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Biomedical subjects

J L Martin

Publications and source records attributed to J L Martin.

At least 55 records · Page 3Linked to original sources
PubMed2001

Transgene overexpression of alphaB crystallin confers simultaneous protection against cardiomyocyte apoptosis and necrosis during myocardial ischemia and reperfusion.

We investigated whether enhanced expression of alphaB crystallin, a stress-inducible molecular chaperone of the small heat shock family, can protect myocardial contractile apparatus against ischemia reperfusion (I/R) injury. Transgenic mice overexpressing alphaB crystallin were generated using the 0.76 kb rat alphaB crystallin cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. Southern analysis confirmed transgene integration and Northern and Western blotting characterized expression (3.1-fold and 6.9-fold elevations in myocardial mRNA and protein levels, respectively). Extent of functional recovery over a 3 h reperfusion period following a 20 min ischemic period in transgenic and wild-type mouse hearts was assessed using an ex vivo work-performing heart preparation. The transgenic group displayed significantly higher values of DP at R45 min (29.14+/-1.9 mm Hg vs. 17.6+/-0.7 mm Hg), R60 min (31.56+/-1.7 mm Hg vs. 17.8+/-0.8 mm Hg), and R75 min (32.5+/-2.2 mm Hg vs. 16.9+/-0.9 mm Hg), and of dLVP/dt at R45 min (1740.2+/-111.5 mm Hg.s-1 vs. 548.7+/-82.2 mm Hg.s-1) and R60 min (1199.8+/-104.6 mm Hg.s-1 vs. 466.9+/-61.1 mm Hg.s-1). The transgenic group also displayed development of less oxidative stress, decreased extent of infarction, and attenuated cardiomyocyte apoptotic cell death. Transgene overexpression of alphaB crystallin was therefore successful in diminishing the independent contributory effects of both necrosis and apoptosis on I/R-induced cell death.

Actins↗
PubMed2001

Role of protein kinase C-epsilon in hypertrophy of cultured neonatal rat ventricular myocytes.

Using adenovirus (Adv)-mediated overexpression of constitutively active (ca) and dominant-negative (dn) mutants, we examined whether protein kinase C (PKC)-epsilon, the major novel PKC isoenzyme expressed in the adult heart, was necessary and/or sufficient to induce specific aspects of the hypertrophic phenotype in low-density, neonatal rat ventricular myocytes (NRVM) in serum-free culture. Adv-caPKC-epsilon did not increase cell surface area or the total protein-to-DNA ratio. However, cell shape was markedly affected, as evidenced by a 67% increase in the cell length-to-width ratio and a 17% increase in the perimeter-to-area ratio. Adv-caPKC-epsilon also increased atrial natriuretic factor (ANF) and beta-myosin heavy chain (MHC) mRNA levels 2.5 +/- 0.3- and 2.1 +/- 0.2-fold, respectively, compared with NRVM infected with an empty, parent vector (P < 0.05 for both). Conversely, Adv-dnPKC-epsilon did not block endothelin-induced increases in cell surface area, the total protein-to-DNA ratio, or upregulation of beta-MHC and ANF gene expression. However, the dominant-negative inhibitor markedly suppressed endothelin-induced extracellular signal-regulated kinase (ERK) 1/2 activation. Taken together, these results indicate that caPKC-epsilon overexpression alters cell geometry, producing cellular elongation and remodeling without a significant, overall increase in cell surface area or total protein accumulation. Furthermore, PKC-epsilon activation and downstream signaling via the ERK cascade may not be necessary for cell growth, protein accumulation, and gene expression changes induced by endothelin.

Adenoviridae↗
PubMed2000

The perpetrators of domestic violence.

There has been little useful research in recent years into those who perpetrate domestic violence. Domestic violence is always anchored in a social context in which the aspirations of men and women are dealt with unequally. The majority of perpetrators of domestic violence are men. Perpetrators are often young, troubled, unemployed, and of low self-esteem; they have often experienced abuse (of various types) themselves. However, these factors do not justify their abusive behaviour. General practitioners and other health workers have a responsibility to broach the subject of domestic violence with both perpetrators and victims. They are in a key position to break the silence that allows it to continue. Programs for stopping domestic violence can be effective for those who are motivated to change their behaviour and see the programs through to completion.

Confidentiality↗
PubMed2000

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 microM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC(50) 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC(50) 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 A (1) and 1.85 A (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Anti-HIV Agents↗
PubMed2000

nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.

Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity.

Animals↗
PubMed2000

New roles for cis-jasmone as an insect semiochemical and in plant defense.

cis-jasmone, or (Z)-jasmone, is well known as a component of plant volatiles, and its release can be induced by damage, for example during insect herbivory. Using the olfactory system of the lettuce aphid to investigate volatiles from plants avoided by this insect, (Z)-jasmone was found to be electrophysiologically active and also to be repellent in laboratory choice tests. In field studies, repellency from traps was demonstrated for the damson-hop aphid, and with cereal aphids numbers were reduced in plots of winter wheat treated with (Z)-jasmone. In contrast, attractant activity was found in laboratory and wind tunnel tests for insects acting antagonistically to aphids, namely the seven-spot ladybird and an aphid parasitoid. When applied in the vapor phase to intact bean plants, (Z)-jasmone induced the production of volatile compounds, including the monoterpene (E)-beta-ocimene, which affect plant defense, for example by stimulating the activity of parasitic insects. These plants were more attractive to the aphid parasitoid in the wind tunnel when tested 48 h after exposure to (Z)-jasmone had ceased. This possible signaling role of (Z)-jasmone is qualitatively different from that of the biosynthetically related methyl jasmonate and gives a long-lasting effect after removal of the stimulus. Differential display was used to compare mRNA populations in bean leaves exposed to the vapor of (Z)-jasmone and methyl jasmonate. One differentially displayed fragment was cloned and shown by Northern blotting to be up-regulated in leaf tissue by (Z)-jasmone. This sequence was identified by homology as being derived from a gene encoding an alpha-tubulin isoform.

Amino Acid Sequence↗
PubMed2000

Electrochromic detection of a coherent component in the formation of the charge pair P(+)H(L)(-) in bacterial reaction centers.

We demonstrate coupling of an intraprotein electron transfer reaction to coherent vibrational motions. The kinetics of charge separation toward the radical pair state P(+)H(L)(-) were studied in reaction centers of Rhodobacter sphaeroides at 15 K. The electrochromic shift of the bacteriochlorophyll monomers is the most prominent spectral feature associated with this charge displacement. The newly reported absolute absorption spectrum of the P(+)H(L)(-) state is discussed in terms of this shift. In wild-type reaction centers, the rise kinetics of the electrochromic shift display a small but significant 30 cm(-)(1) periodic modulation (period of approximately 1 ps). This modulation is also present in FL181Y mutant reaction centers, where overall charge separation is somewhat more rapid than in the wild-type reaction center. In contrast, in YM210L mutant reaction centers, where the charge separation is much slower, the modulation is absent. The conclusion that the motion along the reaction coordinate has a 30 cm(-)(1) coherent component is discussed in light of possible mechanisms of electron transfer.

Electrochemistry↗
PubMed2000

7-Nitroindazole blocks nicotine-induced conditioned place preference but not LiCl-induced conditioned place aversion.

We have shown previously that the neuronal nitric oxide synthase (nNOS) is involved in the rewarding effect of cocaine as determined by the conditioned place preference (CPP) paradigm. In the present study we investigated the effect of the nNOS inhibitor 7-nitroindazole (7-NI) on nicotine-induced CPP and LiCl-induced conditioned place aversion (CPA) in Swiss Webster mice. Mice treated with nicotine (0.5 mg/kg) or saline every other day for 8 days (four drug and four saline sessions) developed CPP that was completely blocked by pretreatment with 7-NI (25 mg/kg). Mice treated with LiCl (150 mg/kg) developed marked aversion to the LiCl-paired compartment. LiCl-induced CPA was not affected by the pretreatment with 7-NI. These findings suggest that nitric oxide (NO) plays a role in the acquisition of reward but not of aversion and that the blockade of nicotine-induced CPP is probably not due to impairment of learning and memory.

Animals↗
PubMed2000

Malignant spinal neurofibrosarcoma.

STUDY DESIGN: A report of a case of metastatic spinal neurofibrosarcoma. OBJECTIVE: To document metastatic neurofibrosarcoma as a cause of spinal cord compression and to review the literature. SUMMARY OF BACKGROUND DATA: Three previously reported cases of metastatic neurofibrosarcoma of the spine were reviewed. METHODS: The patient's clinical record and radiologic investigations as well as the result of a search of the English literature are reported. Magnetic resonance images, computed tomographic scans, and histology photomicrographs are displayed. RESULTS: Paraparesis developed in this patient, due to a posterior extradural thoracic spinal cord compression by a neurofibrosarcoma believed to be metastatic from a neurofibrosarcoma of the femoral nerve. CONCLUSIONS: Malignant spinal metastasis remains a rare complication of neurofibromatosis, with a very poor prognosis.

Fatal Outcome↗
PubMed2000

Blockade of alcohol-induced locomotor sensitization and conditioned place preference in DBA mice by 7-nitroindazole.

Our previous studies indicated that inhibition or ablation of the neuronal nitric oxide synthase (nNOS) prevents the development of sensitization to the locomotor-stimulating effect of cocaine and cocaine-induced conditioned place preference (CPP). The present study was undertaken to investigate the effect of the nNOS inhibitor, 7-nitroindazole (7-NI), on ethanol-induced locomotor sensitization and CPP in DBA/2J mice. Administration of ethanol (1.5 g/kg; i.p.) for 7 days resulted in a progressive increase in the locomotor-stimulating effect of ethanol. Pretreatment with 7-NI (25 mg/kg) blocked the expression of the sensitized response to ethanol. A challenge injection of ethanol given 1 week and then 4 weeks following withdrawal from ethanol indicated that (a) ethanol sensitization was long lasting, and (b) the co-administration of 7-NI and ethanol attenuated the sensitized response to ethanol challenge. The CPP experiments showed that pairing four ethanol (2.5 g/kg) injections with a specific environment resulted in a marked preference for the drug-paired environment. The pretreatment with 7-NI (25 mg/kg) completely blocked ethanol-induced CPP. 7-NI alone produced neither rewarding nor aversive effects. Taken together, results of the present study indicate that blockade of nNOS by 7-NI-attenuated ethanol-induced behavioral sensitization and completely blocked the rewarding effect of ethanol. These findings support the role of NO in ethanol actions and further suggest that the nNOS system is relevant to the rewarding effects of various drugs of abuse.

Animals↗
PubMed2000

Femtosecond resolution of ligand-heme interactions in the high-affinity quinol oxidase bd: A di-heme active site?

Interaction of the two high-spin hemes in the oxygen reduction site of the bd-type quinol oxidase from Escherichia coli has been studied by femtosecond multicolor transient absorption spectroscopy. The previously unidentified Soret band of ferrous heme b(595) was determined to be centered around 440 nm by selective excitation of the fully reduced unliganded or CO-bound cytochrome bd in the alpha-band of heme b(595). The redox state of the b-type hemes strongly affects both the line shape and the kinetics of the absorption changes induced by photodissociation of CO from heme d. In the reduced enzyme, CO photodissociation from heme d perturbs the spectrum of ferrous cytochrome b(595) within a few ps, pointing to a direct interaction between hemes b(595) and d. Whereas in the reduced enzyme no heme d-CO geminate recombination is observed, in the mixed-valence CO-liganded complex with heme b(595) initially oxidized, a significant part of photodissociated CO does not leave the protein and recombines with heme d within a few hundred ps. This caging effect may indicate that ferrous heme b(595) provides a transient binding site for carbon monoxide within one of the routes by which the dissociated ligand leaves the protein. Taken together, the data indicate physical proximity of the hemes d and b(595) and corroborate the possibility of a functional cooperation between the two hemes in the dioxygen-reducing center of cytochrome bd.

Binding Sites↗
PubMed2000

Characteristics of coronary smooth muscle cells and adventitial fibroblasts.

BACKGROUND: Recent findings suggesting the involvement of adventitial cells in coronary repair have raised questions regarding the phenotypic "plasticity" of medial smooth muscle cells (SMCs). Accordingly, the aims of the present study were to examine the characteristics of coronary medial and adventitial cells and to compare the responses of coronary and noncoronary SMCs to stimulation. METHODS AND RESULTS: Enzymatically isolated coronary SMCs (human and porcine) were distinct from noncoronary SMCs, showing poor adhesion and spreading, as well as lower proliferation, collagen synthesis, and LDL degradation. Several extracellular matrix components (Matrigel, collagen I and IV, laminin, vitronectin, fibronectin) or growth factors (epidermal growth factor, platelet-derived growth factor-BB, insulin growth factor-1, interleukin-1alpha) failed to augment the adhesion or proliferation of coronary SMCs to the levels observed in noncoronary SMCs. Unlike coronary SMCs, coronary fibroblasts demonstrated high adhesion, proliferation, collagen synthesis, and avid LDL metabolism. Limited responses of coronary SMCs were associated with sustained expression of differentiation markers (alpha-smooth muscle actin, h-caldesmon, and smooth muscle myosin heavy chain), whereas noncoronary SMCs showed marked phenotypic heterogeneity. CONCLUSIONS: Coronary SMCs appeared to maintain highly differentiated phenotype in response to stimulation, whereas coronary adventitial fibroblasts demonstrated several characteristics that are essential during vascular repair. Coronary SMCs, however, were distinct from noncoronary medial cells, which displayed greater phenotypic heterogeneity and versatility in culture. We postulate that the mechanism of vascular repair may differ among vascular beds, pointing to the importance of coronary artery-specific investigations in vascular biology.

Biomarkers↗
PubMed2000

Detection and measurement of sulfur mustard offgassing from the weanling pig following exposure to saturated sulfur mustard vapor.

Animal models are employed to investigate mechanisms of injury and to evaluate protective measures against sulfur mustard (HD) exposure. The ability to detect and quantify HD enables the researcher to follow safe procedures in handling skin samples. We designed an experimental procedure to measure HD offgassing from animal models. A Minicams--a portable gas chromatograph equipped with a flame photometric detector and on-line sorbent collection and desorption--was used to monitor the HD concentration. Confirming measurements were made using a two-step process that trapped HD on a Tenax sorbent off-line and then transferred the sample by means of an ACEM 900 to a gas chromatograph equipped with either a flame photometric detector or a mass spectrometer. Sulfur mustard offgassing data are presented from three experiments in which weanling pigs were exposed to saturated HD vapor via vapor caps containing 10 microl of HD. The HD concentration was measured in time-weighted-average (TWA) units at a specific HD application site. The current 8-h maximum exposure limit for HD is 3-ng l(-1), (1 TWA unit). The largest TWA value measured near a 3 h time point was a Minicams measurement of 0.48 TWA at 2 h and 53 min after removal of a vapor cap containing HD from a single exposure site on an animal that had 24 concurrent dorsal exposure sites. Gas chromatography/flame photometric detection and gas chromatography/mass spectrometry were used to confirm the Minicams data and to provide greater sensitivity and selectivity down to 0.1 TWA. The gas chromatography/mass spectrometry data confirmed that HD concentrations fell below 0.1 TWA in <5 h for a specific site. These measurements of HD concentrations provided information on the expeditious and safe handling of HD-exposed tissue.

Animals↗
PubMed2000

Effect of riluzole and gabapentin on cocaine- and methamphetamine-induced behavioral sensitization in mice.

RATIONALE: Recent studies have suggested the involvement of excitatory amino acid (EAA) and inhibitory gamma amino butyric acid (GABA) transmission in the effects of psychostimulants such as cocaine and amphetamines. OBJECTIVES: The present study was undertaken to investigate whether drugs that are considered to inhibit glutamate release (e.g., riluzole) or increase GABAergic transmission (e.g., gabapentin) attenuate the induction and expression of sensitization to cocaine and methamphetamine (METH) in Swiss Webster mice. METHODS: Sensitization to the psychomotor stimulating effect of cocaine and METH was rendered by five daily injections of cocaine (20 mg/kg) or METH (1.0 mg/kg). Locomotor activity was measured by infrared beam interrupts. RESULTS: Pretreatment with riluzole (2.5-20.0 mg/kg) affected neither the expression nor the induction of sensitization to cocaine. The pretreatment with riluzole (20 mg/kg) blocked the acute response to METH on day 1 and the expression of the sensitized response on day 5 but not the induction of sensitization to METH. Pretreatment with gabapentin (10 mg/kg and 30 mg/kg) affected neither the expression nor the induction of sensitization to cocaine. The pretreatment with gabapentin attenuated the acute response to METH on day 1 and the expression of the sensitized response on day 5, but it failed to block the induction of sensitization to METH. Psychostimulant-induced conditioned locomotion was affected neither by riluzole nor by gabapentin. CONCLUSIONS: Riluzole and gabapentin had no effect on the induction of sensitization to cocaine and METH; however, they attenuated the expression of sensitization to METH but not to cocaine. These findings suggest that riluzole- and gabapentin-mediated changes in EAA and GABAergic transmission, respectively, had no effect on mechanisms associated with the induction of sensitization, but they may affect the expression of the sensitized response to METH.

Acetates↗
PubMed2000

Scopolamine inhibits cocaine-conditioned but not unconditioned stimulant effects in mice.

RATIONALE: In animal models, cocaine cues contribute to the development of conditioned responses to the psychomotor stimulating and rewarding effects of the drug. OBJECTIVES: In the present study we investigated the effect of scopolamine, known to impair learning and memory, on cocaine-induced conditioned and unconditioned responses in Swiss Webster mice. METHODS: In the first experiment, mice were treated with saline/saline, saline/cocaine (20 mg/kg), scopolamine (1.0 mg/kg)/cocaine, or scopolamine/saline for 5 days. The treatments were paired with the locomotor activity test cage twice, on days 1 and 5. This allowed to determine: (a) the induction and expression of place-dependent sensitization (PDS) to the psychomotor-stimulating effect of cocaine and (b) place-dependent hyperlocomotion (PDH; i.e., conditioning) as defined by the response to saline injection in the test cage. In the second experiment, all injections were delivered in animals' home cage in order to induce place-independent sensitization (PIS) to cocaine and to avoid the development of PDH. In the third experiment, the effect of scopolamine (1.0 mg/kg) on the acquisition of cocaine-induced conditioned place preference (CPP) was investigated. RESULTS: Data from the first experiment suggest that pretreatment with scopolamine had no specific effect on the induction and expression of cocaine-induced PIS. However, scopolamine blocked cocaine-induced PDH. Results from the second experiment confirmed that scopolamine had no effect on the induction of PIS to cocaine. Results from the third experiment showed that scopolamine completely blocked cocaine-induced CPP. CONCLUSIONS: The finding that scopolamine blocked the conditioned behaviors, PDH and CPP, that develop after exposure to cocaine supports the hypothesis that cocaine cue reactivity in the paradigms tested is associated with learning and memory.

Animals↗
PubMed2000

Cocaine-induced kindling is associated with elevated NMDA receptor binding in discrete mouse brain regions.

The present study was undertaken to investigate the involvement of N-methyl-D-aspartate (NMDA) type of glutamate receptors in the induction and maintenance of kindling generated by daily cocaine (35 mg/kg) injections to Swiss Webster mice. In addition, the regulation of NMDA receptor binding following the development of sensitization to horizontal locomotor activity produced by daily injections of a low dose of cocaine (15 mg/kg for 5 days) was investigated. Three days following the administration of the high dose of cocaine (35 mg/kg) a marked augmentation in cocaine-induced horizontal and vertical activities was observed (induction phase). Subsequently, after 10 days of cocaine administration, mice developed stage 5 seizures (Racine scale). Binding of [3H]CGP 39653 to the NMDA receptors revealed a marked increase in receptor densities in the striatum, amygdala and hippocampus associated with the induction phase. The elevation of NMDA receptor binding in the striatum and amygdala was sustained for 10 days following the induction phase. The pattern of altered NMDA receptor binding following the expression of cocaine kindled seizures was different. One day after the expression of kindled seizures NMDA receptor binding was elevated in striatum, amygdala, hippocampus and frontal cortex. However, only the elevation of NMDA receptor binding in the amygdala and hippocampus was sustained for 10 days following the expression of cocaine kindled seizures. In the brains of mice sensitized to the low dose of cocaine (15 mg/kg) no change in NMDA receptor binding was observed compared with control values. The present findings suggest the following: (a) The induction of cocaine kindling is associated with increased NMDA receptor binding activity in the striatum, amygdala and hippocampus; (b) the maintenance of cocaine kindling depends on increased NMDA receptor binding in the amygdala and hippocampus; (c) sensitization to cocaine-induced horizontal locomotor activity may be independent of elevation in NMDA receptor binding.

2-Amino-5-phosphonovalerate↗