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Biomedical subjects

M A Collins

Publications and source records attributed to M A Collins.

At least 55 records · Page 3Linked to original sources
PubMed1996

The inhalation toxicology, genetic toxicology, and metabolism of difluoromethane in the rat.

Difluoromethane (HFC32) is under development as a replacement for chlorofluorocarbons (CFCs) in some refrigeration applications. It has been evaluated by standard studies of toxicity, developmental toxicity, and genotoxicity. In addition, the metabolism and disposition of HFC32 was investigated and a physiologically based pharmacokinetic (PB-PK) model constructed. Inhalation of HFC32 (up to 50,000 ppm) caused no organ-specific effects, but resulted in slight maternal toxicity to the pregnant rat and rabbit and some fetotoxicity to the rat. HFC32 did not sensitize the heart to adrenaline. The pharmacokinetics of [14C]difluoromethane (10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of the inhaled HFC32 was absorbed and that steady state blood levels were achieved within 2 hr and were proportional to dose. Carbon dioxide was the major metabolite of HFC32 at all exposure levels. Carbon monoxide was not detected. The in vivo data were used to validate a PB-PK model to describe the uptake and metabolism of HFC32. Absorption and distribution are adequately described using rat blood:air and tissue:air partition coefficients. Metabolism, which was linear across the dose range, was described by a first order rate constant (Kf = 8.98 hr-1). Of the absorbed HFC32, about 63% was metabolized at all doses; however, when metabolism was expressed as a percentage of the inhaled dose it was much lower, being about 1.4% of the HFC32 entering the airways. Overall, the results indicate that HFC32 is of very low toxicity and should be an acceptable alternative to CFCs.

Animals↗
PubMed1996

On fighting versus accepting stressful circumstances: primary and secondary control among HIV-positive men in prison.

The primacy of primary control over secondary control and ethnic differences in control processes were tested in HIV-positive male state prison inmates. They rated their perceptions of control and psychological distress at an initial interview (N = 95) and 3 months later (N = 78). Regression analyses revealed that primary control had primacy as it had greater adaptive value. However, secondary control did not function as a backup to primary control, and temporal differences in control were not found. No mean differences due to ethnicity (African American vs. White) were found, but there was a strong ethnic difference in the effects of primary control. White participants showed the expected negative relationship between distress and primary control, but African American participants did not. The idea that the benefits of primary control would be the same across various subcultures was not supported.

Adaptation, Psychological↗
PubMed1996

Characterization of a proteinaceous antimicrobial produced by Lactobacillus helveticus CNRZ450.

An antimicrobial substance which resembles a bacteriocin was identified in culture supernatant fluids of Lactobacillus helveticus strain CNRZ450. The bacteriocin was active against a narrow range of strains from closely related species of homofermentative lactobacilli. Its mode of action appeared to be bacteriostatic. Partial purification of the bacteriocin suggested that it was a complex protein with a mol. wt of between 30 and 50 kDa, although there is some evidence that the polypeptide monomer has a mol. wt of around 17 kDa. There was no evidence indicating an extrachromosomal location for its genetic determinant. PCR generated an amplicon from total DNA from strain CNRZ450 using primers based on the helJ gene sequence. A fragment showing homology to this amplicon was located in an EcoRI digest of total DNA from strain CNRZ450. The pattern obtained was different from that obtained with the helveticin J producer strain NCFB481. It is possible, therefore, that the antimicrobial from strain CNRZ450 is related to helveticin J at the DNA sequence level although the physical properties of the two antimicrobials reveal several differences.

Bacteriocins↗
PubMed1996

Binge ethanol-induced brain damage in rats: effect of inhibitors of nitric oxide synthase.

Testing the possible role of endogenous nitric oxide (NO) in the neurotoxicity of ethanol, we examined how two different NO synthase (NOS) inhibitors affected the extent cerebrocortical and olfactory neuronal damage in a modified "binge intoxication" rat model (Collins et al., Alcohol Clin. Exp. Res. 20:284-292, 1996). Male rats intragastrically fed ethanol (6.5 to 12 g/kg/day) in nutrient solution three times daily for 4 days also received NG-nitro-L-arginine methyl ester by chronic intracerebroventricular infusion or 7-nitro-indazole by daily intraperitoneal injection; control rats were given nutrient solution only and/or vehicles. Blood ethanol levels did not differ among the ethanol-treated groups. The amount of ethanol-dependent neuronal degeneration in the entorihinal cortex, dentate gyrus, and olfactory bulb glomeruli--visualized with the de Olmos cupric silver stain and quantitatively assessed in the binge-intoxicated rats--was either unchanged or significantly increased by the NOS inhibitors. Although the efficacies of the inhibitors cannot be directly compared because of various NOS forms were probably inhibited to differing extents, the results do not support the idea that endogenous NO is a neurotoxic mediator of ethanol's effects. Rather NO may have a modest neuroprotectant role in this model of early brain damage induced by ethanol. In addition, the NOS that is localized histochemically as NADPH diaphorase was present primarily in regions and/or cells not damaged by binge ethanol treatment. Assuming that NADPH diaphorase represents most of the NO forming enzyme(s) this suggests a transcellular mechanism for NO. A further observation was that hippocampal CA pyramidal neuron degeneration was extensive in rats infused centrally with NG-nitro-L-arginine methyl ester.

Alcoholic Intoxication↗
PubMed1996

Neuronal degeneration in rat cerebrocortical and olfactory regions during subchronic "binge" intoxication with ethanol: possible explanation for olfactory deficits in alcoholics.

Severe, repetitive ("binge") ethanol intoxication in adult rats (intragastric delivery 3 times daily for 4 days in a modification of the Majchrowicz method) precipitates neuronal degeneration in selected cerebral cortical regions involved in memory and olfaction, confirming the results of Switzer and colleagues (Anat. Rec. 202: 186a, 1982). Neuronal damage was visualized with the de Olmos cupric silver technique for degenerating neurons and processes (argyrophilia), and was quantitated by total counts and densities of argyrophilic cells/fields. The specificity of the degeneration provides a neuropathological basis for the olfactory memory deficits in chronic alcoholics. In highly intoxicated rats, argyrophilia was most extensive among hippocampal dentate gyrus granule cells, pyramidal neurons in layer 3 of the entorhinal cortex, and olfactory nerve terminals in the olfactory bulb. Degenerating pyramidal neurons were also consistently seen in the insular cortex and olfactory cortical regions, such as the piriform and perirhinal cortices. There were few argyrophilic neurons in the CA regions of the hippocampus and none in the cerebellum--regions generally shown to have cell loss in long-term ethanol feeding models--but degenerating mossy fibers in the CA2 region were observed. Degeneration was maximal before the peak period of abstinence symptoms in this model, because argyrophilic densities were no greater 36 hr, compared with 8 hr after the last ethanol dose. High blood ethanol levels were required, because argyrophilia, absent from isocaloric controls, also was only evident in ethanol-intoxicated rats with mean blood ethanol levels for days 2 to 4 above 300 mg/dl; however, it increased substantially between 350 and 550 mg/dl. The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol-induced degeneration may have an excitotoxic basis. Progressive reductions in the seizure threshold (e.g., kindling phenomena that have been documented during binge ethanol intoxication) might be associated with excitotoxic hyperactivity during the repetitive nadirs between high blood and brain ethanol peaks. However, direct toxic actions of ethanol or its metabolites could also be involved. Overall, the model should be useful for studying mechanisms of ethanol-induced selective cortical and olfactory brain damage.

Alcoholic Intoxication↗
PubMed1996

Metabolism and disposition of difluoromethane (HFC32) in the mouse.

1. Difluoromethane (HFC32) is under development as a replacement for chlorofluorocarbons (CFCs) in some refrigeration applications. 2. The metabolism and disposition of [14C]-difluoromethane ([14C]-HFC32) was determined in male Swiss mice as a consequence of a single 6 h inhalation exposure to atmospheres of 10 000 p.p.m. 3. Of the inhaled dose, about 1-2% was recovered in expired air, urine, faeces and carcass suggesting that systemic absorption of this hydrofluorocarbon from the alveolar air space of the lung into blood is poor. Upon cessation of exposure the majority of the systemically absorbed HFC32 was exhaled within 1 h. 4. Carbon dioxide was a major metabolite of HFC32. Carbon dioxide measured post-exposure accounted for about 0.3% of the inhaled dose. Urinary and faecal excretion of non-volatile metabolites accounted for about 0.34% and 0.07% of the inhaled dose, respectively. 5. Carbon monoxide could not be detected. 6. Total metabolism, measured as the sum of the radioactivity recovered in urine, faeces, as carbon dioxide and that retained in the carcass, amounted to about 0.8% of the inhaled dose, equivalent to 64% of the total radioactivity recovered. 7. Analysis of a range of tissues at 4 days post-exposure showed a relatively uniform distribution of radioactivity with the highest concentration in the lung, liver and kidney. There was no evidence of a specific retention in any organ or tissue.

Absorption↗
PubMed1995

(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses.

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.

Animals↗
PubMed1995

Methyl-beta-carbolinium analogs of MPP+ cause nigrostriatal toxicity after substantia nigra injections in rats.

Eleven beta-carbolinium compounds (beta C+s) and MPP+ were stereotaxically injected (40-200 nmol in 5 microliter of vehicle) unilaterally into the substantia nigra of anesthetized adult male Sprague-Dawley rats. The rats were sacrificed after three weeks. The ipsilateral striatum was analyzed for dopamine and DOPAC levels with HPLC. The brainstem injection site was fixed and cut coronally. The largest lesion area in each animal was measured using NIH IMAGE. Three beta C+s produced lesions whose mean areas were nearly as large as that produced by MPP+ (defined as 100%): 2,9-Me2-harman (94%), 2-Me-harmol (74%), and 2,9-Me2-norharman (57%). Three other compounds produced somewhat smaller lesions: 2-Me-harmaline (34%), 6-MeO-2-Me-harman (29%), and 2-Me-harmine (25%). The remaining compounds were ineffective (< or = 12%): norharman, 2-Me-norharman, 2-Me-harman, harmine, and 2-Me-6-MeO-harmalan. A 40 nmol dose of MPP+ reduced ipsilateral striatal dopamine to 0.6% of control. None of the beta C+s approached this, although several did significantly reduce striatal dopamine at doses of either 40 nmol (2,9-Me2-harman (37%), 2,9-Me2-norharman (42%), and 2-Me-harman (63%)) or 200 nmol (2-Me-harmaline (23%), norharman (63%), and 2-Me-norharman (64%)). There was a moderate negative correlation between lesion size and dopamine level (r = -0.65). There were also moderately strong correlation between lesion size and dopamine level (r = -0.65). There were also moderately strong correlations (r = 0.39-0.78) between the beta C+ nigral lesion area or striatal dopamine level potencies and their previously described IC50 values for inhibiting mitochondrial respiration or their toxicity to PC12 cells in culture. Interestingly, our correlation analysis revealed a remarkably strong correlation between beta C+ Ki MAO-A values and their toxicity to PC12 LDH release (r = -0.84) or PC12 protein loss (r = 0.79). Although beta C+s appear to be less specific toxins than MPP+, their levels in human substantia nigra are 8-20-fold higher than in cortex, making their role as relatively selective nigral toxins in Parkinson's disease plausible.

1-Methyl-4-phenylpyridinium↗
PubMed1995

1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo.

Subchronic and chronic studies were carried out in the rat and a developmental toxicity study in the rabbit with exposures to 1,1,1,2-tetrafluoroethane (HFC 134a) by inhalation. In the rat repeated exposure to 50,000 ppm HFC 134a for 13, 52, and 104 weeks elicited no effect on clinical condition, growth, and survival, or on a variety of hematological, clinical chemistry, and urinary parameters. Treatment-related pathological changes were seen only at study termination at 2 years and were confined to increased incidence of Leydig cell hyperplasia and adenoma in male rats exposed to 50,000 ppm. The tumors, which were also seen in control animals, were benign and not life-threatening. A battery of in vitro and in vivo tests gave no evidence of genotoxic activity. With exposure to pregnant rabbits, the only treatment-related effects were of minimal maternal toxicity at high exposure concentrations; there were no effects on fetal development. It is concluded that HFC 134a is of very low toxicity and should be an acceptable alternative to CFCs.

Administration, Inhalation↗
PubMed1995

Computed tomography manifestations of tricuspid regurgitation.

Six patients undergoing dynamic contrast enhanced abdominal computed tomography (CT) for upper abdominal symptoms and signs are described. Each patient demonstrated early, intense opacification of the inferior vena cava (IVC) and hepatic veins, exceeding that in the aorta on scans through the upper abdomen. Opacification of the IVC returned to normal on more caudal slices. All six patients were found to have echocardiographically proven tricuspid regurgitation (TR). It is suggested that this sign occurs in patients with TR due to direct reflux of contrast from the right atrium into the IVC during protracted bolus injection. Additional CT findings included patchy parenchymal liver enhancement in four patients and ascites in five. Recognition of this simple sign may direct the clinician to a cardiac aetiology for upper abdominal symptoms and signs.

Female↗
PubMed1995

Identification and quantification of fluorine-containing metabolites of 1-chloro-2,2,2-trifluoroethane (HCFC133A) in the rat by 19F-NMR spectroscopy.

1-Chloro-2,2,2-trifluorethane (HCFC133a) causes a reduction in testis weight and germinal epithelial cell atrophy in the rat following exposure by inhalation at concentrations of 10,000 ppm and above. Following administration by gavage, an increased incidence of Leydig cell tumors of the testis was seen. The metabolism of HCFC133a has been investigated in respect to the known toxicity of this compound. Male rats were exposed by inhalation to an atmosphere of 50,000 ppm HCFC133a for a period of 6 hr. Analysis of urine, collected during the exposure period and up to 48 hr following exposure, by 19F-NMR spectroscopy identified 2,2,2-trifluoroethanol (TFE; and its beta-glucuronide), trifluoroacetaldehyde (TFAA; as its hydrate and urea adduct), and trifluoroacetic acid (TFA) as fluorine-containing metabolites of HCFC133a. Of the total amount of metabolite eliminated in urine, 83% was excreted within 24 hr postdose, establishing a rapid elimination of metabolites by this route. TFAA, an established testicular toxicant, was the major metabolite accounting for 57% of the total fluorinated metabolites eliminated in urine, whereas TFA and TFE accounted for 29% and 14%, respectively. The presence of these metabolites in urine is consistent with an oxidative route of metabolism of this fluorocarbon.

Animals↗
PubMed1994

Differential cytotoxicities of N-methyl-beta-carbolinium analogues of MPP+ in PC12 cells: insights into potential neurotoxicants in Parkinson's disease.

N-Methylated beta-carbolinium cations that can form in vivo from environmental or endogenous beta-carbolines are putative neurotoxic factors in Parkinson's disease. The cytotoxicities of 11 N-methylated beta-carbolinium cations and N-methyl-4-phenylpyridinium cation (MPP+), the experimental parkinsonian neurotoxicant which the carbolinium cations structurally resemble, were examined using rat pheochromocytoma (PC12) cells cultured in "low energy" N-5 medium; cell death was estimated by released lactate dehydrogenase activity and viable cell protein. Of the eight N2-monomethylated beta-carbolinium cations utilized, only 2-methyl-harmalinium (harmaline-2-methiodide) was as cytotoxic as MPP+. Also, three N2(beta), N9(indole)-dimethylated beta-carbolinium cations displayed cytotoxic effects, with the simplest, 2,9-dimethylnorharmanium, approaching the effectiveness of MPP+ in PC12 cells cultured in N-5 medium. However, when PC12 cells grown in higher energy Dulbecco's modified Eagle's medium were utilized with selected effective cations, it was observed that the cultures were relatively resistant to MPP+ and 2,9-dimethylnorharmanium, but remained vulnerable to 2-methylharmalinium. The results are interpreted to mean that different cytotoxic mechanisms exist for the two most potent beta-carbolinium cations--namely, a mechanism for the 2,9-dimethyl-beta-carbolinium species that, as with MPP+, is conditional on mitochondrial ATP depletion, but a different (or additional) mechanism for 2-methylharmalinium that is independent of mitochondrial inhibition. The possible accumulation of these cytotoxic cations in Parkinson's disease is discussed in the context of these findings.

1-Methyl-4-phenylpyridinium↗
PubMed1994

Fluoride and potassium availability in a new dentifrice that treats hypersensitivity and controls tartar.

The availability and stability of the active ingredients in a Sensitive/Tartar Control dentifrice have been evaluated in this study. The Sensitive/Tartar Control dentifrice contains 5% potassium nitrate as the anti-hypersensitivity agent, 0.243% sodium fluoride as the anti-caries agent, 2% tetrasodium pyrophosphate and 1.5% polyvinylmethyl ether/maleic acid (PVM/MA) copolymer as the antitartar system. The availability of potassium and fluoride from this dentifrice was tested and found to be acceptable in both freshly prepared and aged samples. Fluoride and potassium availability were also tested at dilutions similar to in vivo brushing levels, and the ability of the Sensitive/Tartar Control dentifrice to provide fluoride to enamel and reduce enamel solubility was measured. In these tests the Sensitive/Tartar Control dentifrice performed similarly to commercial fluoride dentifrices. Potassium availability was equal to Crest Sensitivity Protection, a product shown to be clinically effective against tooth sensitivity; fluoride availability and activity was shown to be equal to Crest Tartar Control, a product with published clinical anti-caries effectiveness.

Analysis of Variance↗
PubMed1993

Potential bioactivated neurotoxicants, N-methylated beta-carbolinium ions, are present in human brain.

Potential bioactivated neurotoxicants, 2-N-methyl-beta-carbolinium and 2,9-N,N'-dimethyl-beta-carbolinium ions, as well as N-methylation activities which form these charged species, were analyzed for the first time in the parietal association cortex and the substantia nigra of human brain using GC/MS and HPLC. The brains were taken during forensic autopsies from corpses without obvious degeneration of substantia nigra. In the cortex, 2-methyl-norharmanium ion (2-MeNH) and 2,9-dimethyl-norharmanium ion (2,9-Me2NH) were detected in almost all samples. 2-Methyl-harmanium ions (2-MeHA) and 2,9-dimethyl-harmanium ions (2,9-Me2HA) were detectable in only two samples. In substantia nigra samples pooled from 3 or 4 brains for analysis, 2-MeNH and 2,9-Me2NH levels were higher than those in the cortex, whereas 2-MeHA and 2,9-Me2HA were below detection limits. Their precursors, norharman (NH) and harman (HA), were also measured using HPLC/fluorescence detection. In both regions, NH and HA were present in almost all samples; levels of NH and HA were also significantly higher in the nigra than in the cortex. Using 9-methyl-NH and 2-MeNH as substrates, in vitro N-methylation of the 2[beta] and 9[indole] nitrogens toward beta-carbolines was measured both in the cortex and in the nigra. 2[beta]-N-Methylation activity was significantly higher than 9[indole]-N-methylation activity in both regions. Recent studies show that beta-carbolinium ions resemble the synthetic parkinsonian toxicant, MPP+, with respect to structure and neurotoxic activity. Such 'bioactivated' carbolinium ions could be endogenous causative factors in Parkinson's disease.

Brain Chemistry↗
PubMed1993

Are adaptations to combined endurance and strength training affected by the sequence of training?

The purpose of this study was to determine whether the sequence of strength training before endurance training (ST/ET) is more or less effective than endurance training followed by strength training (ET/ST). Twenty-three females and 11 males were assigned to one of three groups: ST/ET (n = 15), ET/ST (n = 15) or control (n = 4). The 7-week training programme consisted of strength training using 10 exercises for two sets of 3-12 repetitions and running for 20-25 min at 60-90% of heart rate reserve. Maximal oxygen uptake (VO2 max) was measured during a graded treadmill test, and muscular strength was assessed using one-repetition maximum tests for the bench press (BP), shoulder press (SP), arm curl (AC) and leg press (LP). The VO2 max significantly (P < 0.05) increased 6.7 and 6.2% for the ST/ET and ET/ST groups, respectively. There was no significant (P > 0.05) difference between the two experimental groups. Muscular strength significantly (P < 0.05) improved by 15.2% (BP), 16.6% (SP), 17.2% (AC) and 11.9% (LP) for the ST/ET group and 19.9% (BP), 24.1% (SP), 20.9% (AC) and 14.0% (LP) for the ET/ST group. There were no significant (P > 0.05) differences between the two experimental groups for the BP, AC and LP; however, the ET/ST group increased (P < 0.05) SP strength more than the ST/ET group. In conclusion, adaptations to a combination of short-term endurance and strength training as assessed by VO2 max and BP, AC and LP strength appear to be independent of whether endurance training occurs prior to or following strength training.

Adaptation, Physiological↗
PubMed1993

Mast cell and myofibroblast in wound healing.

Growing evidence in the literature indicates that mast cells are integrally involved in the process of dermal wound repair. They are resident cells of the normal dermis and have several cytokines stored in their granules that are stimulatory to fibroblasts. They also contain serine proteases that may be involved in remodeling of the extracellular matrix during healing. Mast cells are found in increased numbers in acute wounds and in certain chronic fibrotic diseases. Their influence on fibroblast growth and collagen production may be an important element in fibrosis. The effects of mast cell mediators on dermal fibroblasts are currently being explored by our laboratory and others. Myofibroblasts are implicated in the phenomenon of wound contraction. These phenotypically altered fibroblasts express some features of smooth muscle cells, notably actin filaments, and are abundant in granulation tissue. It has been proposed that they are responsible for wound contraction and possibly certain types of contracture. However, this hypothesis has been challenged by studies demonstrating the presence of myofibroblasts in wounds that do not contract, or the process of contraction in vitro in the absence of myofibroblasts. At this time the issue remains open to debate and further research.

Fibroblasts↗