.

Animals↗
PubMed1997

gp49B1, an inhibitory signaling receptor gene of hematopoietic cells, is induced by leukemia inhibitory factor in the uterine endometrium just before implantation.

Leukemia inhibitory factor (LIF) is a cytokine involved in hematopoiesis, neuropoiesis, and embryogenesis. Transcriptional activation of various genes occurs subsequent to LIF signal transduction in its target cells. Using the mRNA differential display method, a LIF-inducible gene was isolated from LIF-stimulated M1 murine myeloid leukemia cells. By DNA sequencing, this gene turned out to be gp49B1, which has been reported as an inhibitory signaling receptor to attenuate mast cell activation. Because gp49B1 expression was limited to the uterus of a pregnant mouse, its uterine expression was examined especially in relation to LIF expression during pregnancy. gp49B1 was expressed specifically on day 4.0 of pregnancy, as was LIF, and the site of the most abundant expression of LIF and gp49B1 mRNA was the luminal epithelium of the uterine endometrium. These findings suggest that the gp49B1 expression in the uterine endometrium is induced just before implantation by paracrine and/or autocrine effects of LIF. Considering its function as an inhibitory signaling receptor on mast cells, a possible role for gp49B1 on the surface of the uterine endometrium as an immunoreceptor that allows blastocyst attachment is proposed.

Animals↗
PubMed1997

Detection of antibodies to a recombinant gag protein derived from human endogenous retrovirus clone 4-1 in autoimmune diseases.

To investigate whether human endogenous retroviruses (HERV) contribute to autoimmune diseases, we prepared a recombinant p30gag protein derived from clone 4-1 of the HERV family, using a baculovirus-vector system. This p30gag protein (CA41B) was approximately 30 kDa, as expected, and reacted with antibodies for p30gag purified from both murine and feline leukemia virus. This result suggested that the antigenic determinant for p30gag was well conserved in CA41B. Analysis of serum antibodies to p30gag in patients with autoimmune diseases was done by Western blotting. CA41B detected anti-p30gag antibodies in 48.3% of systemic lupus erythematosus (SLE) patients, 35.0% of Sjögren's syndrome (SS) patients, and 33.3% of mixed connective tissue disease (MCTD) patients, whereas no anti-p30gag antibodies were found in healthy subjects. This suggested that HERV p30gag or other retroviral p30gag proteins possessing the same antigenic determinant as CA41B may play a role in these diseases. Although detection of antibodies to HERV p30gag in autoimmune diseases is indirect evidence that HERV proteins are involved, this study showed that patients with autoimmune diseases have antibodies to HERV p30gag using a recombinant HERV protein rather than synthetic peptides based on HERV or retroviral proteins of other species.

Animals↗
PubMed1997

Differences in refractory-period response of canine subendocardium and subepicardium to bunazosin, an alpha1-adrenoceptor antagonist, and propranolol during myocardial ischemia.

Our objective was to investigate the effects of alpha1- or beta-adrenoceptor blockers on endocardial and epicardial refractory-period changes during myocardial ischemia in alpha-chloralose-anesthetized dogs. The first and second diagonal branches of the left anterior descending coronary artery were ligated. The refractory period was determined by an S1-S2 extrastimulus method. Dogs were treated with the alpha1-blocker bunazosin (0.1-0.2 mg/kg, i.v.; n = 16), the beta-blocker propranolol (0.2 mg/kg, i.v.; n = 15), or saline (n = 11). Dogs that developed ventricular tachycardia/fibrillation (VT/VF) during the experiment were excluded from the statistical assessment in refractory periods. In all groups, coronary ligation produced a significant shortening of the refractory period of ischemic epicardial tissue (p < 0.05) but only minimal shortening of ischemic endocardial refractory periods, resulting in an increased difference in repolarization time between the endo- and epicardial sites. Treatment with bunazosin ameliorated this ischemia-related shortening of refractory periods at both the endo- and epicardial sites, with a greater effect seen epicardially (p < 0.05), resulting in values similar to those in the nonischemic tissue. Treatment with propranolol prolonged refractory periods more in the epicardial (p < 0.01) than in endocardial sites, exacerbating the disparity in the refractory period between the endo- and epicardial sites (p < 0.05). Propranolol also prolonged the refractory period of nonischemic tissue (p < 0.05 and p < 0.01 in endo- and epicardial sites, respectively), resulting in a significant difference between the ischemic and normal myocardium at the endocardial site (p < 0.05). Results suggest that the alpha1-blocker bunazosin reduces the refractory-period disparity between the ischemic and normal myocardium without increasing the disparity between the endo- and epicardial surfaces, whereas propranolol produces a greater disparity.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1997

Natural history of psoriasis: a study from the Indian subcontinent.

Clinical and epidemiological data from 1220 patients with psoriasis is presented. Psoriatics accounted for 2.3% of the total dermatology outpatients. There was a distinct male preponderance. Mean age of onset was lower in women at 27.6 years, although the severity of the disease was the same in both sexes. Family history was positive in just 2% of patients. Plaque type disease was the most common, seen in over 93% of the patients. Lesional pruritus was a problem in 65%. Remission in summer was experienced by 43%. The scalp was the first site of onset in 25.2%. Nail and joint involvement were seen in 55.7% and 4.4%, respectively. Complete remission of disease activity was experienced by 35% of the patients during some part of the year in the course of their disease.

Adolescent↗
PubMed1997

Does erythropoietin accelerate malignant transformation in multiple myeloma?

Growth factors or humoral agents can support haemopoiesis in various bone marrow disorders. They have the ability to act on multiple cell lineages and in myeloid cells, and the potential to act on the neoplastic equivalent of normal cells. Anaemia is a common feature of multiple myeloma seen in at least two-thirds of patients at presentation. Erythropoietin is increasingly being used with variable effect for the treatment of this anaemia, especially in cases associated with renal failure and in patients in whom blood transfusion may be undesirable or contraindicated. We describe a patient treated with recombinant erythropoietin who developed fulminating malignant transformation. The demonstration of erythropoietin receptors on a human myeloma cell line and the occurrence of the rare complication of plasma cell leukaemia in our patient stresses the need for caution and invites detailed clinical and laboratory studies before its general use.

Anemia↗
PubMed1997

Abnormal beta-adrenergic transmembrane signaling in rabbits with adriamycin-induced cardiomyopathy.

We investigated alterations in the beta-adrenergic receptor-adenylate cyclase system in rabbits with congestive heart failure induced by adriamycin cardiotoxicity. A dose of 24 mg/kg adriamycin was administered over 16 weeks in 16 rabbits. Five of them died and 4 of them could not tolerate the full dose of adriamycin. Complete data were obtained in the remaining 7 rabbits. Another 7 rabbits received physiological saline for the same period and served as controls. Plasma norepinephrine concentration increased in adriamycin-treated rabbits, but not in the control rabbits. Cardiac output was lower in the adriamycin-treated group than in the control group. Both the left and right ventricular end-diastolic pressure were higher in the adriamycin-treated group. The density of myocardial beta-adrenergic receptors and the norepinephrine content were reduced in both ventricles in the adriamycin-treated group. Basal and isoproterenol-, sodium fluoride- and forskolin-stimulated adenylate cyclase activities were lower in the adriamycin-treated group. Thus, alterations in beta-adrenergic signaling occurred in both ventricles in animals with chronic biventricular failure induced by adriamycin. These may be the result of post-receptor abnormalities, including abnormalities of guanine nucleotide-binding proteins or of the catalytic unit of adenylate cyclase.

Adenylyl Cyclases↗
PubMed1997

Effect of chronic digoxin on beta-adrenergic receptors in rabbits with heart failure.

This study investigated the effect of chronic digitalis glycoside use on beta-adrenergic sympathetic activities in heart failure. Twenty-two Japanese white rabbits were anesthetized by intravenous injection of chloral hydrate. Aortic regurgitation (AR) was produced by perforating aortic valves in 14 rabbits. Digoxin was given for 1 week to 7 rabbits with AR (AR + Dig) and saline to 7 rabbits with AR (AR + C). Sham operation was performed in the remaining 8 rabbits (S). The left ventricular end-diastolic pressure was higher in AR + C than S (p < 0.05). It was lower in AR + Dig than AR + C (p < 0.05). Cardiac output was lower in AR + C than S (p < 0.05). There was no difference between AR + Dig and S. Both the left ventricular end-diastolic and end-systolic diameters were larger in AR + C (p < 0.05) than S, but they were similar between AR + Dig and S. Plasma norepinephrine level was lower in AR + Dig than AR + C. Myocardial beta-adrenergic receptors number determined by radioligand binding assay using 30-800 pM 125I-iodocyanopindolol was lower in AR + C than S (28.8 +/- 7.9 vs. 69.9 +/- 12.3 fmol/mg protein, p < 0.05). It was higher in AR + Dig (39.9 +/- 9.8) than AR + C (p < 0.05). Myocardial norepinephrine content was lower in both AR + C (p < 0.05) and AR + Dig than S (p < 0.05). Thus, digitalis glycosides exert favorable effects on beta-adrenergic sympathetic activities in addition to the effects on hemodynamic variables in this animal model of heart failure.

Animals↗
PubMed1997

Differentiating agent, hexamethylene bisacetamide, inhibits neointimal formation after vascular injury.

BACKGROUND: Hexamethylene bisacetamide (HMBA), a potent differentiating agent of transformed cell lines, has been reported to affect phenotypic modulation and suppress proliferation of vascular smooth muscle cells (VSMCs). The effects of HMBA on the growth of VSMCs were studied in the rat carotid injury model. METHODS: HMBA was added to culture medium of VSMCs explanted from aorta of Sprague Dawley rats and the cell number was counted after 5 days of incubation. The carotid artery of Sprague Dawley rats was denuded with a balloon embolectomy catheter. The rats were treated with continuous infusion of HMBA (1 g/day) or saline for 7 days after injury. RESULTS: HMBA inhibited VSMC proliferation in a dose-dependent manner (at a HMBA concentration of 1-5 mM). Plasma concentration of HMBA during continuous infusion was in the range 0.8-1.0 mM. Immunohistochemistry of proliferating cell nuclear antigen showed that HMBA inhibited VSMC proliferation after vascular injury. Cell number in the intima and neointimal thickening were significantly reduced in HMBA-treated rats at 14 days after injury. CONCLUSIONS: Systemic administration of HMBA inhibited VSMC proliferation in the rat carotid injury model.

Acetamides↗
PubMed1996

Sulfatide is expressed in both erythrocytes and platelets of bovine origin.

A novel sulfated glycosphingolipid containing a sulfated galactosyl residue was isolated from bovine erythrocyte ghosts, and purified to homogeneity by column chromatography on DEAE-Sephadex and silica beads. Structural characterization included compositional analyses, permethylation studies, proton nuclear magnetic resonance (NMR) spectroscopy, negative secondary ion mass spectrometry (SIMS), solvolysis and immunostaining on thin-layer chromatogram. As a result, the structure of this glycolipid is proposed as HSO3-Gal beta 1-1 Cer. The ceramide portion contained d18:1, d18:0 and t18:0, and the predominant fatty acid consisted of palmitate and palmitate with a hydroxy group, as deduced by both compositional analysis and negative SIMS mass spectrometry. The component of this glycosphingolipid probably originates from erythrocytes and platelets as indicated by the results of flow cytometry analysis using Sulph I monoclonal antibody. The yield of galactosyl sulfatide was about 0.37 mg/kg wet bovine erythrocyte membranes, about three times that of human kidney. Our results strongly suggest that galactosylceramide sulfate on erythroid cells may play an important biological role in cell to cell interaction and recognition.

Animals↗
PubMed1996

Synergistic effect of epinephrine and shearing on platelet activation.

Platelet activation mediated through the interaction between von Willebrand factor (vWF) and platelet glycoprotein (GP) Ib is known to occur under high shear rate. We have demonstrated that low concentration of epinephrine could reduce the threshold level of shear rate necessary to cause platelet activation with purified system devoid of the effect of plasma proteins other than vWF. Both the extent of platelet aggregation and [Ca2+]i were continuously measured with optically modified cone-and-plate viscometer. No aggregation with no change in [Ca2+]i occurred under shear rate less than 7,200 s-1 in the absence of exogeneously added epinephrine. Epinephrine enhanced platelet aggregation under moderate level of shear rate (7,200 s-1) in a dose dependent manner. Significant aggregation with rise in [Ca2+]i was demonstrated even under the low shear rate of 1,200 s-1 when exogeneously added low concentration of epinephrine (0.05 microM) which did not cause platelet activation by itself was present. Aggregation and rise in [Ca2+]i under low shear in the presence of epinephrine was abolished by monoclonal antibodies against A1 domain of vWF or GP Ib, like aggregation and the rise in [Ca2+]i occurred under high shear rate (10,800 s-1), alpha 2-receptor blockade yohimbine completely antagonized the enhancing effects of epinephrine. Our findings suggested that epinephrine and shearing synergistically activated platelets through vWF interaction to GP Ib, which might suggest the role of sympathetic stimulation for the onset of acute arterial thrombosis.

Blood Viscosity↗
PubMed1996

Ceramide induces apoptosis via CPP32 activation.

Although both ceramide and interleukin-1beta converting enzyme (ICE) family proteases are key molecules during apoptosis, their relationship remains to be elucidated. We report here that cell-permeable ceramide induced cleavage and activation of CPP32, a Ced-3/ICE-like protease, but not ICE. Ceramide-induced apoptosis of Jurkat cells was blocked by the CPP32-specific tetrapeptide inhibitor DEVD-CHO, but not by the ICE inhibitor YVAD-CHO. Furthermore, variant Jurkat cells with defective CPP32 activation were resistant to both anti-Fas- and ceramide-induced apoptosis. These results indicate that CPP32 activation is required for ceramide-induced apoptosis, and suggest sphingomyelin-ceramide pathway functions upstream of CPP32.

Apoptosis↗
PubMed1996

Controlling substrate preference and transglycosylation activity of neopullulanase by manipulating steric constraint and hydrophobicity in active center.

The substrate specificity and the transglycosylation activity of neopullulanase was altered by site-directed mutagenesis on the basis of information from a three-dimensional structure predicted by computer-aided molecular modeling. According to the predicted three-dimensional structure of the enzyme-substrate complex, it was most likely that Ile-358 affected the substrate preference of the enzyme. Replacing Ile-358 with Trp, which has a bulky side chain, reduced the acceptability of alpha-(1-->6)-branched oligo- and polysaccharides as substrates. The characteristics of the I358W-mutated enzyme were quite different from those of wild-type neopullulanase and rather similar to those of typical starch-saccharifying alpha-amylase. In contrast, replacing Ile-358 with Val, which has a smaller side chain, increased the preference for alpha-(1-->6)-branched oligosaccharides and pullulan as substrates. The transglycosylation activity of neopullulanase appeared to be controlled by manipulating the hydrophobicity around the attacking water molecule, which is most likely used to cleave the glucosidic linkage in the hydrolysis reaction. We predicted three residues, Tyr-377, Met-375, and Ser-422, which were located on the entrance path of the water molecule might be involved. The transglycosylation activity of neopullulanase was increased by replacing one of the three residues with more hydrophobic amino acid residues; Y377F, M375L, and S422V. In contrast, the transglycosylation activity of the enzyme was decreased by replacing Tyr-377 with hydrophilic amino acid residues, Asp or Ser.

Amino Acid Sequence↗
PubMed1996

A simple assay method for bacterial binding to glycosphingolipids on a polyvinylidene difluoride membrane after thin-layer chromatography blotting and in situ mass spectrometric analysis of the ligands.

A simple assay method for bacterial binding to glycosphingolipids on a polyvinylidene difluoride (PVDF) membrane has been developed. Glycosphingolipids were separated on a high-performance thin-layer chromatography (HPTLC) plate and transferred onto a PVDF membrane by TLC blotting [Taki, T., Handa, S., and Ishikawa, D. (1994) Anal. Biochem. 221, 312-316]. The PVDF membrane was blocked with phosphate-buffered saline containing 4% casein and 0.1% methionine and overlaid with 35S-labeled Escherichia coli possessing K99 fimbriae (E. coli K99) at 37 degrees C for more than 2 h. Binding of the 35S-labeled E. coli K99 was detected with a bioimaging analyzer. Radioactivities were located on the bands corresponding to N-glycolylneuraminic acid containing glycosphingolipids such as sialylparagloboside, GM2, and GM3 with hydroxy fatty acid in ceramide moiety, and a weak binding was detected on the band of N-acetylneuraminylparagloboside. Furthermore, an in situ mass spectrometric analysis of the ligand glycosphingolipids on the membrane was demonstrated. The present method has several advantages compared with the overlay binding assay on the HPTLC plate as follows: (i) the method is simple and rapid; (ii) the membrane is easy to handle; (iii) binding is clear with low background; (iv) a small amount of [35S]methionine is required; and (v) sensitive ligand characterization can be done by in situ mass spectrometric analysis.

Bacterial Adhesion↗