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J L Martin

Publications and source records attributed to J L Martin.

At least 91 records · Page 5Linked to original sources
PubMed1999

Crystal structure of mammalian purple acid phosphatase.

BACKGROUND: Mammalian purple acid phosphatases are highly conserved binuclear metal-containing enzymes produced by osteoclasts, the cells that resorb bone. The enzyme is a target for drug design because there is strong evidence that it is involved in bone resorption. RESULTS: The 1.55 A resolution structure of pig purple acid phosphatase has been solved by multiple isomorphous replacement. The enzyme comprises two sandwiched beta sheets flanked by alpha-helical segments. The molecule shows internal symmetry, with the metal ions bound at the interface between the two halves. CONCLUSIONS: Despite less than 15% sequence identity, the protein fold resembles that of the catalytic domain of plant purple acid phosphatase and some serine/threonine protein phosphatases. The active-site regions of the mammalian and plant purple acid phosphatases differ significantly, however. The internal symmetry suggests that the binuclear centre evolved as a result of the combination of mononuclear ancestors. The structure of the mammalian enzyme provides a basis for antiosteoporotic drug design.

Acid Phosphatase↗
PubMed1999

Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease.

High-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15-17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained to adopt a beta-strand conformation which is preorganized for protease binding. An unusual feature of the binding of C-terminal macrocyclic inhibitors is the interaction between a positively charged secondary amine and a catalytic aspartate of HIVPR. A bicyclic inhibitor binds similarly through its secondary amine that lies between its component N-terminal and C-terminal macrocycles. In contrast, the corresponding tertiary amine of the N-terminal macrocycles does not interact with the catalytic aspartates. The amine-aspartate interaction induces a 1.5 A N-terminal translation of the inhibitors in the active site and is accompanied by weakened interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may facilitate peptide cleavage and product dissociation during catalysis. Proteases [Aba67,95]HIVPR and [Lys7,Ile33,Aba67,95]HIVPR used in this work were shown to have very similar crystal structures.

Aminobutyrates↗
PubMed1999

Oncogenic ras causes resistance to the growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3) in breast cancer cells.

Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits proliferation and promotes apoptosis in normal and malignant cells. In MCF-10A human mammary epithelial cells, 30 ng/ml human plasma-derived IGFBP-3 inhibited DNA synthesis to 70% of control. This inhibition appeared IGF-independent, since neither an IGF-receptor antibody nor IGFBP-6 inhibited DNA synthesis. Malignant transformation of MCF-10A cells by transfection with Ha-ras oncogene abolished the inhibitory effect of IGFBP-3, concomitant with an increase in IGFBP-3 secretion and cell association of approximately 60 and 300%, respectively. When mitogen-activated protein (MAP) kinase activation was partially inhibited using PD 98059, IGFBP-3 sensitivity in ras-transfected cells was restored, with a significant inhibitory effect at 10 ng/ml IGFBP-3. PD 98059 had no effect on IGFBP-3 secretion or cell association by ras-transfected or parent MCF-10A cells. Hs578T, a tumor-derived breast cancer cell line that expresses activated Ha-ras, similarly has a high level of secreted and cell-associated IGFBP-3. In the absence of PD 98059, DNA synthesis by Hs578T cells was reduced to 70% of control by 1000 ng/ml IGFBP-3. PD 98059 increased sensitivity to IGFBP-3, so that this level of inhibition was achieved with 100 ng/ml IGFBP-3. These results suggest that MAP kinase activation by oncogenic ras expression causes IGFBP-3 resistance, a possible factor in the dysregulation of breast cancer cell growth.

Apoptosis↗
PubMed1999

Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.

BACKGROUND: The Lyon Diet Heart Study is a randomized secondary prevention trial aimed at testing whether a Mediterranean-type diet may reduce the rate of recurrence after a first myocardial infarction. An intermediate analysis showed a striking protective effect after 27 months of follow-up. This report presents results of an extended follow-up (with a mean of 46 months per patient) and deals with the relationships of dietary patterns and traditional risk factors with recurrence. METHODS AND RESULTS: Three composite outcomes (COs) combining either cardiac death and nonfatal myocardial infarction (CO 1), or the preceding plus major secondary end points (unstable angina, stroke, heart failure, pulmonary or peripheral embolism) (CO 2), or the preceding plus minor events requiring hospital admission (CO 3) were studied. In the Mediterranean diet group, CO 1 was reduced (14 events versus 44 in the prudent Western-type diet group, P=0.0001), as were CO 2 (27 events versus 90, P=0.0001) and CO 3 (95 events versus 180, P=0. 0002). Adjusted risk ratios ranged from 0.28 to 0.53. Among the traditional risk factors, total cholesterol (1 mmol/L being associated with an increased risk of 18% to 28%), systolic blood pressure (1 mm Hg being associated with an increased risk of 1% to 2%), leukocyte count (adjusted risk ratios ranging from 1.64 to 2.86 with count >9x10(9)/L), female sex (adjusted risk ratios, 0.27 to 0. 46), and aspirin use (adjusted risk ratios, 0.59 to 0.82) were each significantly and independently associated with recurrence. CONCLUSIONS: The protective effect of the Mediterranean dietary pattern was maintained up to 4 years after the first infarction, confirming previous intermediate analyses. Major traditional risk factors, such as high blood cholesterol and blood pressure, were shown to be independent and joint predictors of recurrence, indicating that the Mediterranean dietary pattern did not alter, at least qualitatively, the usual relationships between major risk factors and recurrence. Thus, a comprehensive strategy to decrease cardiovascular morbidity and mortality should include primarily a cardioprotective diet. It should be associated with other (pharmacological?) means aimed at reducing modifiable risk factors. Further trials combining the 2 approaches are warranted.

Aged↗
PubMed1999

Effects of cocaine, nicotine, dizocipline and alcohol on mice locomotor activity: cocaine-alcohol cross-sensitization involves upregulation of striatal dopamine transporter binding sites.

We investigated if repeated administration of cocaine, nicotine, dizocipline (MK-801) and alcohol yields behavioral cross-sensitization between these agents. Swiss Webster mice received in their home cage one of the following intraperitoneal (i. p.) injections for 5 consecutive days: (a) saline, (b) cocaine (20 mg/kg), (c) nicotine (0.5 mg/kg), (d) MK-801 (0.3 mg/kg) and (e) ethanol (2.0 g/kg). After a 10-day drug free period, each group (n=30) was divided into three subgroups (n=10) and received challenge injections of either cocaine, nicotine or MK-801. The horizontal and vertical movements of the mice were recorded in locomotor activity cages (test cage). Among the various drugs tested, only the cocaine and ethanol experienced mice developed sensitization to a challenge injection of cocaine; MK-801 pretreated mice showed a sensitized response only to a challenge injection of MK-801. In a second experiment, mice in their home cages received (a) saline, (b) cocaine (20 mg/kg) or (c) ethanol (2.0 g/kg) for 5 days, and challenged with an i.p. ethanol injection (2.0 g/kg) after a 10-day drug free period. Both, cocaine and ethanol experienced mice developed marked sensitization to ethanol challenge compared with the saline experienced mice. Assessment of the densities of striatal dopamine transporter (DAT) sites (by [3H]mazindol binding) 11 days after the extinction of repeated treatment with either cocaine or ethanol revealed a significant increase (71-108%) in the number of DAT binding sites. Thus, among the various psychostimulants investigated in the present study cross-sensitization between cocaine and ethanol was only observed. The behavioral sensitization we measured was primarily 'drug-dependent', rather than 'context-dependent', because animals were exposed to the test cage only once. The finding that cocaine- and ethanol-induced behavioral sensitization is associated with upregulation of striatal DAT binding sites supports the hypothesis that similar neural substrates are involved in the psychomotor/rewarding effects of cocaine and alcohol.

Animals↗
PubMed1999

Local intramural heparin delivery during primary angioplasty for acute myocardial infarction: results of the Local PAMI Pilot Study.

The feasibility and safety of local heparin delivery during acute infarct angioplasty was evaluated in a prospective, multicenter, 120-patient series. Angioplasty was performed using standard techniques, after which heparin (4,000 U) was delivered locally; 25% of patients received stents. Procedural success was reported in 98% of patients; 6.7% of patients suffered death, reinfarction, recurrent ischemia, or stroke during the index hospitalization. The 6-month target vessel revascularization rate was 12.5%. Local heparin therapy with provisional stenting in acute myocardial infarction patients is safe, feasible, associated with a low rate of infarct artery revascularization at 6 months, and may potentially eliminate the need for systemic heparin following the procedure.

Aged↗
PubMed1999

Modulation of tolerance by mutant heat shock transcription factors.

It ought to be possible to recruit normal cellular defenses to mitigate ischemia/reperfusion damage and to reduce toxicity of chemotherapeutic drugs. Stress-preconditioned cells acquire a tolerant state characterized by increased resistance to such insults. This state is widely believed to be mediated, partially, by heat shock proteins (Hsps). Indirect evidence suggests that stress-induced Hsp expression is controlled by heat shock transcription factor 1 (Hsf1), which factor may therefore represent a preferred target for therapeutic modulation of tolerance. In support, positively acting (Hsf1(+)) and negatively acting (Hsf1(-)) mutants of Hsf1 were identified. Inhibition of endogenous Hsf1 activity by Hsf1(-) prevents stress-induced Hsp synthesis and development of tolerance. Hsf1(+) drastically enhances expression of major Hsps in the absence of stress and induces tolerance against heat, simulated ischemia and toxicity by cyclophosphamide. Where compared, tolerance induced was slightly better than that produced by heat preconditioning. Thus, development of the tolerant state is dependent on increased levels of the cohort of Hsps induced by stress preconditioning, and Hsf1 can induce accumulation of a typical set of Hsps, which proteins are alone capable of providing tolerance at a similar level as heat preconditioning. These findings make Hsf1 a preferred target for pharmacological intervention to deliberately induce tolerance.

Cell Division↗
PubMed1999

Polypharmacy and elderly patients.

Medication therapy in elderly patients is difficult to manage and always has the potential of being hazardous. With the age-related changes that affect the pharmacokinetics and pharmacodynamics of a medication, prescribing medications is further complicated. Similarly, assessment of a medication's efficacy is difficult. The situation becomes more complicated when the patient is taking multiple medications. Nurses in the perioperative area need to be cognizant of a patient's preoperative medication regime and the medications that have been prescribed in the perioperative setting. As medication interactions increase substantially with the number of medications taken, the most pertinent nursing intervention is accurate assessment of the patient. Early recognition of potentially harmful medication effects is critical.

Aged↗
PubMed1999

Effect of the dopaminergic neurotoxin MPTP on cocaine-induced locomotor sensitization.

The blockade of dopamine (DA) uptake via the dopamine transporter (DAT) in the nucleus accumbens (NAC) and striatum by cocaine has a major role in the reinforcing and psychomotor stimulating effects of the drug. Here we investigated the effect of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the expression and induction of sensitization to the locomotor stimulating effect of cocaine. MPTP (20 mg/kg x 4) caused 72 and 76% depletion of DAT sites in the NAC and striatum, respectively, in C57BL/6 mice. The magnitude of this depletion 3 and 19 days after MPTP administration was the same. To determine the effect of MPTP on the expression of the sensitized response to cocaine, cocaine-experienced mice (20 mg/kg for 5 days) received MPTP 3 days before a challenge cocaine injection was given on day 15. Cocaine/MPTP mice were significantly more sensitive to the challenge cocaine injection than the cocaine/saline-pretreated mice. To determine whether depletion of NAC and striatal DAT affects the induction of sensitization to cocaine, mice were pretreated with MPTP 3 days before the administration of cocaine (20 mg/kg for 5 days). The magnitude of the sensitized response of MPTP/cocaine-pretreated mice to cocaine challenge was the same as the sensitized response of mice treated with saline/cocaine, while the number of DAT binding sites in the MPTP/cocaine group was significantly lower than the saline/cocaine group. The present study indicates that MPTP exacerbates the expression of locomotor sensitization to cocaine, but it had no effect on the induction of sensitization. We conclude that the expression, but not the induction, of locomotor sensitization to cocaine may be dependent on the level of DAT binding sites.

Animals↗
PubMed1999

BDNF stimulates expression, activity and release of tissue-type plasminogen activator in mouse cortical neurons.

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in neuronal development and synaptic plasticity. Although the physiological effects of BDNF have been examined in detail, target proteins which mediate its actions remain largely unknown. Here, we report that BDNF stimulates the expression of tissue-type plasminogen activator (tPA) in primary cultures of cortical neurons in a time- and concentration-dependent manner. Among the other members of the neurotrophin family, neurotrophin-4 (NT-4) and to a lesser extent neurotrophin-3 (NT-3) also increased tPA mRNA expression, while nerve growth factor (NGF) was devoid of any effect. Induction of tPA expression by BDNF is accompanied by an increase in the proteolytic activity of tPA associated with cortical neurons and a release of tPA into the extracellular space. Release of tPA induced by BDNF depends on extracellular Ca2+ since it is markedly reduced in the presence of ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA). Up-regulation of tPA expression by BDNF is followed by the induction of plasminogen activator inhibitor 2 (PAI-2), an inhibitor of tPA. Together these results suggest that activation of tPA by BDNF may contribute to structural changes associated with neuronal development or synaptic plasticity.

Animals↗
PubMed1999

Combined chemoradiotherapy for unresectable pancreatic cancer.

This study was undertaken to evaluate the efficacy of a regimen of combined chemoradiotherapy in patients with unresectable adenocarcinoma of the pancreas. An analysis was undertaken on 27 patients from January 1992 to May 1996. Patients had a median age of 70 years (range, 40-78) and Eastern Cooperative Oncology Group Performance Status of 0-2. Eighteen patients had locoregional disease (T2-T3, N0-N1, M0), and nine had metastatic disease. Chemotherapy consisted of four cycles of 5-fluorouracil 1 gm/m2/day as a continuous infusion over 110 hours, streptozotocin 300 mg/m2/day over 30 minutes on days 2-4, and cisplatin 100 mg/m2 over 2 hours on day 4 only, followed by a maintenance regimen of 5-fluorouracil and leucovorin every 2 weeks. The radiotherapy was administered as a split course concurrently with chemotherapy to a total dose of 6000 cGy. Toxicity was frequent, but there were no treatment-related deaths. Grade III and IV toxicity was primarily limited to myelosuppression, stomatitis, and gastrointestinal side effects. Fifteen patients (56%) were able to complete either three or four cycles of chemoradiotherapy. All patients were evaluable for toxicity, response, and survival. Nine patients (33%) had an objective response (four complete response 5 partial response), two remained stable, and 16 (59%) had disease progression. Median survival for the entire group was 19 weeks (2-139), and the median survival for overall responders was 56 weeks (15-139). No patient with localized disease underwent subsequent surgical resection. The authors conclude that those patients who are able to tolerate the entire treatment regimen may achieve a useful prolongation of time to tumor progression.

Adenocarcinoma↗
PubMed1999

Immunochemical evidence against the involvement of cysteine conjugate beta-lyase in compound A nephrotoxicity in rats.

BACKGROUND: Compound A, a degradation product of sevoflurane, causes renal corticomedullary necrosis in rats. Although the toxicity of this compound was originally hypothesized to result from the biotransformation of its cysteine conjugates into toxic thionoacyl halide metabolites by renal cysteine conjugate beta-lyase, recent evidence suggests that alternative mechanisms may be responsible for compound A nephrotoxicity. The aim of this study was to evaluate these issues by determining whether mercapturates and glutathione conjugates of compound A could produce renal corticomedullary necrosis in rats, similar to compound A, and whether renal covalent adducts of the thionacyl halide metabolite of compound A could be detected immunochemically. METHODS: Male Wistar rats were administered, intraperitoneally, N-acetylcysteine conjugates (mercapturates) of compound A (90 or 180 micromol/kg) or glutathione conjugates of compound A (180 micromol/kg) with or without intraperitoneal pretreatments with aminooxyacetic acid (500 micromol/kg) or acivicin (250 micromol/kg). Rats were killed after 24 h, and kidney tissues were analyzed for toxicity by histologic examination or for protein adducts by immunoblotting or immunohistochemical analysis, using antisera raised against the covalently bound thionoacyl halide metabolite of compound A. RESULTS: Mercapturates and glutathione conjugates of compound A both produced renal corticomedullary necrosis similar to that caused by compound A. Aminooxyacetic acid, an inhibitor of renal cysteine conjugate beta-lyase, did not inhibit the toxicity of the mercapturates, whereas acivicin, an inhibitor of gamma-glutamyltranspeptidase, potentiated the toxicity of both classes of conjugates. No immunochemical evidence for renal protein adducts of the thionacyl halide metabolite was found in rats 24 h after the administration of the mercapturates of compound A or in the kidneys of rats, obtained from a previous study, 5 and 24 h after the administration of compound A. CONCLUSION: The results of this study are consistent with the idea that a mechanism other than the renal cysteine conjugate beta-lyase pathway of metabolic activation is responsible for the nephrotoxicity of compound A and its glutathione and mercapturate conjugates in male Wistar rats.

Anesthetics, Inhalation↗
PubMed1999

Crystallization and preliminary X-ray diffraction studies of mammalian purple acid phosphatase.

The oxidized form of purple acid phosphatase from pig allantoic fluid has been crystallized in the presence of phosphate using the hanging-drop technique. The crystals belong to the space group P2(1)2(1)2(1) and have unit-cell parameters a = 66.8, b = 70.3, c = 78.7 A. Diffraction data collected from a cryocooled crystal using a conventional X-ray source extend to 1.55 A resolution. A knowledge of the three-dimensional structure of mammalian purple acid phosphatase will aid in understanding the substrate specificity of the enzyme and will be important in the rational design of inhibitors, with potential in the treatment of bone diseases.

Acid Phosphatase↗
PubMed1999

Psychological defense styles in women who report childhood sexual abuse: a controlled community study.

OBJECTIVE: The psychological defense styles of women who reported childhood sexual abuse were assessed and compared to those of women without childhood sexual abuse. METHOD: Subjects in a random community sample (N = 354) of New Zealand women were interviewed and completed two relevant questionnaires, the Defense Style Questionnaire and the Dissociative Experiences Scale. RESULTS: Women reporting childhood sexual abuse showed more immature defense styles, and those who experienced the most severe childhood sexual abuse showed the most immature styles. Dissociation, however, as measured on the Dissociative Experiences Scale, was not linked to childhood sexual abuse. CONCLUSIONS: Reporting childhood sexual abuse was associated with more immature coping styles, although not dissociation, in this community sample of women. Coping styles are likely to be a major mechanism through which childhood sexual abuse increases rates of later psychological problems.

Adaptation, Psychological↗