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Biomedical subjects

M T Lin

Publications and source records attributed to M T Lin.

At least 73 records · Page 4Linked to original sources
PubMed1999

Prophylactic treatment with growth hormone and insulin-like growth factor I improve systemic bacterial clearance and survival in a murine model of burn-induced gut-derived sepsis.

The purpose of this investigation was to evaluate the effects of GH and IGF-I administration in a murine model of burn-induced gut-derived sepsis. BALB/C mice were treated with 4.8 mg/kg/day of GH, 24 mg/kg/day of IGF-I or saline for 4 days. They were then administered 10(10) E. coli by gavage and subjected to 20% full thickness flame burn. All mice received allogeneic blood transfusion 5 days before burn injury to induce mild immunosuppression. Seventy-three mice were observed for survival and 51 mice were sacrificed at 4 and 20 h postburn. Blood, mesenteric lymph nodes (MLN), spleen and liver were harvested aseptically, and viable bacterial counts in the organs were determined. The small intestine was harvested for the evaluation of villus height and mitoses in the crypts. GH and IGF-I groups showed a significantly better survival than the control group. GH and IGF-I groups had significantly greater villus height and mitoses/crypt than the control group. Translocation of bacteria was not significantly different among groups, however, the relation between the numbers of viable bacteria in MLN and blood suggests that both GH and IGF-I reduced systemic spread of translocated bacteria. It is concluded that GH and IGF-I had positive effects on outcome in this model of burn-induced gut-derived sepsis. It appears that GH and IGF-I may have immune-enhancing effects and that administration of these agents may be useful for burn injury.

Animals↗
PubMed1999

Enteral administration of glutamine in purulent peritonitis.

The intestinal hypomotility associated with purulent peritonitis is generally regarded as a contraindication to enteral nutrition. However, enteral nutrition may be feasible in suppurative peritonitis if administered with great caution, i.e., assuring the appropriate amount, delivery speed, and osmolality of the enteral formulation. Glutamine (Gln) increases muscle protein synthesis and decreases muscle protein degradation in sepsis, regardless of the route of administration. Therefore, administering small amounts of supplemental Gln via the enteral route to peritonitis patients may be beneficial. Two purulent peritonitis patients received L-Gln through a jejunostomy tube. The average amount of supplemental Gln was 16 g/d. Systemic inflammatory responses, i.e., high temperature and a high serum C-reactive protein level, persisted throughout the treatment period. Femoral arterial and venous blood samples were drawn simultaneously for determination of amino acid levels before and after 7 d of Gln supplementation. Enterally administered Gln was well-tolerated by both patients. There was an increase in plasma Gln levels after Gln supplementation. Moreover, the release of Gln, alanine, and phenylalanine from the lower extremities was lower after as compared to before Gln supplementation. Enteral administration of Gln may be feasible even in purulent peritonitis.

Amino Acids↗
PubMed1999

Central control of blood pressure by nitrergic mechanisms in organum vasculosum laminae terminalis of rat brain.

Experiments were carried out to explore the possible role played by the nitric oxide (NO) system in the organum vasculosum laminae terminalis (OVLT) of rat brain in arterial pressure regulation. Intracerebroventricular (ICV) or intra-OVLT administration of NO donors such as hydroxylamine, sodium nitro-prusside or s-nitro-acetylpenicillamine caused an up to 55 mmHg decrease in blood pressure (BP) but an increase in NO release (measured by porphyrin/nafion coated carbon fibre electrodes in combination with voltammetry) in the OVLT. In contrast, ICV or intra-OVLT administration of N(G)-nitro-L-arginine methyl ester (L-NAME; a constitutive NO synthase inhibitor) caused an up to 45 mmHg increase in BP but a fall in NO release in the OVLT. Compared with the BP responses induced by ICV injection of NO donors or NO synthase inhibitors, the OVLT route of injection required a much lower dose of NO donors or NO synthase inhibitors to produce a similar BP effect. The depressor effects induced by ICV or intra-OVLT administration of NO donors were attenuated by pretreatment with intra-OVLT injection of methylene blue (an inhibitor of guanylate cyclase), haemoglobin (a NO scavenger), L-NAME or spinal transection. On the other hand, the L-NAME-induced pressor effects were attenuated by pretreatment with intra-OVLT injection of L-arginine or spinal transection. The data suggest that activation of cyclic GMP-dependent NO synthase in the OVLT of rat brain causes cyclic GMP-dependent decreases in arterial pressure via inhibiting the sympathetic efferent activity.

Animals↗
PubMed1999

alpha-Difluoromethylornithine blocks thymocyte apoptosis via a reduction in tyrosine phosphorylation.

The effect of alpha-difluoromethylornithine on cell apoptosis was investigated. Freshly isolated mouse thymocytes were cultured in the medium alone or with dexamethasone, and apoptotic cell death was monitored after 6 h. A correlation was seen between cell apoptosis and a reduction in the polyamine levels of thymocytes. Addition of exogenous polyamines decreased the levels of apoptosis induced spontaneously in the culture medium or by dexamethasone. However, addition of alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, to the cultures did not enhance apoptosis but rather caused inhibition of thymocyte apoptosis. Analysis of the mechanism of alpha-difluoromethylornithine-mediated inhibition of apoptosis indicated that alpha-difluoromethylornithine treatment blocked protein tyrosine phosphorylation, which was elevated drastically during the first hour of thymocyte cultivation. Treatment with the phosphotyrosine phosphatase inhibitor phenylarsine oxide reversed this inhibitory effect of alpha-difluoromethylornithine on apoptotic cell death. Our results provide an alternative mechanism for alpha-difluoromethylornithine showing the inhibition of apoptosis via reduction of protein tyrosine phosphorylation.

Animals↗
PubMed1999

Pathogenesis of an experimental heatstroke model.

1. Heatstroke was induced by exposure under general anaesthesia to a high ambient temperature. The moment in which the mean arterial pressure (MAP) began to decrease from its peak level was taken as the onset of heatstroke. 2. Compared with normothermic controls, rats with heatstroke had higher values for colon temperature, neuronal damage score and heart rate, but lower MAP and cerebral blood flow. 3. Induction of heat shock protein, antagonism of interleukin-1 or N-methyl-D-aspartate receptors or depletion of brain monoamines protects against the heatstroke-induced arterial hypotension and cerebral ischaemic injury. 4. Thus, it appears that arterial hypotension and cerebral ischaemic damage is the main reason for development of heatstroke syndromes.

Animals↗
PubMed1999

Antiviral tannins from two Phyllanthus species.

Seven ellagitannins isolated from Phyllanthus myrtifolius and P. urinaria (Euphorbiaceae) have been shown, for the first time, to be active against Epstein-Barr virus DNA polymerase (EBV-DP) at the microM level. All these compounds have the same moiety of a corilagin, and differ from each other by different substitutions at C-2 and C-4 of the glucose core. SAR analysis and molecular modeling reveal that the essential pharmacophore of these tannins resides in the corilagin moiety. The outer complex carboxylic acid moieties appear to act only as auxopharmacore.

Antiviral Agents↗
PubMed1999

Identification of sporadic mutations in the helix initiation motif of keratin 6 in two pachyonychia congenita patients: further evidence for a mutational hot spot.

Pachyonychia congenita (PC) is a rare, autosomal dominant, ectodermal dysplasia characterized most distinctly by the presence of symmetric nail hypertrophy. In the Jadassohn-Lewandowsky form, or PC-1, additional cutaneous manifestations may include palmoplantar hyperkeratosis, hyperhidrosis, follicular keratoses, and oral leukokeratosis. Mutations have previously been identified in the 1A helix initiation motif of either keratin 6 or keratin 16 in patients with PC-1. In the current study, we have identified 2 sporadic, heterozygous mutations in the 1A helix region of the K6 isoform (K6a). The first mutation identified was a 3 base pair deletion (K6adelta N171). The second mutation was a C-to-A transversion resulting in an amino acid substitution (K6a N171K). These data, in combination with previous reports, provide further evidence that this location is a mutational hot spot.

Amino Acid Sequence↗
PubMed1999

Streptococcal pyrogenic exotoxin B induces apoptosis and reduces phagocytic activity in U937 cells.

Treatment of U937 human monocyte-like cells with Streptococcus pyogenes led to an induction of apoptosis in these cells. A comparison between the wild-type strain and its isogenic protease-negative mutant indicated that the production of streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, caused a greater extent of apoptosis in U937 cells. Further study using purified SPE B showed that this protease alone could induce U937 cells to undergo apoptosis, which was characterized by morphologic changes, DNA fragmentation laddering on the gel, and an increase in the percentages of hypodiploid cells. The protease activity of SPE B was required for apoptosis to proceed, since treatment with cysteine protease inhibitor E64 or heat inactivation abrogated this death-inducing effect. The SPE B-induced apoptosis pathway was interleukin-1beta converting enzyme (ICE) family protease dependent. Further experiments showed that the phagocytic activity of U937 cells was reduced by SPE B. Treatment with E64 and heat inactivation both abrogated this phagocytosis-inhibitory effect. Taken together, the present data show that SPE B not only possesses the ability to induce apoptosis in monocytic cells but also helps bacteria to resist phagocytosis by host cells.

Apoptosis↗
PubMed1999

Heat shock protein expression protects against cerebral ischemia and monoamine overload in rat heatstroke.

This study attempted to ascertain whether the ischemic damage to neurons and monoamine overload in brain that occur during rat heatstroke can be attenuated by heat shock protein (HSP) 72 induction. Effects of heatstroke on mean arterial pressure (MAP), cerebral blood flow (CBF), brain dopamine (DA) and serotonin (5-HT) release, and neural damage score were assayed in rats 0, 16, or 48 h after heat shock (42 degrees C for 15 min) or chemical stress (5 mg/kg sodium arsenite ip). Brain HSP 72 in rats after heat shock or chemical stress was detected by Western blot, and brain monoamine was determined by a microdialysis probe combined with high-performance liquid chromatography. Heatstroke was induced by exposing the animal to a high ambient temperature (43 degrees C); the moment at which MAP and CBF decreased from their peak values was taken as the time of heatstroke onset. Prior heat shock or chemical stress conferred significant protection against heatstroke-induced hyperthermia, arterial hypotension, cerebral ischemia, cerebral DA and 5-HT overload, and neural damage and correlated with expression of HSP 72 in brain at 16 h. However, at 48 h, when HSP 72 expression returned to basal values, the above responses that occurred during the onset of heatstroke were indistinguishable between the two groups (0 h vs. 48 h). These results lead to the hypothesis that the brain can be preconditioned by thermal or chemical injury, that this preconditioning will induce HSP 72, and that HSP 72 induction will correlate quite well with anatomic, histochemical, and hemodynamic protection in rat heatstroke.

Animals↗
PubMed1999

Allogeneic stem cell transplantation for patients with high-risk myelodysplastic syndrome.

Allogeneic stem cell transplantation (allo-SCT) is the only treatment with curative potential for patients with myelodysplastic syndrome (MDS). From June 1986 to April 1997, we treated 12 patients with primary MDS (5 men, 7 women, median age, 36.5 years) by allo-SCT. All patients had one or more of the following poor prognostic factors: intermediate-2 or high-risk categories according to the International Prognostic Scoring System; disease progression during follow-up; heavy transfusion requirements and recurrent infections. The median duration from diagnosis of MDS to allo-SCT was 6 months. The preconditioning regimen included total body irradiation combined with either high-dose cytarabine (n = 6), high-dose cyclophosphamide (n = 4), or other regimens (n = 2). Ten patients received bone marrow transplantations and two patients received peripheral blood stem cell transplantations. Prophylaxis for graft-versus-host disease (GVHD) consisted of standard cyclosporin and short-course methotrexate. Acute GVHD of grade 2 or above occurred in 10 patients, while chronic GVHD occurred in seven of the nine patients who survived longer than 6 months after allo-SCT. With a median follow-up of 50 months, all nine patients with human leukocyte antigen (HLA)-matched sibling donors survived. One patient had a relapse 6 months after transplantation and achieved complete remission again with low-dose cytarabine therapy. The three patients receiving allo-SCT from unrelated or HLA-mismatched donors died of grade 3 to 4 acute GVHD and infection within 5 months after transplantation. The estimated disease-free survival at 4 years was 67% (95% confidence interval, 40-93%), and the overall survival was 75% (95% confidence interval, 50-99%). Our data suggest that allo-SCT should be considered early in the clinical course for young MDS patients with a poor prognosis and a matched sibling donor.

Adult↗
PubMed1999

Ratio of bacteria to polymorphonuclear neutrophils (PMNs) determines PMN fate.

This study was designed to investigate how live Escherichia coli influence the fate of polymorphonuclear neutrophils (PMNs) in vitro. PMNs from 10 healthy volunteers were cocultured with or without live E. coli at different ratios. Heat-killed E. coli (Hk) were also added to PMNs at a ratio of 1:10. The PMNs were then analyzed by flow cytometry for cell death, reactive oxygen intermediates (ROI) production, and CD16 expression. Morphologic features were also assessed. PMN apoptosis was confirmed by DNA gel electrophoresis. Low doses of E. coli (PMN:E. coli ratios of 1:0.01 and 1:0.1) inhibited PMN apoptosis. In contrast, a high dose of E. coli (PMN:E. coli ratio of 1:10) increased PMN necrosis. ROI production was significantly greater at PMN:E. coli ratios of 1:10 and 1:10 (Hk) than at ratios of 1:0.01 and 1:0.1, or in PMNs cultured alone after a 15 or 30 minute coculture. CD16 expressions were significantly lower in PMNs cocultured with E. coli than in those cultured alone after a 4 or 12-h coculture. Tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6 levels in cell-free supernatants were also measured. The mean percentages of apoptosis at PMN:E. coli ratios of 1:0.01 and 1:10 (Hk), and in PMNs cultured alone after a 12-h coculture showed significant inverse correlations with these cytokine levels in cell-free supernatants at 12 h. Our results demonstrate that low doses of live E. coli inhibits predominantly PMN apoptosis, whereas a high dose of E. coli increases necrosis. Augmented PMN bactericidal function, via inhibition of PMN cell death, may be beneficial for host defense against bacterial infection and/or sepsis.

Apoptosis↗
PubMed1998

Heat shock protein expression protects against death following exposure to heatstroke in rats.

Rats 0, 16, or 48 h after heat shock (42 degrees C core temperature for 15 min) or chemical stress (5 mg/kg sodium arsenite, i.p.) were exposed to a high ambient temperature (43 degrees C) to induce heatstroke onset. The moment in which the mean arterial pressure and cerebral blood flow began to decrease from their peak values was taken as the onset of heatstroke. Prior heat shock or chemical stress conferred significant protection against heatstroke-induced arterial hypotension, cerebral ischemia, cerebral neuronal damage and death, and correlated with expression of HSP72 in brain, heart, liver and kidney at 16 h. However, at 48 h, when HSP72 expression returned to basal values, the above responses that occurred after the onset of heatstroke of two groups (0 h group VS 48 h group) were indistinguishable. The data suggest that HSP72 presence increases survival in rat heatstroke by attenuating arterial hypotension, cerebral ischemia and neuronal damage.

Animals↗
PubMed1998

Striatal glutamate release is important for development of ischemic damage to striatal neurons during rat heatstroke.

This study attempted to ascertain whether heatstroke-induced ischemia is associated with augmented striatal glutamate release and can be attenuated by NMDA receptor antagonists. Mean arterial pressure (MAP), striatal cerebral blood flow (CBF), striatal glutamate release and striatal neuronal damage score were assessed in saline-treated rats and in rats treated with NMDA receptor antagonists. Heatstroke was induced by exposing the animals to a high ambient temperature; the moment at which MAP and CBF began to decrease from their peak levels was taken as the onset of heatstroke. During onset of heatstroke, rats displayed higher values of colonic temperature, striatal glutamate release and striatal neuronal damage score, and lower values of MAP and striatal blood flow compared with normothermic control rats. The decreased MAP, the diminished striatal blood flow, the augmented striatal glutamate release and the increased striatal neuronal damage score during onset of heatstroke were significantly attenuated by pretreatment with an NMDA receptor antagonist such as MK-801 or ketamine. In addition, the survival time (interval between onset of heatstroke and death) of the rats was extended by pretreatment with one of these two NMDA receptor antagonists. These results suggest that marked accumulation of glutamate in the striatum is important for the development of ischemic damage to striatal neurons during the onset of heatstroke.

Animals↗
PubMed1998

The role of IL-10 in mouse hepatitis virus-induced demyelinating encephalomyelitis.

Interleukin 10 (IL-10) is an important anti-inflammatory cytokine. To examine its role in virus-induced encephalomyelitis, IL-10-deficient (IL-10 -/-) mice were infected with a neurotropic strain of mouse hepatitis virus (JHMV). JHMV-infected IL-10 -/- mice, compared to IL-4 -/- and syngeneic C57BL/6 mice, exhibited increased morbidity and mortality. Virus was cleared from the CNS of all groups of mice with equal kinetics by day 9 postinfection and the lack of either IL-4 or IL-10 did not alter the distribution of viral antigen, suggesting a lack of correlation between viral replication and the increased clinical disease in IL-10 -/- mice. In moribund IL-10 -/- mice, a moderate increase in mononuclear cell infiltration was correlated with increased expression of tumor necrosis factor-alpha, interferon-gamma, and inducible nitric oxide synthase mRNAs. In the small percentage of IL-10 -/- mice that survived, no differences in either demyelination or inflammation were observed. Together, these results suggest that IL-10 is not required for viral clearance, and although it appears to be one of the mechanisms responsible for inhibiting the extent of inflammation in the CNS during acute JHMV infection, it has little role in the eventual resolution of CNS inflammatory responses.

Animals↗
PubMed1998

CTL effector function within the central nervous system requires CD4+ T cells.

CTL responses induced during most viral infections are independent of help derived from the CD4+ T cell population. However, clearance of virus from the central nervous system (CNS) during infection with the neurotropic JHM strain of mouse hepatitis virus is inhibited in the absence of CD4+ T cells. Adoptive transfer of activated CD8+ T cells with virus-specific cytolytic activity into CD4+ T cell-depleted hosts demonstrated that CD4+ T cells were one component of the host response required for expression of CTL effector function(s) within the CNS. Analysis of mice infected with the JHM strain of mouse hepatitis virus demonstrated that, in contrast to CD8+ T cells, few CD4+ T cells entered the brain parenchyma. Although fewer CD8+ T cells entered the brain parenchyma in mice depleted of CD4+ T cells, access of CTL was not inhibited in the absence of CD4+ T cells. The number of apoptotic lymphocytes in the CNS increased in the absence of CD4+ T cells, suggesting that CTL enter the CNS during viral infection in a CD4-independent manner. However, these cells rapidly undergo apoptosis, indicating that expression of CTL effector function with the parenchyma of the CNS is CD4 dependent. These data raise the possibility that programmed cell death of CD8+ T cells within the CNS is due to the increased Ag present in the CNS of infected CD4 depleted mice or that autocrine cytokines, which maintain CTL activity within peripheral tissues, are inhibited in the microenvironment of the CNS.

Animals↗
PubMed1998

Nitric oxide donor decreases neutrophil adhesion in both lung and peritoneum during peritonitis.

BACKGROUND: As nitric oxide (NO) is an antiadhesive molecule, exogenous NO may modulate neutrophil adhesion in organs. This study was designed to examine the effects of the NO donor SNAP (S-nitroso-acetyl penicillamine) on neutrophil adhesion at the inflammatory site and in remote organs, in peritonitis using a fluorescent microscopic method. MATERIALS AND METHODS: In experiment 1, rats (n = 12) were given saline or 10 micrograms/kg of SNAP intravenously followed by continuous infusion of saline, or of 2, 20, or 200 micrograms/kg/h SNAP until sacrifice. Ten minutes after injection of saline or SNAP, 10(7) Escherichia coli were injected into the peritoneal cavity. Five hours after challenge, 10(6) fluorescein-labeled neutrophils were infused. Peritoneal samples, lungs, liver, and kidney were harvested for counting of labeled neutrophils under epifluorescent microscopy. In experiment 2, rats (n = 25) were treated with saline or 10 micrograms/kg of SNAP intravenously and infused with saline or 20 micrograms/kg/h SNAP; E. coli was injected as in experiment 1. Before or 5 h after challenge, hemodynamic data were obtained. Then, labeled neutrophils were infused for counting of neutrophil numbers in organs. Arterial blood gas data and the circulating neutrophil number were also determined. RESULTS: Experiment 1. Twenty and 200 micrograms/kg/h SNAP infusions tended to reduce labeled neutrophil numbers in lungs, while all three SNAP doses decreased the peritoneal labeled neutrophil numbers. RESULTS: Experiment 2. Five hours after bacterial injection, SNAP infusion simultaneously decreased both pulmonary and peritoneal labeled neutrophil numbers. SNAP had no effect on hemodynamic and blood gas data, or on circulating neutrophil numbers. CONCLUSION: NO donors may be useful for preventing neutrophil-associated lung injury, but should be used with caution in light of the possible adverse effects on host defense in the peritoneal cavity.

Animals↗
PubMed1998

Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis.

Thrombospondin (TSP) 2, and its close relative TSP1, are extracellular proteins whose functions are complex, poorly understood, and controversial. In an attempt to determine the function of TSP2, we disrupted the Thbs2 gene by homologous recombination in embryonic stem cells, and generated TSP2-null mice by blastocyst injection and appropriate breeding of mutant animals. Thbs2-/- mice were produced with the expected Mendelian frequency, appeared overtly normal, and were fertile. However, on closer examination, these mice displayed a wide variety of abnormalities. Collagen fiber patterns in skin were disordered, and abnormally large fibrils with irregular contours were observed by electron microscopy in both skin and tendon. As a functional correlate of these findings, the skin was fragile and had reduced tensile strength, and the tail was unusually flexible. Mutant skin fibroblasts were defective in attachment to a substratum. An increase in total density and in cortical thickness of long bones was documented by histology and quantitative computer tomography. Mutant mice also manifested an abnormal bleeding time, and histologic surveys of mouse tissues, stained with an antibody to von Willebrand factor, showed a significant increase in blood vessels. The basis for the unusual phenotype of the TSP2-null mouse could derive from the structural role that TSP2 might play in collagen fibrillogenesis in skin and tendon. However, it seems likely that some of the diverse manifestations of this genetic disorder result from the ability of TSP2 to modulate the cell surface properties of mesenchymal cells, and thus, to affect cell functions such as adhesion and migration.

Animals↗