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Biomedical subjects

M Martin

Publications and source records attributed to M Martin.

At least 199 records · Page 11Linked to original sources
PubMed1999

Cytolytic T lymphocyte-associated antigen-4 and the TCR zeta/CD3 complex, but not CD28, interact with clathrin adaptor complexes AP-1 and AP-2.

The negative signaling receptor cytolytic T lymphocyte-associated Ag-4 (CTLA-4) resides primarily in intracellular compartments such as the Golgi apparatus of T cells. However, little is known regarding the molecular mechanisms that influence this accumulation. In this study, we demonstrate binding of the clathrin adaptor complex AP-1 with the GVYVKM motif of the cytoplasmic domain of CTLA-4. Binding occurred primarily in the Golgi compartment of T cells, unlike with AP-2 binding that occurs mostly with cell surface CTLA-4. Although evidence was not found to implicate AP-1 binding in the retention of CTLA-4 in the Golgi, AP-1 appears to play a role in shuttling of excess receptor from the Golgi to the lysosomal compartments for degradation. In support of this, increased CTLA-4 synthesis resulted in an increase in CTLA-4/AP-1 binding and a concomitant increase in the appearance of CTLA-4 in the lysosomal compartment. At the same time, the level of intracellular receptor was maintained at a constant level, suggesting that CTLA-4/AP-1 binding represents one mechanism to ensure steady state levels of intracellular CTLA-4 in T cells. Finally, we demonstrate that the TCR zeta/CD3 complex (but not CD28) also binds to AP-1 and AP-2 complexes, thus providing a possible link between these two receptors in the regulation of T cell function.

Abatacept↗
PubMed1999

32-Indolyl ether derivatives of ascomycin: three-dimensional structures of complexes with FK506-binding protein.

32-Indole ether derivatives of tacrolimus and ascomycin retain the potent immunosuppressive activity of their parent compounds but display reduced toxicity. In addition, their complexes with the 12-kDa FK506-binding protein (FKBP) form more stable complexes with the protein phosphatase calcineurin, the molecular target of these drugs. We have solved the three-dimensional structures of the FKBP complexes with two 32-indolyl derivatives of ascomycin. The structures of the protein and the macrolide are remarkably similar to those seen in the complexes with tacrolimus and ascomycin. The indole groups project away from the body of the complex, and multiple conformations are observed for the linkage to these groups as well as for a nearby peptide suggesting apparent flexibility in these parts of the structure. Comparison of these structures with that of the ternary complex of calcineurin, FKBP, and tacrolimus suggests that the indole groups interact with a binding site comprising elements of both the calcineurin alpha- and beta-chains and that this interaction is responsible for the increased stability of these complexes.

Crystallography, X-Ray↗
PubMed1999

IL-13 and IFN-gamma secretion by activated T cells in HIV-1 infection associated with viral suppression and a lack of disease progression.

The immunopathology of HIV-1 infection includes immune defects in T cell cytokine secretion, resulting in decreased Ag-specific responses. In this report, IL-13 and IFN-gamma were analyzed in progressive HIV-1 disease. Both cytokines exert positive effects on Ag presentation and inhibit HIV-1 infection of macrophages. Anti-CD3/anti-CD28-activated PBMC from HIV-1-infected individuals (n = 74) compared with uninfected subjects (n = 30) secreted significantly less IL-13 (median, 0.64 ng/ml vs 2.07 ng/ml; p < 0. 001) and IFN-gamma (median, 40.96 ng/ml vs 129.5 ng/ml; p < 0.005). Decreased IL-13 and IFN-gamma secretion in HIV infection was present in sorted CD4+ and CD8+ T cell subsets, and additional analysis determined concurrent deficiency at the protein and transcriptional level. Longitudinal analysis showed that cytokine secretion levels correlated positively with CD4 count and negatively with plasma HIV-1 viral load. Patients changing to suppressive antiretroviral therapy during the study showed increases in IL-13 and IFN-gamma secretion. Overall, results show a decline in IL-13 and IFN-gamma secretion in progressive HIV-1 infection and suggest a role for both cytokines as part of T cell adaptive responses associated with a lack of disease progression.

CD4-Positive T-Lymphocytes↗
PubMed1999

In vitro analysis of the role of DCC in mucus-secreting intestinal differentiation.

The deleted in colorectal cancer (DCC) gene was initially described as a colon cancer-associated tumor suppressor gene and subsequently proposed to be involved in goblet cell differentiation, but its precise role in normal intestine physiology and in cancer remains to be established. We have analyzed DCC mRNA expression in a panel of human colorectal cancer cell lines with a variety of differentiation phenotypes by reverse transcription-polymerase chain reaction (RT-PCR) and have shown that (1) most cell lines showed lower levels of DCC mRNA than normal colonic tissue; (2) only 1 cell line lacked detectable levels of DCC mRNA expression; (3) a discrepancy was found between the detectability of RT-PCR products corresponding to the extracellular and intracellular domains of DCC; and (4) there was no association between the presence of DCC transcripts and the differentiation phenotype. Specifically, DCC was not exclusively associated with the mucus-secreting phenotype, as determined by Alcian blue staining and Northern blotting with mucin gene probes. This was further supported by immunohistochemical results on DCC product and mucins in normal colon: DCC was detected in both goblet and absorptive cells. The introduction of full-length DCC cDNA in undifferentiated HT-29 cells did not have any effect on their differentiation phenotype, as shown by morphological studies and analysis of markers for this process in colon, such as mucins, dipeptidylpeptidase IV, villin and sucrase-isomaltase. There were no effects on cell proliferation in vitro. Our results indicate that DCC is not selectively involved in the mucosecretory differentiation pathway and that it is neither sufficient nor essential for normal intestinal differentiation.

Cell Adhesion Molecules↗
PubMed1999

Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study.

PURPOSE: To establish a successful treatment of subcutaneous fibrosis developing after high doses of gamma rays, suitable for use in clinical practice. METHODS AND MATERIALS: We used an animal model of acute localized gamma irradiation simulating accidental overexposure in humans. Three groups of 5 Large White pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of necrosis developed within a few weeks which had healed after 26 weeks to leave a block of subcutaneous fibrosis involving skin and skeletal muscle. One experimental group of 5 pigs was dosed orally for 26 weeks starting 26 weeks after irradiation with 1600 mg/120 kg body weight of pentoxifylline (PTX) included in the reconstituted food during its fabrication, and another group of 5 was dosed orally for the same period with a daily dose of 1600 mg/120 kg body weight of PTX combined with 2000 IU/120 kg body weight of alpha-tocopherol. Five irradiated control pigs were given normal food only. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Depth of scar tissue was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 26 weeks after treatment started. The density, length, width, and depth of the block of fibrotic scar tissue, and the areas and volume of its projected cutaneous surface, were compared before treatment, 6 and 13 weeks thereafter, and at 26 weeks. RESULTS: The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. No modifications were observed in the block of fibrotic scar tissue of pigs dosed with PTX alone. However, significant softening and shrinking of this block were noted in the pigs dosed with PTX + alpha-tocopherol 13 weeks after treatment started and at autopsy, when mean regression was approximately 30% for length, approximately 50% for width and depth, and approximately 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar tissue. The 50% decrease in the linear dimensions of the scar tissue, were comparable to the results obtained in our previous clinical studies, and were highly significant compared to the clinical and autopsy results for the controls. Histologic examination of the residual scar tissue revealed tissue which was more homogenous and less cellular and inflammatory than in control and PTX-dosed pigs. The tissular and cellular immunolocalization of tumor necrosis factor alpha (TNFalpha) was similar in the residual fibrotic tissues of all three groups of pigs, whereas the immunostaining of transforming growth factor beta-1(TGFbeta-1) diminished much more in the residual fibrotic scar tissue of the PTX + alpha-tocopherol-dosed pigs than in the two other groups. CONCLUSIONS: The present results showed a striking regression of the subcutaneous fibrotic scar tissue that develops as a consequence of high doses of gamma rays.

Drug Combinations↗
PubMed1999

Combination of inositol and serotonin reuptake inhibitors in the treatment of depression.

BACKGROUND: Inositol has been reported to be an effective treatment in depression, and we hypothesized that inositol addition might enhance or speed up response to serotonin selective reuptake inhibitors (SSRI). METHODS: Twenty-seven depressed patients completed a double-blind controlled 4-week trial of SSRI plus placebo or SSRI plus inositol. Hamilton Depression Rating Scale was used as an assessment tool at baseline, and 1, 2, 3, and 4 weeks. RESULTS: No significant difference was found between the two treatment groups. CONCLUSIONS: Previous studies combining different effective antidepressant therapies similarly found no evidence for additive effects [e.g., monoamine oxidase inhibitors (MAOI) plus tricyclic antidepressants (TCA), TCA plus lithium]. By contrast, augmentation by lithium or MAOI after a failed course of antidepressant treatment is effective and should be studied with inositol.

Adult↗
PubMed1999

Glutamine synthesis is heterogeneous and differentially regulated along the rabbit renal proximal tubule.

Glutamine synthesis, a major process for ammonia detoxification and the control of acid-base balance, occurs from various precursors in suspensions of rabbit proximal tubules. However, no data are currently available on the distribution of glutamine synthesis along the rabbit proximal tubule, and its modulation by changes of substrate concentration. Therefore we have microdissected and incubated the three parts (S1, S2 and S3) of rabbit proximal tubules and measured glutamine synthesis from alanine and aspartate. With a physiological concentration of alanine (0.25 mM) or aspartate (0.05 mM), glutamine synthesis in the S1 segment was about half of that in the S2 and S3 segments, and was greater from alanine than from aspartate along the entire proximal tubule. Elevation of alanine and aspartate concentrations to 5 mM increased glutamine synthesis in both a substrate- and segment-dependent manner. It is concluded that glutamine synthesis occurs from alanine and aspartate along the entire rabbit proximal tubule; however, contrary to what might have been expected on the basis of measurement of glutamine synthetase activity, the basal rate of glutamine synthesis and its adaptation to increased substrate availability are heterogeneous along this nephron segment.

Alanine↗
PubMed1999

Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition.

Structural aspects of human TCRs that allow the activation of autoreactive T cells by diverse microbial peptides were examined using two human myelin basic protein (MBP)-specific T cell clones. The TCR sequences of these clones differed only in the N region of TCR-alpha and -beta since the clones had the same Valpha-Jalpha and Vbeta-Jbeta rearrangements. The two clones had a similar fine specificity for the MBP peptide, except for the P5 position of the peptide (lysine). In the crystal structure of the HLA-DR2/MBP peptide complex, P5 lysine is a prominent, solvent-exposed residue in the center of the DR2/MBP peptide surface. Five microbial peptides with conservative or nonconservative changes at the P5 position (lysine to arginine, serine, or proline) activated one of these clones. In contrast, the other clone was activated only by three of these peptides which had a conservative lysine to arginine change at P5. The degree of specificity/degeneracy in recognition of the P5 side chain was the key difference between these TCRs since the Escherichia coli/Haemophilus influenzae peptide stimulated both clones when the P5 position was substituted from serine to arginine. These results demonstrate that the complementarity-determining region 3 loops contribute to the degree of degeneracy in peptide recognition by human MBP-specific TCRs.

Amino Acid Sequence↗
PubMed1999

Benthic community structure and biomarker induction in grass shrimp in an estuarine system

The impact of polycyclic aromatic hydrocarbons (PAHs) and lead contamination on benthic community structure and grass shrimp (Palaeomonetes sp.) biochemical markers were investigated in a bayou that has been heavily contaminated by PAHs and heavy metals. The benthic community had decreased species richness as well as decreased numbers of individuals along a contamination gradient. Grass shrimp collected in the field showed a contaminant-gradient increase in heat shock protein 63 and cytochrome P450 1A (as measured by ECOD metabolism). Grass shrimp had elevated ECOD metabolism when exposed in the laboratory to sediments from the most contaminated site. However, individual variation was too great for statistically significant changes. In addition, heat shock protein levels were not significantly elevated in laboratory exposed shrimp. Benthic community structure and wild-caught grass shrimp are clearly impacted in this bayou.http://link.springer-ny. com/link/service/journals/00244/bibs/37n4p512.html</HEA

Journal Article↗
PubMed1999

Acute myeloid leukemia M2 and t(8;21)(q22;q22) with an unusual phenotype: myeloperoxidase (+), CD13 (-), CD14 (-), and CD33(-).

Cases of myeloid surface antigen-negative acute myeloid leukemia (AML) are rare. We describe the morphological, cytochemical, immunologic, and cytogenetic features of two patients with AML with maturation (FAB M2) and the phenotype MPO+, CD13 (-), CD33(-), CD56(+). Cytogenetic studies demonstrated t(8;21)(q22;q22). These findings suggest an association between the lack of CD13 and CD33 in myeloperoxidase-positive AML and the presence of t(8;21).

Adult↗
PubMed1999

Modeling surgical expertise for motor skill acquisition.

BACKGROUND: This work is part of an ongoing effort to introduce an innovative medical teaching technique to assist the efficient acquisition of surgical hand skills required to perform an inguinal hernia repair with a McVay technique. The purpose was to determine the effect of expert cognitive modeling, auditory elaboration, and split-screen video analysis on the surgical hand movements required while performing inguinal hernia surgery on cadavers. PURPOSE: Six surgical residents were videotaped performing a McVay procedure inguinal hernia in a pretest-posttest control group design. The experimental group received expert cognitive modeling, auditory elaboration, and split-screen analysis after the pretest. RESULTS: A distinct advantage for surgical instrument control and manipulation was found for the experimental group on the posttest surgeries. Less time was required to perform the operation, and more purposeful movements were exhibited by the experimental group. CONCLUSION: The treatment condition favored mindfulness learning of the McVay technique for an inguinal hernia repair.

Cadaver↗
PubMed1999

Human cytokine responses to coronary artery bypass grafting with and without cardiopulmonary bypass.

BACKGROUND: Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response. This has been attributed to cytokine release caused by extracorporeal circulation and myocardial ischemia. This study compares the inflammatory response after CABG with cardiopulmonary bypass and after minimally invasive direct coronary artery bypass grafting (MIDCABG) without cardiopulmonary bypass. METHODS: Cytokine release and complement activation (interleukin-6 and interleukin-8, soluble tumor necrosis factor receptors 1 and 2, complement factor C3a, and C1 esterase inhibitor) were determined in 24 patients before and after CABG or MIDCABG. The maximum body temperature, chest drainage, and fluid balance were recorded for 24 hours after operation. RESULTS: Release of interleukin-6, interleukin-8, and tumor necrosis factor receptors 1 and 2 was significantly higher (p < or = 0.005) in the CABG group than the MIDCABG group just after operation. After 24 hours, a significant increase in interleukin-6 was also found in the MIDCABG group (p = 0.001) compared with preoperative value. Body temperature and fluid balance were significantly higher after CABG (p < or = 0.001). CONCLUSIONS: Minimally invasive direct coronary artery bypass grafting represents a less traumatizing technique of surgical revascularization. The reduction in the inflammatory response may be advantageous for patients with a high degree of comorbidity.

Aged↗
PubMed1999

Handedness and season of birth: a gender-invariant relation.

In an earlier study, Dellatolas, Curt and Lellouch (1991) concluded that handedness is not related to season of birth. However, post-hoc exploration of their and other sets of data has shown that there is an apparent tendency for left-handedness to be more prevalent in the period March-July than in the period August-February. The present work tested this seasonal hypothesis prospectively among university students. It was found that the proportion of all left-handed participants who were born in the period March-July was indeed significantly greater than the proportion of all right-handed participants who were born in the same period. Furthermore, the pattern of seasonal influence upon handedness did not vary significantly between females and males. The relation between handedness and season of birth may be linked to seasonal variation in other factors such as the incidence of infectious agents.

Adolescent↗
PubMed1999

Definition of the alpha 2 region of HLA-DR molecules involved in CD4 binding.

HLA class II molecules present antigenic peptides to the T cell receptor of CD4+ T lymphocytes and interact with CD4 during the antigen recognition process. A major CD4 binding site encompassing amino acids (aa) 134-148 in the beta 2 domain of HLA-DR has been previously identified and residues located within the alpha 2 subunit of murine MHC class II I-Ad molecules have been shown to contribute to CD4-class II interaction. To characterize the alpha 2 region of HLA-DR molecules involved in the binding of CD4, we have synthesized overlapping linear and cyclic peptides derived from a region encompassing aa 121-143. We demonstrate that two linear peptides (aa 124-138 and 130-143) and a cyclic one (aa 121-138) specifically bind to CD4-sepharose affinity columns. Although cyclic analogues exhibit more ordered populations as detected by circular dichroism measurements, cyclization did not improve the activity of some peptides. Peptide sequence positioning in HLA-DR1 dimer model indicates that alpha 2 residues 124 to 136 form a solvent-exposed loop which faces the beta 2 loop delimited by residues 134-148. These data suggest that one CD4 molecule contacts both alpha 2 and beta 2 loops of the HLA-DR homodimer.

Amino Acid Sequence↗
PubMed1999

Pulsatile vs. continuous parenteral tocolysis: comparison of side effects.

Bolus tocolysis has been developed to reduce the dose of fenoterol compared to continuous tocolysis. Whereas the high efficacy of pulsatile application of fenoterol has been shown, the proof of reduced side effects is still lacking. A total of 59 patients with preterm labor were divided in three groups: (1) continuous tocolysis and oral application of magnesium (n=19), (2) continuous tocolysis and parenteral application of magnesium (n=20), (3) pulsatile tocolysis (bolus tocolysis) and oral application of magnesium (n=20). Heart rate, systolic and diastolic blood pressure, serum K+ and serum Mg++ were quantified before tocolysis and after 2, 8 and 24 h. Beta-blockers and water balance were recorded over 24 h. Subjective side effects were quantified using a questionnaire with scales graduated covering palpitations, tremor, diaphoresis, thirst, precardialgia and nausea/vomiting. The analysis of the data revealed significantly fewer side effects concerning heart rate, plasma K+ level and the subjective side effects among patients treated with bolus tocolysis than among those treated with continuous tocolysis. Between the latter two groups, no significant difference was found. Concerning blood pressure and need for beta-blockers, no significant differences were found between the three groups. The results of the present study show that especially the side effects subjectively found to be disagreeable by the patients are reduced by pulsatile tocolysis, whereas other side effects show only slight differences between the study groups.

Adrenergic beta-Antagonists↗
PubMed1999

ERM proteins in cell adhesion and membrane dynamics.

Ezrin, radixin and moesin, collectively known as the ERM proteins, are a group of closely related membrane-cytoskeleton linkers that regulate cell adhesion and cortical morphogenesis. ERM proteins can self-associate through intra- and inter-molecular interactions, and these interactions mask several binding sites on the proteins. ERM activation involves unfolding of the molecule, and allows the protein to bind to plasma membrane components either directly, or indirectly through linker proteins. The discovery that the tumour-suppressor NF2, also known as merlin/schwannomin, is related to ERM proteins has added a new impetus to investigations of their roles. This review discusses current understanding of the structure and function of members of the ERM family of proteins.

Blood Proteins↗