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Biomedical subjects

S Martin

Publications and source records attributed to S Martin.

At least 37 records · Page 2Linked to original sources
PubMed2001

Quantitative measurement of short-range chemical bonding forces.

We report direct force measurements of the formation of a chemical bond. The experiments were performed using a low-temperature atomic force microscope, a silicon tip, and a silicon (111) 7x7 surface. The measured site-dependent attractive short-range force, which attains a maximum value of 2.1 nanonewtons, is in good agreement with first-principles calculations of an incipient covalent bond in an analogous model system. The resolution was sufficient to distinguish differences in the interaction potential between inequivalent adatoms, demonstrating the ability of atomic force microscopy to provide quantitative, atomic-scale information on surface chemical reactivity.

Journal Article↗
PubMed2001

Isolation and structure elucidation of Chlorofusin, a novel p53-MDM2 antagonist from a Fusarium sp.

Wild-type p53 plays a crucial role in the prevention of cancer. Since dysfunction of p53 can be caused by increased levels of the protein MDM2, small molecules which antagonize the interaction between these two proteins have potential in cancer therapy. The discovery and structure determination of a fungal metabolite, chlorofusin, which antagonizes the p53/MDM2 interaction are reported.

Antineoplastic Agents↗
PubMed2001

Evidence for the involvement of diacylglycerol kinase in the activation of hypoxia-inducible transcription factor 1 by low oxygen tension.

Hypoxia-inducible factor 1 (HIF-1) induces a gene expression program essential for the cellular adaptation to lowered oxygen environments. The intracellular mechanisms by which hypoxia induces HIF-1 remain poorly understood. Here we show that exposure of various cell types to hypoxia raises the intracellular level of phosphatidic acid primarily through the action of diacylglycerol kinase (DGK). Pharmacological inhibition of DGK activity through use of the specific DGK inhibitors and abrogated specifically HIF-1-dependent transcription analyzed with a HIF-1-responsive reporter plasmid. A more detailed analysis revealed that pharmacological inhibition of DGK activity prevented the hypoxia-dependent accumulation of the HIF-1alpha subunit and the subsequent HIF-1-DNA complex formation as well as hypoxia-induced activity of the HIF-1 transactivation domains localized to amino acids 530-582 and 775-826 of the HIF-1alpha subunit. Our results demonstrate for the first time that accumulation of phosphatidic acid through DGK underlines oxygen sensing and provide evidence for the involvement of this lipid kinase in the intracellular signaling that leads to HIF-1 activation.

Cell Nucleus↗
PubMed2001

Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and lack of antibody production. Numerous T cell defects have been described, including reduced gene expression and production of IL-2. Since some of the T cell defects could be explained by lack of IL-2, we have been investigating the effects of in vivo IL-2 treatment. Here, a long-acting form of IL-2, PEG-IL-2, was given for 12-18 months to 15 randomly chosen CVID subjects, in comparison to 39 CVID subjects who served as controls. After 6 to 12 months of treatment, T cell proliferative responses to mitogens and to IL-2 were significantly enhanced; proliferative responses to tetanus and candida antigens increased up to 50-fold. Four of eight subjects immunized with the neoantigen bacteriophage φX 174 displayed increased antibody responses after treatment. Treated subjects recorded reduced, but not overall statistically significant, days of bronchitis, diarrhea, and joint pain. These data indicate that IL-2 might serve as an adjuvant to therapy in some subjects with CVID, enhancing T cell functions and reversing T cell anergy in most.

Adolescent↗
PubMed2001

Dominant role of intercellular adhesion molecule-1 in the pathogenesis of autoimmune diabetes in non-obese diabetic mice.

Intercellular adhesion molecule (ICAM)-1 is involved in forming the immunological synapse. The contribution of ICAM-1 to immune responses is not critical because mice with a disrupted ICAM-1 gene do not have grossly abnormal immune reactivity. Here we report on the surprising finding that diabetes-prone NOD mice with a disrupted ICAM-1 gene (ICAM-1(-/-)) are completely protected from disease development. While 64% of ICAM-1(+/+) and 44% of ICAM-1(+/-) female NOD mice developed overt diabetes until 310 days old, no ICAM-1(-/-) NOD mice became hyperglycaemic. Histological examinations revealed minor infiltration around pancreatic islets of ICAM1(-/-) NOD mice. Administration of cyclophosphamide caused a progression to severe islet destruction in ICAM-1(+/+) NOD mice within 10 days. In contrast, ICAM-1(-/-) mice showed only mild insulitis. Furthermore, ICAM-1(+/+) NOD mice showed an increase of IFN-gamma, interleukin (IL)-12p40 and IL-12p35 pancreatic mRNA levels, leading to an increased ratio of IFN-gamma: IL-4 and IL-12p40: IL-12p35 expression. In contrast, ICAM-1(-/-) NOD mice did not upregulate IFN-gamma or IL-12p40 gene expression but maintained IL-4 and increased IL-12p35 gene expression. These results identify a dominant and non-redundant role of ICAM-1 in the development of autoimmune diabetes.

Animals↗
PubMed2001

Leukocyte recruitment and neuroglial activation during facial nerve regeneration in ICAM-1-deficient mice: effects of breeding strategy.

Intercellular adhesion molecule 1 (ICAM-1) is a widely expressed glycoprotein involved in leukocyte extravasation and the interaction of lymphocytes with antigen-presenting cells. We examined these aspects of ICAM-1 function in the central nervous system after axonal injury in wild-type and ICAM-1-deficient mice. ICAM-1 immunoreactivity in the normal mouse facial nucleus was restricted to the vascular endothelium. Transection of the facial nerve led to a fast upregulation of ICAM-1 on activated microglia in the axotomized facial nucleus and the infiltration of ICAM-1-positive lymphocytes. Labeling elsewhere was unchanged. In homozygous ICAM-1 mutant mice, ICAM-1 was absent from endothelial cells and lymphocytes, but low levels of ICAM-1 were detected on cell membranes of reactive microglial cells. Comparison of wild-type animals with homozygously bred, ICAM-1-deficient mice showed a reduction of astrocytic and microglial activation, massive late axonal sprouting, and decreased lymphocyte infiltration. These experiments were repeated in F1 progeny of heterozygous mice on a C57BL/6 background. Neuroglial activation and lymphocyte infiltration in F1 homozygously deficient mice was unaffected compared with wild-type siblings. The invading ICAM-1-deficient lymphocytes also adhered to the ICAM-1-positive phagocytotic microglial cells in the ICAM-1 mutants. No change in the recruitment of macrophages and granulocytes into the crushed facial nerve, and no effect on axonal regeneration occurred. These data argue against the requirement of endothelial ICAM-1 in the recruitment of leukocytes into the crushed peripheral nerve or the axotomized facial motor nucleus and stress the importance of adequately matched controls in studying the effects of gene deletion in experimental animals.

Animals↗
PubMed2001

Localized lymphadenopathy due to leishmanial infection.

A 25-year-old female patient presented with an isolated cervical lymph node enlargement several months after having returned from Spain and Latin America. She had no other signs or symptoms of disease. Leishmania infantum/chagasi was identified as the causative agent. With extended travel activities localized lymph node enlargement due to leishmanial infection should be included in the differential diagnosis of lymphadenopathy of unknown origin.

Adult↗
PubMed2001

Anastomotic strictures following radical prostatectomy: insights into incidence, effectiveness of intervention, effect on continence, and factors predisposing to occurrence.

OBJECTIVES: To examine the incidence, effectiveness of intervention, effect on continence, and factors predisposing to the occurrence of anastomotic strictures following radical retropubic prostatectomy. METHODS: Between January 1994 and June 1999, 753 radical retropubic prostatectomies were performed by a single surgeon. Anastomotic strictures were managed by dilatation followed by a self-catheterization regimen. Dilatations were repeated unless more than three dilatations were required over a 9-month interval. A control group representing a randomly selected group of men who did not develop anastomotic strictures was identified. The largest width of the midline vertical abdominal scar was measured. RESULTS: Of the 753 radical retropubic prostatectomies, 36 (4.8%) developed an anastomotic stricture. The mean time interval between the surgical procedure and diagnosis of the stricture was 4.22 months. Of the 26 cases of anastomotic strictures with at least 1-year follow-up, 24 (92.3%) were managed successfully by dilatations alone. No baseline characteristics before surgery were associated with the development of a stricture. The maximal scar width was the only factor that was associated with the development of a stricture in this study. Men with a maximal scar of greater than 10 mm were eight times more likely to develop strictures than men with smaller scars. The percentage of men who required protective pads 1 year following radical retropubic prostatectomy in the control and stricture groups was 12.5% and 46.2%, respectively. CONCLUSIONS: Anastomotic strictures are relatively rare following radical prostatectomy and have a negative effect on the development of continence. Most men are successfully managed with dilatations alone. The development of anastomotic strictures in some men appears to be related to a generalized hypertrophic wound-healing mechanism.

Anastomosis, Surgical↗
PubMed2001

Efficacy of first-generation Cavermap to verify location and function of cavernous nerves during radical prostatectomy: a multi-institutional evaluation by experienced surgeons.

OBJECTIVES: To evaluate, using five experienced surgeons, the efficacy of the first-generation Cavermap Surgical Aid to identify the cavernous nerves intraoperatively and to predict the recovery of sexual function. This study was not designed to determine whether this device improves the ability to preserve the nerves or improve outcome. METHODS: Fifty men younger than 60 years old (mean age 52.5 years; range 43 to 59) with clinically localized prostate cancer (76% T1c, mean Gleason score 6, prostate-specific antigen level less than 10 ng/mL) underwent nerve-sparing radical prostatectomy (90% bilateral). Intraoperatively, the Cavermap device was used to test for the presence of the cavernous nerves once the neurovascular bundle was identified visually and to determine whether the nerves were intact after the prostate was removed. Erectile function was evaluated using the International Index of Erectile Function; men were considered potent if they were able to achieve unassisted intercourse in at least one half of their attempts. RESULTS: Before the removal of the prostate, the tumescence response to stimulation of the neurovascular bundle was 87.8%; when tissue not containing the neurovascular bundle was stimulated, no tumescence response occurred in 54%. After prostatectomy, a bilateral response to stimulation occurred in 90%, a unilateral response in 5%, and no response in 5%. Postoperatively, 71% of the patients were potent at 12 months. In the patients who demonstrated bilateral stimulation after removal of the prostate, 78% were potent at 12 months. CONCLUSIONS: After radical prostatectomy performed by experienced surgeons, patient-reported potency rates in men younger than 60 years of age were high. Cavermap stimulation demonstrated an 87.8% sensitivity and 54% specificity in locating the neurovascular bundle as identified by experienced surgeons. The lack of specificity of this first-generation device limits its application for deciding which structures can be safely preserved or excised. Because virtually all patients demonstrated a positive response after removal of the prostate, the value of stimulation to predict the recovery of sexual function is yet to be determined.

Adult↗
PubMed2001

Methodology for identifying patients at high risk for osteoporotic fracture.

BACKGROUND: Osteoporotic fractures are associated with significant morbidity, mortality, and health care costs. OBJECTIVE: The purpose of this paper is to present and validate a mathematical model that managed care organizations can apply to administrative claims data to help locate members at risk for osteoporotic fracture and estimate future fracture rates. METHODS: Using known risk factors from previous clinical studies, 92,000 members of a large Midwest health plan were placed in 1 of 4 risk categories based on historical claims markers: demographic/lifestyle (age, sex, smoking, alcoholism); steroid use; medical history (previous osteoporotic fracture, ordinary bone fracture, osteoporosis diagnosis, bone mineral density test); or steroid use with medical history. Logistic regression was used to assign a probability of fracture for the 4 groups over the next 2 years. These predictions were compared with actual fracture rates, and refined models were produced. The models were then validated by applying them to current data and comparing the predicted fracture rate for each group to known results. RESULTS: The model predicted that 1.26% of the study members would experience osteoporotic fracture over the next 2 years; the actual result was 1.27%. Within the 4 risk groups, the predicted fracture rates were lower than the actual rates for the demographic risk group (0.87% predicted vs 0.97% actual) and higher than the actual rates for the steroid use (1.78% predicted vs 1.58% actual), medical history (5.90% predicted vs 4.94% actual), and the steroid use with medical history groups (7.80% predicted vs 6.42% actual). CONCLUSION: The application of this risk model to an administrative claims database successfully identified plan members at risk for osteoporotic fracture.

Aged↗
PubMed2001

A comparison of enzyme-linked immunoabsorbent assays and flow cytometry techniques for the detection of HLA specific antibodies.

LATM, Quikscreen (QS), and B-Screen (QSB) are ELISA-based tests for the detection of HLA specific antibodies. FlowPRA beads are microparticles coated with HLA antigens for the detection of HLA specific antibodies by flow cytometry. The aim of this study was to evaluate the sensitivity and specificity of the LATM, QS, QSB, and FlowPRA screening tests. One hundred sixty-three sera from renal transplant patients were tested using LATM, FlowPRA, QS, and QSB. Discrepant results were further investigated using complement dependent cytotoxicity, QuikID, and PRA-STAT. When QS was compared with LATMI and FlowPRAI for the detection of HLA class I specific antibodies the overall concordance was 82.8% with no particular specificity missed by any one test. Comparing QSB with LATMII and FlowPRAII, for the detection of HLA class II specific antibodies, there was 90.7% concordance. Although the overall concordance was better for class II specific antibodies, QSB failed to detect antibodies to HLA-DQ in a number of samples from different patients. Of the methods tested, flow cytometry using FlowPRA beads appeared to be the most sensitive and specific, missing the least number of specificities. However, the ELISA methods offer the advantage of being more suitable for testing large numbers of samples in a more time- and cost-effective manner.

Antibody Specificity↗
PubMed2001

[Moderate alcohol consumption and cardiovascular diseases].

While excessive ethanol consumption can result in higher rate of morbidity and mortality resulting from several diseases including cancer and cirrhosis, epidemiological studies suggest that moderate alcohol ingestion reduces the risk of cardiovascular diseases. However, the precise mechanisms by which moderate alcohol consumption protects against coronary heart disease (CHD) is not fully understood. Epidemiological studies suggest that alcohol consumption influences several risk factors for CHD including blood pressure, plasma cholesterol levels, platelet function, and fibrinolytic parameters, preventing both vascular thrombosis and occlusion. Turning to molecular and cellular levels, ethanol has been shown to act on several signal transduction mechanisms involve in the inhibition of smooth muscle cells proliferation and migration and in the activation of the release of vasoactive factors from vascular cells such as nitric oxide (NO). The latter is of importance since NO has been shown to possess antioxidant, antiaggregant properties, to regulate vascular tone and to inhibit both proliferation of smooth muscle cells and adhesion of leukocytes. Altogether, the above mentioned beneficial properties of moderate concentration of ethanol might help to explain the cardio- and vascular protection induced by ethanol. This review compels several bibliographic data concerning the cardiovascular effect of moderate alcohol consumption.

Animals↗
PubMed2001

Scale-up of filamentous organisms from tubes and shake-flasks into stirred vessels.

The choice of small-scale fermentation systems contributes significantly to a successful scale-up. Creasing of flasks and the chosen shaker parameters influence the production of secondary metabolites in a strain- and even compound-specific manner. Using actinomycetes and fungi as model organisms the influence of the small-scale fermentation system on the production of various secondary metabolites is described and the effects on screening success and scale-up are considered.

Journal Article↗
PubMed2001

Expression of bcl-2, bax and bcl-xl in human gliomas: a re-appraisal.

We have analyzed the expression of the anti-apoptotic proteins bcl-2, bcl-xl and that of bax, a pro-apoptotic protein, in human WHO grade II astrocytomas (LGA) and WHO grade IV glioblastoma multiforme (GBM). Tumors were obtained immediately after surgical resection and were analyzed by immunohistochemistry (IHC), laser confocal microscopy (LCM) and immunoblots. Both IHC and immunoblot analysis indicated that the expression of bcl-xl was not significantly different between LGA and GBM. IHC indicated that the expression of bcl-2 was inversely correlated to the grade of the tumors (i.e more cells were bcl-2 positive in LGA than in GBM) while the expression of bax was unaffected by the grade of the tumor. In contrast, immunoblots revealed a parallel increase in the expression of bcl-2 and bax from the low to high grade tumor, suggesting a co-regulation of the expression of these two proteins during tumoral progression. Confocal analyses provide us with another possible level of complexicity in the regulation of apoptosis in these tumors, as these markers exhibited different subcellular localizations: bcl-2 was strictly associated with mitochondria and bcl-xl was present in both cytosolic and mitochondrial compartments while bax was found essentially in the cytosol of the tumoral cells. Taken together, our data suggest that the role of bcl-2 related proteins could be regulated at different levels in human astrocytomas (expression, subcellular localization, antigen exposure ...) which should be studied by different techniques.

Adult↗