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Biomedical subjects

M P Thomas

Publications and source records attributed to M P Thomas.

At least 19 recordsLinked to original sources
PubMed2005

Mononuclear phagocytes in the pathogenesis of neurodegenerative diseases.

Brain mononuclear phagocytes (MP, bone marrow monocyte-derived macrophages, perivascular macrophages, and microglia) function to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. MP are activated by a variety of environmental cues and such inflammatory responses elicit cell injury and death in the nervous system. MP immunoregulatory responses include secretion of neurotoxic factors, mobilization of adaptive immunity, and cell chemotaxis. This incites tissue remodelling and blood-brain barrier dysfunction. As disease progresses, MP secretions engage neighboring cells in a vicious cycle of autocrine and paracrine amplification of inflammation leading to tissue injury and ultimately destruction. Such pathogenic processes tilt the balance between the relative production of neurotrophic and neurotoxic factors and to disease progression. The ultimate effects that brain MP play in disease revolves "principally" around their roles in neurodegeneration. Importantly, common functions of brain MP in neuroimmunity link highly divergent diseases (for example, human immunodeficiency virus type-one associated dementia, Alzheimer's disease and Parkinson's disease). Research into this process from our own laboratories and those of others seek to harness MP inflammatory processes with the intent of developing therapeutic interventions that block neurodegenerative processes and improve the quality of life in affected people.

AIDS Dementia Complex↗
PubMed2001

Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions.

Connexin 43 (Cx43alpha1) gap junction has been shown to have an essential role in mediating functional coupling of neural crest cells and in modulating neural crest cell migration. Here, we showed that N-cadherin and wnt1 are required for efficient dye coupling but not for the expression of Cx43alpha1 gap junctions in neural crest cells. Cell motility was found to be altered in the N-cadherin-deficient neural crest cells, but the alterations were different from that elicited by Cx43alpha1 deficiency. In contrast, wnt1-deficient neural crest cells showed no discernible change in cell motility. These observations suggest that dye coupling may not be a good measure of gap junction communication relevant to motility. Alternatively, Cx43alpha1 may serve a novel function in motility. We observed that p120 catenin (p120ctn), an Armadillo protein known to modulate cell motility, is colocalized not only with N-cadherin but also with Cx43alpha1. Moreover, the subcellular distribution of p120ctn was altered with N-cadherin or Cx43alpha1 deficiency. Based on these findings, we propose a model in which Cx43alpha1 and N-cadherin may modulate neural crest cell motility by engaging in a dynamic cross-talk with the cell's locomotory apparatus through p120ctn signaling.

Animals↗
PubMed2001

Management of acute cardiac failure with mechanical assist: experience with the ABIOMED BVS 5000.

BACKGROUND: Mechanical circulatory assist industries have developed ventricular assist devices (VAD) for short-, intermediate-, and long-term use. The purpose of this report is to describe the progress made with the ABIOMED Biventricular System (BVS) 5000 (ABIOMED, Inc, Danvers, MA) short-term VAD. METHODS: From June 1994 through August 2000, all cardiogenic shock patients who required short-term mechanical assist were supported with the ABIOMED BVS 5000. Insertion criteria included any condition that may potentially result in cardiac recovery. A formal algorithm for timing of insertion was established to standardize implantation criteria. RESULTS: A total of 45 patients were supported at Hahnemann University Hospital, Philadelphia, PA. There were 26 male and 19 female patients, with a mean age of 57.9 years (range 33 to 80 years). Devices were inserted for postcardiotomy shock in 36 patients (80%) and precardiotomy shock in 9 patients (20%). The average duration of support was 8.3 days (range 1 to 31 days). Overall, there were 22 (49%) patients weaned from support and 14 (31%) discharged from the hospital. For patients in whom the device was implanted in accordance with an established protocol (group A), the wean and discharge rates were 60% and 43%, respectively. The most common morbidities included bleeding and adverse neurologic events. CONCLUSIONS: The ABIOMED BVS 5000 VAD continues to be a valuable form of short-term mechanical assist for acute cardiogenic shock. The formation of a uniform VAD insertion algorithm has helped to standardize protocols in management.

Acute Disease↗
PubMed2001

Compliance issues related to the selection of antibiotic suspensions for children.

OBJECTIVE: To evaluate the palatability, cost and other compliance issues as variables in the selection of antibiotic suspensions for children. METHODS: Eighty-six physicians and health care personnel randomly sampled amoxicillin (used as a standard for comparison) and 11 other antibiotics, evaluating them in categories of appearance, smell, texture, taste and aftertaste. Overall scoring was then adjusted for cost, duration of therapy and dosing intervals. RESULTS: Overall taste (palatability) ranking of antibiotics, highest to lowest, was as follows: loracarbef, cefdinir, cefixime, azithromycin, ciprofloxacin, trimethoprim-sulfamethoxazole, clarithromycin, trimethoprim, amoxicillin/clavulanate, cefpodoxime and cefuroxime. Overall rating of antibiotics was greatly influenced by other compliance variables, in order of their impact: cost; duration of therapy (5 vs. 10 days); and dosing intervals. Cost was not judged to be a major factor by most participants unless antibiotic expense was >$50.00 for treatment of otitis media in our hypothetical 2-year-old, 13-kg child. Taking all variables into consideration, final ranking from highest to lowest was azithromycin, cefdinir, loracarbef, cefixime, amoxicillin, trimethoprim-sulfamethoxazole, cefpodoxime, trimethoprim, clarithromycin, ciprofloxacin, cefuroxime and amoxicillin/clavulanate. CONCLUSIONS: Variables related to compliance for families filling antibiotic prescriptions and children taking these products are important in the selection of antimicrobial therapy. Because final assessment is likely to vary considerably among health care personnel, decisions must be made on an individual basis.

Amoxicillin↗
PubMed2001

N-cadherin and Cx43alpha1 gap junctions modulates mouse neural crest cell motility via distinct pathways.

Our previous studies showed an essential role for connexin 43 or alpha1 connexin (Cx43alpha1) gap junctions in the modulation of neural crest cell motility. Cx43alpha1 gap junctions and N-cadherin containing adherens junctions are expressed in migrating cardiac neural crest cells. Analysis of the N-cadherin knockout (KO) mouse model revealed that N-cadherin is essential for gap junction mediated dye coupling but not for expression of Cx43alpha1 gap junctions in neural crest cells. Time lapse videomicroscopy and motion analysis showed that the motility of N-cadherin KO neural crest cells were altered, but the motility changes differed compared to Cx43alpha1 KO neural crest cells. These observations suggest that the role of N-cadherin in cell motility is not simply mediated via the modulation of Cx43alpha1 mediated cell-cell communication. This was confirmed by a parallel analysis of wnt-1 deficient neural crest cells, which also showed a reduction in dye coupling, and yet no change in cell motility. Analysis of p120 catenin (p120ctn), an Amardillo family protein known to play a role in cell motility, showed that it is colocalized with N-cadherin and Cx43alpha1 in migrating neural crest cells. This subcellular distribution was altered in the N-cadherin and Cx43alpha1 KO neural crest cells. Given these results, we propose that N-cadherin and Cx43alpha1 may modulate neural crest cell motility by engaging in a dynamic cross-talk with the cell's locomotory apparatus through p120ctn signaling.

Animals↗
PubMed2000

Dynamics of NMDAR-mediated neurotoxicity during chronic ethanol exposure and withdrawal.

We have utilized a hippocampal brain slice explant system to assess cellular and synaptic mechanisms underlying the expression of alcohol withdrawal hyperexcitability. Previously, we observed a role for NMDA receptors in the expression of electrographic seizures (EGS) observed immediately upon withdrawal from chronic ethanol exposure in this system. One possible cellular mechanism responsible for these prior results involves NMDAR-mediated neurotoxicity, which was assessed in the present study. Explants were exposed to 35 or 75 mM ethanol for 6 or 12 days and incubated with propidium iodide (PI) to label non-viable cells and then imaged digitally. PI labeling was significantly reduced (36% of control levels) following chronic ethanol exposure (75 mM). When tested following ethanol withdrawal, PI labeling remained significantly reduced in the 75 mM exposed group. We next assessed the effect of an NMDA challenge 24 h following withdrawal. The 35 mM and 75 mM ethanol exposed groups displayed significant 6-fold and 13-fold NMDAR-mediated increases in PI labeling respectively; control explants displayed a 3-fold increase. These data suggest that chronic ethanol exposure prior to withdrawal has a minor neuroprotective effect that slightly diminishes within 24 h of ethanol withdrawal. Furthermore, the data indicate that direct NMDAR activation is required for induction of ethanol withdrawal neurotoxicity.

Alcoholism↗
PubMed1999

Structural analysis of a mutational hot-spot in the EcoRV restriction endonuclease: a catalytic role for a main chain carbonyl group.

Following random mutagenesis of the Eco RV endonuclease, a high proportion of the null mutants carry substitutions at Gln69. Such mutants display reduced rates for the DNA cleavage step in the reaction pathway, yet the crystal structures of wild-type Eco RV fail to explain why Gln69 is crucial for activity. In this study, crystal structures were determined for two mutants of Eco RV, with Leu or Glu at residue 69, bound to specific DNA. The structures of the mutants are similar to the native protein and no function can be ascribed to the side chain of the amino acid at this locus. Instead, the structures of the mutant proteins suggest that the catalytic defect is due to the positioning of the main chain carbonyl group. In the enzyme-substrate complex for Eco RV, the main chain carbonyl of Gln69 makes no interactions with catalytic functions but, in the enzyme-product complex, it coordinates a metal ion bound to the newly liberated 5'-phosphate. This re-positioning may be hindered in the mutant proteins. Molecular dynamics calculations indicate that the metal on the phosphoryl oxygen interacts with the carbonyl group upon forming the pentavalent intermediate during phosphodiester hydrolysis. A main chain carbonyl may thus play a role in catalysis by Eco RV.

Binding Sites↗
PubMed1999

Coronary artery disease in identical twins.

The incidence of coronary artery disease in identical twins is unknown. The knowledge of ischemic heart disease in this patient population is represented by case reports. There is considerable controversy regarding the environmental and genetic factors that play a role in the pathogenesis of this disorder. The natural history of coronary artery disease in an asymptomatic twin with a symptomatic counterpart is unclear. We present a case report and literature review of coronary artery disease in identical twins. On the basis of our patient and the information of other patients, asymptomatic twins of symptomatic counterparts require aggressive assessment and management for occult coronary artery disease.

Aged↗
PubMed1999

Coronary artery bypass surgery in nonagenarians.

As the number of nonagenarians increases yearly in the United States, surgeons will be asked more often to evaluate the possibility of intervention for coronary artery disease in this age group. The purpose of this study is to document experience with patients 90 years of age or older in order to determine whether coronary artery bypass grafting surgery is justified. Eleven patients aged 90 years or more underwent cardiac surgery for symptomatic coronary artery disease refractory to medical management between January 1, 1987, and December 31, 1996. All patients were in NYHA Class IV preoperatively. In-hospital death occurred in two patients (18%). In-hospital morbidity occurred in all patients (100%) including seven cardiac, four respiratory, two neurologic, and one infectious. All survivors left the hospital symptomatically improved. The mean length of stay was 28 days. Four patients died at a mean of 2 years and 2 months postoperatively. Five patients remain alive at a mean of 1 year and 7 months. Coronary artery bypass grafting in nonagenarians can be performed successfully in selected cases. However, increased mortality and morbidity rates and length of stay are associated with this age group. For survivors, the quality of life is improved and the projected life expectancy restored.

Aged↗
PubMed1998

Survival and functional demonstration of interregional pathways in fore/midbrain slice explant cultures.

An important general question in neurobiology concerns the development and expression of the rich context of neuronal phenotypes, especially in relation to the diverse patterns of connectivity. Organotypic cultures of brain slices may offer distinct advantages for such studies if such a preparation survives, maintains a wide diversity of neuronal phenotypes and displays appropriate synaptic connections between regions. To address these requirements, we utilized long-term organotypic cultures of intact horizontal slices of rat forebrain and midbrain and assessed a variety of markers of phenotype in combination with functional tests of connectivity. This explant preparation displayed a distinct viability requirement such that the greatest explant survival was seen in slices taken from pups of less than postnatal day 7 and was independent of N-methyl-D-aspartate channel blockade. The anatomical features of the major brain regions (e.g., neocortex, striatum, septum, hippocampus, diencephalon and midbrain) were observed in their normal boundaries. The presence of cholinergic and catecholaminergic neurons was demonstrated with acetylcholinesterase histochemistry and tyrosine hydroxylase immunohistochemistry. Labelled neurons displayed multiple, regionally-appropriate cytoarchitectures and, in some cases, could be seen to project to brain regions in a manner quite similar to that seen in vivo. Finally, the direct demonstration of spontaneous and evoked interregional excitatory synaptic transmission was made using whole-cell patch-clamp recordings from striatal neurons which revealed an intact glutamate-using corticostriatal pathway. This simple explant preparation appears to contain a rich diversity of neuronal types and synaptic organization. Therefore, this preparation appears to have several distinct advantages for basic neurobiologic research since it combines long-term culture viability and many features of mature brain including complex interregional neuronal systems.

Acetylcholinesterase↗
PubMed1998

Amiodarone-associated hemoptysis.

Amiodarone is a benzofuran derivative with a chemical structure similar to thyroxine. Originally introduced to treat angina pectoris, amiodarone was found to have antiarrhythmic properties, and in 1985, was approved in the United States for treatment of life-threatening ventricular arrhythmias. It is now used for various ventricular and supraventricular arrhythmias refractory to conventional first-line medications, and as a result, side effects have been observed with increased frequency. The most severe and potentially life-threatening of these side effects is the development of pulmonary toxicity. Typically, amiodarone pulmonary toxicity (APT) is manifested by acute pneumonitis and chronic fibrosis. Amiodarone-associated hemoptysis (AAH) is a rare occurrence. The authors describe a case of AAH successfully treated with cessation of drug and steroid therapy.

Amiodarone↗
PubMed1998

Organotypic brain slice cultures for functional analysis of alcohol-related disorders: novel versus conventional preparations.

Assessment of long-term alterations in neural function and phenotype has usually involved culture techniques that utilize dissociated preparations. Recently, we have approached such topics in alcohol research by using brain slice cultures, also known as explant or organotypic preparations. In this symposium presentation, two preparations will be discussed, and examples of the particular advantages of these preparations will be presented in relation to alcohol research. First, we use the hippocampal explant preparation for assessment of long-term alterations in N-methyl-D-aspartate receptor (NMDAR) function due to chronic ethanol exposure and subsequent withdrawal. This preparation displays many synaptic, structural, and enzymatic phenotypes indicative of normal neural preparations. Patch clamp recordings reveal NMDAR-mediated excitatory postsynaptic current (EPSC) elicited upon stimulation of Schaffer collateral fibers and recorded from CA1 pyramidal cells. Long-term ethanol exposure followed by subsequent withdrawal resulted in a specific enhancement of NMDAR-mediated synaptic responses which preceded the expression of epileptiform events that occurred after prolonged withdrawal periods. Second, we describe a novel explant preparation, derived from horizontal slices of the entire forebrain and midbrain of the rat. These long-term explants displayed multiple normal phenotypes including Nissl, AChE, TH, and GFAP staining. Electrophysiologically, these explants displayed a functional corticostriatal pathway recorded with field and patch clamp techniques and elicited by synaptic stimulation. Taken together, these explant preparations display utility for long-term study of ethanol effects on neural systems, especially relating to withdrawal hyperexcitability as well as systems involved in drug-seeking behavior.

Alcoholism↗
PubMed1998

Evidence for a causative role of N-methyl-D-aspartate receptors in an in vitro model of alcohol withdrawal hyperexcitability.

Synaptic mechanisms underlying hyperexcitability due to withdrawal from chronic ethanol exposure were investigated in a hippocampal explant model system using electrophysiological techniques. Whole-cell voltage clamp recordings from CA1 pyramidal cells demonstrated that acute ethanol exposure inhibited N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents by over 40%. Chronic ethanol exposure for 6 to 11 days at 35 or 75 mM induced no differences from control explants in the fast component of the population synaptic response (non-NMDAR-mediated). Prolonged field potential recordings (to 10 hr) were used to monitor the withdrawal process in vitro. Ethanol-exposed explants from both 35 and 75 mM groups displayed an increase (60% and 89%, respectively) in the NMDAR-mediated component of synaptic transmission on withdrawal from chronic exposure. Prolonged tonic-clonic electrographic seizure activity was consistently observed after ethanol withdrawal only after the increase in NMDAR function. This hyperexcitability was inhibited by the NMDAR antagonist D-2-amino-5-phosphonovaleric acid and returned once the NMDAR component was reestablished after antagonist washout. In situ hybridization studies suggest that expression of NR2B subunit mRNA may be enhanced in explants after chronic ethanol exposure. No lasting differences were observed in the NMDAR component after acute in vitro ethanol exposure and withdrawal. These data suggest that the occurance of ethanol withdrawal hyperexcitability in this system may be directly dependent on alterations in NMDAR function after chronic exposure. Since this region and others that contain ethanol sensitive NMDARs may serve as epileptic foci, long term alterations in NMDAR function may be expected to generate paroxysmal depolarizing shifts underlying ictal events after withdrawal from ethanol exposure.

Animals↗