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R J Martin

Publications and source records attributed to R J Martin.

At least 19 recordsLinked to original sources
PubMed2006

Adenosine A2A receptors are expressed by GABAergic neurons of medulla oblongata in developing rat.

During early development, adenosine contributes to the occurrence of respiratory depression and recurrent apneas. Recent physiological studies indicate that GABAergic mechanisms may be involved in this inhibitory action of adenosine, via their A(2A) receptors. In the present study, in situ hybridization with ribonucleotide probes for A(2A) receptor (A(2A)R) mRNA was combined with the immunolabeling technique for parvalbumin and transneuronal retrograde tracing method using green fluorescent protein expressing pseudorabies virus (GFP-PRV) to (1) characterize age-dependent changes in the expression of adenosine A(2A)Rs mRNA in brain stem regions where GABAergic neurons are located; (2) determine whether GABA-containing neurons express A(2A)R mRNA traits, and (3) identify whether bulbospinal GABAergic neurons projecting to phrenic nuclei contain A(2A)R mRNA. Results revealed expression of A(2A) receptors in regions of medulla oblongata containing GABAergic neurons, namely in the ventral aspect of the medulla, within the Bötzinger region and caudal to it, the gigantocellular reticular nucleus, midline neurons and the caudal ventrolateral medulla oblongata. Furthermore, a subpopulation of identified GABAergic neurons, projecting to the phrenic motor nuclei, possess A(2A)R mRNA. It is concluded that adenosine A(2A)Rs expressed by GABAergic neurons are likely to play a role in mediating adenosine-induced respiratory depression.

Age Factors↗
PubMed2005

Drug resistance and neurotransmitter receptors of nematodes: recent studies on the mode of action of levamisole.

Here we review recent studies on the mode of action of the cholinergic anthelmintics (levamisole, pyrantel etc.). We also include material from studies on the free living nematode Caenorhabditis elegans. The initial notion that these drugs act on a single receptor population, while attractive, has proven to be an oversimplification. In both free living and parasitic nematodes there are multiple types of nicotinic acetylcholine receptor (nAChR) on the somatic musculature. Each type has different (sometimes subtly so) pharmacological properties. The implications of these findings are: (1) combinations of anthelmintic that preferentially activate a broad range of nAChR types would be predicted to be more effective; (2) in resistant isolates of parasite where a subtype has been lost, other cholinergic anthelmintics may remain effective. Not only are there multiple types of nAChR, but relatively recent research has shown these receptors can be modulated; it is possible to increase the response of a parasite to a fixed concentration of drug by altering the receptor properties (e.g. phosphorylation state). These findings offer a potential means of increasing efficacy of existing compounds as an alternative to the costly and time consuming development of new anthelmintic agents.

Adenosine Triphosphate↗
PubMed2005

Current treatment options for asthma in adults.

Asthma is a common disorder with an increasing prevalence in the developed world. It is a serious health problem affecting health care costs, lost productivity, and death. Unfortunately, uncontrolled asthma is common and often unrecognized by physicians; of equal concern, uncontrolled asthma is accepted by asthmatic patients as they are uneducated as to what to expect from asthma therapy. Many learn to live with the limitations of daily activity and to overuse their rescue inhalers and yet when asked by their physicians, ''How's your asthma?'' the answer is ''okay''. The pursuit of more revealing questions regarding frequency in the use of rescue medications, nocturnal symptoms, activity limitations, and compliance with controller medications may be then overlooked. To achieve the goal of normal life on as few medications as possible will start with a well-educated patient. Understanding intermittent from persistent asthma and then tailoring the best regimen for each patient is imperative. The treatment options and the advances in the understanding of the pathophysiology of asthma in the past 3 decades have been remarkable. There are increasing resources for both physicians and patients available to facilitate a better understanding of asthma management and the several treatment options. Currently established guidelines are an excellent starting point for initiating therapy for intermittent and mild, moderate, and severe persistent asthma. The short-acting beta 2 agonists are first-line therapy for intermittent asthma, exercise-induced asthma, and acute exacerbations. Long-acting Beta 2 agonists, cromolyn and nedocromil, and leukotriene modifiers may also be used for exercise. Systemic corticosteroids may be needed for acute exacerbations. The treatment of choice for persistent asthma is ICS and, depending on the severity, add-on therapy with long-acting beta 2 agonists, theophylline, and leukotriene modifiers are next. Lastly, omalizumab, anti-IgE therapy, will make an important place for its use in certain persistent moderate and severe asthma. This will be particularly true if the cost of the medication is reduced in the future. Asthma control, morbidity, and mortality will improve with a careful and comprehensive medical regimen using the current multiple treatment options.

Adult↗
PubMed2003

Hypercapnia-induced activation of brainstem GABAergic neurons during early development.

During early development, GABAergic mechanisms contribute to the regulation of respiratory timing in response to CO2. In 5-7 day old piglets, a double labeling technique was used to determine whether GABA-containing neurons are activated by normoxic hypercapnia (10% CO2, 21% O2, and 69% N2). The c-Fos gene encoded protein (c-Fos) was employed to localize CO2 activated cells within the piglet medulla oblongata. Parvalbumin was used as a marker for GABAergic neurons. In animals breathing room air, only scant c-Fos-like immunoreactive neurons were observed. A marked increase in c-Fos positive cells was induced after a 60 min exposure to hypercapnia. Colocalization studies revealed that hypercapnia significantly increased c-Fos expression in GABA-containing neurons in the medulla oblongata, especially in the ventral aspect of the medulla, within the Bötzinger region, the gigantocellular reticular nucleus, and the caudal raphe nuclei. Only a few double-labeled cells were observed within the nucleus tractus solitarius. Therefore, brainstem GABAergic neurons are part of the neural networks that respond to CO2 and may contribute to respiratory frequency responses to hypercapnia during early development.

Analysis of Variance↗
PubMed2003

Changes in adenosine transport associated with melaminophenyl arsenical (Mel CY) resistance in Trypanosoma evansi: down-regulation and affinity changes of the P2 transporter.

Studies of the kinetics of adenosine transport were carried out on the P1 and P2 transporters of drug-sensitive Trypanosoma evansi and its cloned derivative, resistant to the melaminophenyl arsenical Mel CY. Characterization of adenosine uptake was made by estimation of the maximum concentration taken up at time infinity (Amax). Amax on the P2 transporter of sensitive T. evansi was greater than Amax on the P1 transporter. Amax of the P2 transporter was significantly decreased in drug-resistant trypanosomes. The effect of adenosine concentration and inhibitors, on the rate of adenosine uptake, was described by Michaelis-Menten equations. In sensitive T. evansi, the maximum velocity of adenosine uptake (Vmax) of the P2 transporter was 2-fold greater than Vmax of the P1 transporter. The Vmax of the P2 transporter in resistant parasites was reduced 9-fold. The binding constants Km and Ki on the P2 transporter of resistant T. evansi, showed that resistance was associated with an increased affinity for adenosine, and a decreased affinity for adenine and Berenil. We suggest that resistance to melaminophenyl arsenicals in T. evansi, occurs via 2 mechanisms: (1) a reduction in the number of expressed P2 transporter molecules resulting in decreased uptake of melaminophenyl arsenicals; (2) a change in the binding properties of the P2 transporter.

Adenine↗
PubMed2003

"CADASIL coma": an underdiagnosed acute encephalopathy.

The main clinical features of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) are stroke, dementia, and migraine. A reversible acute encephalopathy was the principal presentation in six of 70 patients in a British prevalence study. The episodes lasted seven to 14 days, presenting with fever, acute confusion, coma, and fits; there was full recovery but in two cases identical episodes recurred some years later. All patients had a previous history of migraine with aura and were originally misdiagnosed as viral encephalitis. CADASIL should be considered in acute unexplained encephalopathies. MRI white matter changes, previous migraine with aura, and a family history of stroke and dementia may be useful pointers to the diagnosis.

Acute Disease↗
PubMed2003

Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic progressive airflow limitation which occurs as a result of chronic inflammation of the airways and lung parenchyma. However, the role of inhaled corticosteroids in the treatment of COPD is controversial. We hypothesised that inhaled corticosteroids reduce the progression of airflow limitation in COPD. METHODS: A comprehensive literature search was conducted and data were analysed using random effects methodology. The effect of inhaled steroids on annual change in forced expiratory volume in 1 second (FEV1) was determined for all trials, for trials with high dose treatment regimens, and for trials in subjects with moderate to severe airflow limitation. RESULTS: Data from eight controlled clinical trials of > or =2 years were included (n=3715 subjects). Meta-analysis of all study data revealed that inhaled corticosteroids reduce the rate of FEV1 decline by 7.7 ml/year (95% confidence interval (CI) 1.3 to 14.2, p=0.02). Meta-analysis of studies with high dose regimens revealed a greater effect of 9.9 ml/year (95% CI 2.3 to 17.5, p=0.01) compared with the meta-analysis of all studies. CONCLUSIONS: Inhaled corticosteroid treatment for > or =2 years slows the rate of lung function decline in COPD. The effect observed with high dose regimens is greater than that with all regimens combined. These data suggest a potential role for inhaled corticosteroids in modifying the long term natural history of COPD.

Administration, Inhalation↗
PubMed2002

Diagnostic strategies in CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migraine, recurrent stroke, and dementia. It results from mutations in the notch3 gene but mutations may occur at multiple sites making molecular diagnosis time consuming. It has been suggested that the presence of granular osmiophilic material (GOM) on skin biopsy and involvement of the anterior temporal lobe and external capsule on MRI may help in diagnosis. METHODS: The authors identified 83 potential index cases from the British population and screened exons 2 to 23 of notch3. MRI scans were scored using a modified Scheltens scale. Skin biopsy was performed in a subgroup. RESULTS: Fifteen different point mutations were identified in 48 families, 73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5 and 6. Moderate or severe involvement of the anterior temporal pole on MRI had a sensitivity of 89% and specificity of 86% for diagnosis of CADASIL, whereas external capsule involvement had a high sensitivity of 93% but a low specificity of 45%. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%. CONCLUSIONS: The spectrum of mutations in this study can be used to plan appropriate screening protocols; a suggested protocol is to screen exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin biopsy is diagnostic but can be negative. Anterior temporal pole involvement on MRI is a useful diagnostic marker.

Adult↗
PubMed2002

The time-course of the response to the FMRFamide-related peptide PF4 in Ascaris suum muscle cells indicates direct gating of a chloride ion-channel.

We investigated the effects of PF4 on Ascaris suum somatic muscle cells using a 2 electrode current-clamp technique. PF4 is a FaRP (FMRFamide-related peptide), originally isolated from the free-living nematode Panagrellus redivivus. PF4 caused hyperpolarization and an increase in chloride ion conductance when it was applied to the muscle cells of the Ascaris body wall. The delay between the application of the peptide and the appearance of the response was measured and compared with that of gamma-amino butyric acid (GABA), a compound that directly gates ion channels, and with PF1, a FaRP that acts via an intracellular signal transduction mechanism. The PF4 and GABA delay times were not significantly different; they were 1.51+/-0.11 sec and 1.22+/-0.10 sec respectively. The delay following application of PF1, 3.75+/-0.51 sec, was significantly longer. The rapid response to PF4 is consistent with direct gating of a chloride ion channel, which has not been described elsewhere in the literature.

Animals↗
PubMed2002

Effects of macrocyclic lactone anthelmintics on feeding and pharyngeal pumping in Trichostrongylus colubriformis in vitro.

The effects of macrocyclic lactone anthelmintics (MLs) on feeding by Trichostrongylus colubriformis nematodes in vitro were examined using inulin uptake as a measure of ingestion and electropharyngeograms as a record of the electrical events associated with pharyngeal pumping. Inulin uptake was inhibited by the 4 MLs tested (EC50s 0.045-4.57 nM), with an order of potency of eprinomectin (most potent), ivermectin, ivermectin monosaccharide, and ivermectin aglycone. The MLs caused both the frequency and amplitude of pharyngeal electrical events to decrease. In individual worms the inhibition of pump frequency preceded the inhibition of pump amplitude. The order of potency of the MLs as inhibitors of frequency was ivermectin aglycone, ivermectin, ivermectin monosaccharide and eprinomectin. The difference compared with the inulin assay results are probably due to the dynamics of drug uptake in the two systems. It was possible that the nematodes in the electrophysiology experiments were effectively orally ligated by enclosure of the worm's head in the recording pipette which contained no drug. Despite this difference in relative potencies, both the ingestion assays and the electrical events indicate that MLs are potent inhibitors of the pharynx in T. colubriformis in vitro. The sequence of effects on pharyngeal electrical activity suggests that ML action involves an initial inhibitory effect on the rate of pharyngeal contractions, followed by a decrease in the amplitude of the potentials associated with pharyngeal pumping events.

Animals↗
PubMed2002

Safety of sputum induction in moderate-to-severe chronic obstructive pulmonary disease.

This retrospective study was designed to evaluate the safety and efficacy of a bronchoprotective sputum induction protocol in moderate to severe chronic obstructive pulmonary disease (COPD). Forty-two adults with COPD (FEV1 = 51.7 +/- 3.2% predicted (mean +/- SEM)) under went sputum induction using a protocol designed to minimize hypertonic saline-induced bronchoconstriction. Hypertonic (3%) saline was used for subjects with FEV1 > or = 50%, and normal (0.9%) saline was used for subjects with FEV1 < 50%. Primary outcomes were change in peak flow, FEV1 and oxygen saturation. Mean decline in peak flow during sputum induction was 13.2 +/- 2.1%. FEV1 fell by 11.4 +/- 2.3%, an absolute fall of 0.14 +/- 0.031. Oxygen saturation did not change. A fall in peak flow of > or = 20% reliably predicted a fall in FEV1 of > or = 20%. Thirty-five of 42 subjects (83.3%) produced an acceptable sputum sample. Sputum eosinophil and neutrophil percentages were 2.8 +/- 0.9 and 73.0 +/- 3.0%, respectively, and were not correlated with changes in peak flow, FEV1 or oxygen saturation. A protocol for sputum induction which restricts the use of hypertonic saline based on lung function is both safe and effective in subjects with moderate to severe COPD.

Adult↗
PubMed2001

Changes in properties of adenosine transporters in Trypanosoma evansi and modes of selection of resistance to the melaminophenyl arsenical drug, Mel Cy.

Resistance to arsenical drugs in trypanosomes has been linked to changes in adenosine uptake. The transport of melaminophenyl arsenicals into Trypanosoma brucei was shown to be mediated by an unusual adenosine nucleoside transporter, P2 (Carter and Fairlamb, 1993), and the loss of this transporter is associated with resistance to melaminophenyl arsenicals in these parasites. To further understand the mechanisms of arsenical resistance, we generated several lines of Mel Cy-resistant T. evansi from a drug-sensitive isolate using both in vivo and in vitro selection methods. Uptake of the melaminophenyl arsenical, Mel Cy on the P2 transporter was studied in the drug-sensitive as well as Mel Cy-resistant parasites, by means of inhibition of Mel Cy-induced lysis of trypanosomes, in an in vitro lysis assay. Adenosine uptake was also investigated using competition inhibition assays. Our study shows that T. evansi, TREU 1840, possesses the P1/P2 adenosine transport system as reported in T. brucei and T. equiperdum. However, in T. evansi, the P2 transporter is the larger transport process instead of the P1. The P2 transporter in T. evansi mediated the uptake of Mel Cy in the drug-sensitive parasites. The P2 was retained in all the arsenical-resistant T. evansi lines studied. However, the activity of the transporter was reduced to different extents in the different-resistant lines. The residual P2 activity related well to the levels of drug resistance in each line, suggesting that P2 activity could be an important marker for arsenical resistance. Furthermore, important differences were observed between the in vivo- and the in vitro-selected arsenical-resistant parasites suggesting that there may be differences in resistance phenotypes selected on the field.

Adenine↗
PubMed2001

TNFalpha induces and insulin inhibits caspase 3-dependent adipocyte apoptosis.

Regulation of fat cell number by apoptosis is proposed to be part of a normal physiological cycle in adipose growth and development. To investigate this process, cultured rat adipocytes were treated with various concentrations of tumor necrosis factor alpha (TNFalpha) and/or insulin to determine the roles of these factors in adipocyte apoptosis. The cells were analyzed by flow cytometry using a TUNEL assay. TNFalpha increased adipocyte apoptosis in a dose-dependent fashion. TNFalpha-mediated apoptosis was detectable within 6 h of treatment and continued to increase with time. Decreasing media insulin concentration from 8.5 to 0.85 nM resulted in increased adipocyte apoptosis, whereas high doses of insulin protected adipocytes from TNFalpha-induced apoptosis. TNFalpha-activated apoptosis was accompanied by an increase in caspase 3 activity and could be inhibited by a caspase 3-specific inhibitor. These data suggest that adipose tissue cell number is regulated, in part, by an apoptotic signaling pathway that involves TNFalpha, insulin, and caspase 3.

Adipocytes↗
PubMed2001

Cardiorespiratory events recorded on home monitors: Comparison of healthy infants with those at increased risk for SIDS.

CONTEXT: Home monitors designed to identify cardiorespiratory events are frequently used in infants at increased risk for sudden infant death syndrome (SIDS), but the efficacy of such devices for this use is unproven. OBJECTIVE: To test the hypothesis that preterm infants, siblings of infants who died of SIDS, and infants who have experienced an idiopathic, apparent life-threatening event have a greater risk of cardiorespiratory events than healthy term infants. DESIGN: Longitudinal cohort study conducted from May 1994 through February 1998. SETTING: Five metropolitan medical centers in the United States. PARTICIPANTS: A total of 1079 infants (classified as healthy term infants and 6 groups of those at risk for SIDS) who, during the first 6 months after birth, were observed with home cardiorespiratory monitors using respiratory inductance plethysmography to detect apnea and obstructed breathing. MAIN OUTCOME MEASURES: Occurrence of cardiorespiratory events that exceeded predefined conventional and extreme thresholds as recorded by the monitors. RESULTS: During 718 358 hours of home monitoring, 6993 events exceeding conventional alarm thresholds occurred in 445 infants (41%). Of these, 653 were extreme events in 116 infants (10%), and of those events with apnea, 70% included at least 3 obstructed breaths. The frequency of at least 1 extreme event was similar in term infants in all groups, but preterm infants were at increased risk of extreme events until 43 weeks' postconceptional age. CONCLUSIONS: In this study, conventional events are quite common, even in healthy term infants. Extreme events were common only in preterm infants, and their timing suggests that they are not likely to be immediate precursors to SIDS. The high frequency of obstructed breathing in study participants would likely preclude detection of many events by conventional techniques. These data should be important for designing future monitors and determining if an infant is likely to be at risk for a cardiorespiratory event.

Airway Obstruction↗
PubMed2001

MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited, autosomal dominant condition caused by mutations of the Notch3 gene. Affected individuals have migraine, mood disturbance, and recurrent strokes, often progressing to subcortical dementia and premature death. MRI findings include focal lacunar infarcts and diffuse T2-weighted hyperintensity, or leukoaraiosis. However, such findings are seen much more commonly in patients with cardiovascular risk factors, particularly hypertension, where they are believed to represent cerebral small vessel disease. No previous study has sought to identify specific radiologic markers of CADASIL. METHODS: MRI scans from 20 consecutive patients with CADASIL and 20 patients with sporadic leukoaraiosis due to presumed small-vessel disease were compared using the previously validated semiquantitative MRI rating scale devised by Scheltens et al. Analysis was blinded to clinical category. RESULTS: Scores for hyperintensities of the temporal white matter and external capsule-insula region were significantly higher in patients with CADASIL. Hyperintensity confined to the pole of the temporal lobe was a characteristic finding in CADASIL, occurring in 19 patients with CADASIL but no patients with ischemic leukoaraiosis. Involvement of the external capsule, though less specific, was seen early in the disease course. In a few patients with CADASIL, involvement of the corpus callosum was observed. CONCLUSIONS: Temporal pole hyperintensity is a radiologic marker of CADASIL. Involvement of the external capsule and corpus callosum are also characteristic findings that may help to distinguish the disease.

Adult↗