Search PubMed⌕ Search

Biomedical subjects

G R Martin

Publications and source records attributed to G R Martin.

At least 55 records · Page 3Linked to original sources
PubMed1998

Cranial vascular effects of zolmitriptan, a centrally active 5-HT1B/1D receptor partial agonist for the acute treatment of migraine.

The anti-migraine drug zolmitriptan is a novel 5-HT1B/1D receptor partial agonist which, unlike sumatriptan, has been shown to cross the intact blood-brain barrier. In this study we examined whether or not the ability to access the cerebro-vascular intima affects the way in which a centrally-active 5-HT1B/1D receptor agonist influences cranial haemodynamics. The effects of zolmitriptan on carotid arterial blood flow distribution were studied in anaesthetised cats using radiolabelled microspheres. Zolmitriptan (10-1000 microg kg(-1) i.v.) selectively reduced arteriovenous-anastomotic (AVA) conductance producing a maximum decrease of 92.5+/-2.3%. The drug also produced a modest reduction in extra-cerebral conductance (23.9+/-6.5% maximum reduction at 30 microg kg(-1), i.v.), but was without effect on cerebral conductance. Using laser doppler flowmetry in anaesthetised cats, zolmitriptan (1-30 microg kg(-1), i.v.) produced dose-dependent decreases in ear microvascular conductance (15+/-5 to 60+/-6%) which mirrored decreases in carotid arterial conductance (12+/-11 to 61+/-5%). By contrast, zolmitriptan at doses up to 1000 microg kg(-1) was without effect on cerebral microvascular conductance. Although zolmitriptan crosses the blood-brain barrier and can therefore access the cerebro-vascular intima, this study suggests that this property does not adversely affect cerebrovascular function.

Animals↗
PubMed1998

Muscle-specific cell ablation conditional upon Cre-mediated DNA recombination in transgenic mice leads to massive spinal and cranial motoneuron loss.

We describe here a binary transgenic system based on Cre-mediated DNA recombination for genetic cell ablation in mice that enabled us to obtain skeletal muscle-deficient embryos by mating two phenotypically normal transgenic lines. In those embryos, skeletal muscles are eliminated as a consequence of the expression of the gene encoding the diphtheria toxin A fragment. Cell ablation occurs gradually beginning approximately on embryonic day (E) 12.5, and by E18-5 almost all skeletal muscle is absent. Analysis of the consequences of muscle cell ablation revealed that almost all spinal motoneurons are lost by E18.5, providing strong evidence that survival of spinal motoneurons during embryogenesis is dependent on signals from their target tissue, skeletal muscle, and that trophic signals produced by nonmuscle sources are sufficient to support survival of no more than 10% of embryonic spinal motoneurons in the absence of muscle-derived signals. There was also substantial loss of cranial (hypoglossal and facial) motoneurons in the muscle-deficient embryos, thus indicating that cranial motoneuron survival is also dependent on trophic signals produced by their target tissue. Although spinal motoneurons are a major target of spinal interneurons, the loss of motoneurons did not affect interneuron survival. Muscle-deficient embryos had a cleft palate and abnormalities of the lower jaw, raising the possibility that they might serve as a mouse model for the human disorder, Robin sequence. The data reported here demonstrate the utility of a binary transgenic system for obtaining mouse embryos in which a specific cell population has been ablated, so that its role in embryonic development can be studied.

Animals↗
PubMed1998

Mechanisms underlying intestinal adaptation after massive intestinal resection in the rat.

BACKGROUND/PURPOSE: The regulatory events that control the adaptive response after massive intestinal resection are poorly understood. An improved understanding could lead to improved clinical therapies. This study tests the hypothesis that massive intestinal resection increases nutrient transport by upregulation of mRNA for the sodium glucose cotransporter (SGLT1). METHOD: Male Lewis rats (225 to 250 g) were studied. Control animals (Con, n = 6) underwent ileal transection 15 cm proximal to the cecum; resected animals (Res, n = 8) underwent resection of all bowel proximal to the terminal 15 cm of ileum. Animals were followed up for 14 days, pair fed, and weighed daily. At the time of death the terminal ileum was studied quantifying SGLT1 mRNA using reverse transcriptase-polymerase chain reaction (RT-PCR) normalized to B-actin, in vitro glucose transport in Ussing Chambers, and histology. RESULTS: All animals survived; animals that were transected regained preoperative weight by day 10, and underwent resection by day 14. Significant adaptation occurred with increases in villus height, (control jejunum 934 +/- 79; control ileum, 811 +/- 64 v resected ileum, 949 +/- 83 [P < .05]). Nutrient flux (J mucosal --> serosa; Jms) was increased in resected ileum (3-0 Methyl-D-Glucose flux: 0.71 +/- 0.2 v 0.56 +/- 0.04 in Con ileum [P < .05; units, micromol/cm2/hr of 3-0 Methyl-D-Glucose]). This was paralleled by an increase in expression of the SGLT1 gene in resected ileum, 104 +/- 14, versus Con ileum, 74 +/- 9 (P < .05; values normalized versus expression of B-actin). CONCLUSION: SGLT1 expression may be useful as a marker of the adaptive process after massive resection and potentially may be used as an endpoint of therapy after resection clinically.

Adaptation, Physiological↗
PubMed1998

An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination.

We describe a strategy for generating an allelic series of mutations at a given locus that requires the production of only one targetted mouse line. The 'allelogenic' mouse line we produced carries a hypomorphic allele of Fgf8, which can be converted to a null allele by mating to cre transgenic animals. The hypomorphic allele can also be reverted to wild-type by mating the allelogenic mice to flp transgenic animals, thereby generating a mouse line suitable for Cre-induced tissue-specific knockout experiments. Analysis of embryos carrying different combinations of these alleles revealed requirements for Fgf8 gene function during gastrulation, as well as cardiac, craniofacial, forebrain, midbrain and cerebellar development.

Actins↗
PubMed1998

Decreased mivacurium requirements and delayed neuromuscular recovery during sevoflurane anesthesia in children and adults.

UNLABELLED: The purpose of this study was to compare the mivacurium infusion requirements and neuromuscular recovery in adults and children during propofol/opioid and sevoflurane anesthesia. Seventy-five adult and 75 pediatric patients were randomized to receive propofol/opioid 0.5 or 1.0 minimum alveolar anesthetic concentration (MAC) (age-related) sevoflurane anesthesia. Plasma cholinesterase (PChE) activity was measured. Neuromuscular blockade was monitored by train-of-four (TOF) stimulation every 10 s and adductor pollicis electromyography. A bolus of 2 x the 95% effective dose of mivacurium (0.25 mg/kg) was followed by an infusion titrated to maintain 90%-95% blockade. Mivacurium doses were recorded every 5 min. At the end of surgery, the infusion was stopped, and recovery from mivacurium was monitored until TOF > or =0.7. PChE concentrations were within the normal range (adults 4-12 KU/L, children 6-16 KU/L) and correlated with mivacurium dose. Mivacurium infusion rates were higher in children than in adults: at 30 min, the rates in children were 13.1 +/- 6.4, 8.1 +/- 4.7, and 5.2 +/- 2.9 microg x kg(-1) x min(-1) at 0, 0.5, and 1.0 MAC sevoflurane, respectively; the corresponding rates in adults were 5.9 +/- 3.1, 4.3 +/- 1.7, and 2.9 +/- 0.7 microg x kg(-1) x min(-1) (P < 0.01). Sevoflurane decreased mivacurium requirements, maximal decreases at 45 min in children and 10 min in adults, and delayed neuromuscular function recovery. Children recovered twice as quickly as adults, achieving TOF > or =0.7 at 9.8 +/- 2.5, 11.4 +/- 2.8, and 19.6 +/- 6.3 min compared with 19.9 +/- 5.4, 26.4 +/- 8.3, and 32.9 +/- 9.8 min in adults (P < 0.0001). In conclusion, mivacurium requirements were correlated with PChE, were greater in children than in adults, and were reduced by sevoflurane. Neuromuscular recovery occurred more rapidly in children and was delayed by sevoflurane. IMPLICATIONS: The mivacurium infusion requirement to maintain constant 90%-95% neuromuscular block during anesthesia is correlated with plasma cholinesterase activity. It is increased in children and reduced by the inhaled anesthetic sevoflurane. Despite the larger dose administered to children, recovery from block occurred more rapidly in children than in adults and was delayed by sevoflurane.

Adult↗
PubMed1998

Cardiovascular complications adversely affect survival during extracorporeal membrane oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has been used in the management of infants with cardiorespiratory failure. ECMO causes a decrease in load-dependent measures of cardiac performance that have not been demonstrated to affect patient outcome, while other cardiovascular complications occur which may affect outcome. The purpose of this study was to describe the cardiovascular complications associated with ECMO, and to determine their relationship to survival. DESIGN: Data were obtained, retrospectively, from the medical records of 500 consecutive newborns treated with ECMO at our institution since 1984. RESULTS: Hypertension (mean arterial pressure of >65 mm Hg) was the most common complication, requiring medical intervention in 192 infants. Myocardial stun, the near-total absence of systolic function during ECMO, occurred in 59 infants. Rhythm abnormalities, including noncannulation-related bradycardia, occurred in 43 infants, cardiac arrest, and pericardial effusion in 17 infants, and noninfective thrombosis in 9 infants. Only one infant required ligation of a patent ductus arteriosus during ECMO. Infants with at least one cardiovascular complication had a lower survival rate, compared with those infants without a complication. Survival rates were decreased in infants with myocardial stun, arrhythmia, and cardiac arrest. Hypertension and pericardial effusion were not associated with decreased survival. CONCLUSION: These findings suggest that some cardiovascular complications during ECMO are more common than previously thought, and cardiovascular complications may adversely impact outcome.

Cardiovascular Diseases↗
PubMed1998

Zolmitriptan: a new acute treatment for migraine.

Zolmitriptan is a new oral acute treatment for migraine. It is a selective and potent agonist at the serotonin (5-HT)(1B/1D) receptor and was developed to improve on the oral bioavailability, tissue selectivity and CNS penetration of earlier compounds. Animal studies confirmed that these objectives had been attained. In man, zolmitriptan is rapidly absorbed after oral administration, with at least 75% of the eventual C(max) reached within 1 h. Oral bioavailability is approximately 40%. The elimination half-life of zolmitriptan is approximately 2.5 h and the primary route of elimination is metabolism, with one of the metabolites being pharmacologically active. A consistent 2-h headache response rate of 60-70% was observed at doses of 2.5 mg and above. Long-term treatment response is high (> 80%) and consistent. In addition, there is evidence from electrophysiology in migraineurs that zolmitriptan has a central action not shared by sumatriptan. Zolmitriptan is well-tolerated. The nature and incidence of the most frequently reported adverse events are similar to those of other 5-HT(1B/1D) agonists. Long-term zolmitriptan usage was associated with an improvement in quality of life. Zolmitriptan is a suitable first-line drug for acute treatment for migraine.

Journal Article↗
PubMed1998

Traumatic aortic injuries in children: radiologic evaluation.

OBJECTIVE: The purpose of this study was to evaluate the radiographic findings in children with traumatic aortic injuries and discuss the imaging techniques currently available for diagnosis. MATERIALS AND METHODS: A retrospective review of 10,886 children examined because of blunt trauma from 1987 to April 1996 identified seven patients (0.064%) who sustained traumatic aortic injuries. The mechanism of injury, location of aortic injury, additional injuries suffered, trauma scores, sequences of radiologic evaluation, imaging findings, treatment, and outcome were recorded for each child. RESULTS: Six children had pathologically proven aortic ruptures, and the remaining child had an intimal injury diagnosed with contrast-enhanced helical CT and confirmed with transesophageal echocardiography. All seven children were victims of motor vehicle accidents (six passengers, one pedestrian), all had injuries of the aortic isthmus, and all had additional severe injuries. The mean trauma score, injury severity score, and probability of survival were 14, 39, and 75%, respectively. Imaging techniques included chest radiography (n = 7), conventional CT (n = 1), helical CT (n = 3), aortography (n = 2), and transesophageal echocardiography (n = 3). The initial outcomes included death (n = 1), paraplegia (n = 1), paraparesis (n = 2), and recovery without morbidity (n = 3). CONCLUSION: Traumatic aortic injuries are rare in children. The most common findings on plain films are a left apical cap, pulmonary contusion, aortic obscuration, and mediastinal widening. Helical CT and transesophageal echocardiography can be used in the diagnosis of traumatic aortic injuries in children.

Adolescent↗
PubMed1998

Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses.

Cannabinoid receptors couple to both Gs and Gi proteins and can consequently stimulate or inhibit the formation of cAMP. To test whether there is specificity among cannabinoid receptor agonists in activating Gs- or Gi-coupled pathways, the potency and intrinsic activity of various cannabinoid receptor ligands in stimulating or inhibiting cAMP accumulation were quantified. The rank order of potencies of cannabinoid receptor agonists in increasing or inhibiting forskolin-stimulated cAMP accumulation, in CHO cells expressing hCB1 receptors, was identical (HU-210 > CP-55,940 > THC > WIN-55212-2 > anandamide). However, the activities of these agonists were different in the two assays with anandamide and CP-55,940 being markedly less efficacious in stimulating the accumulation of cAMP than in inhibiting its formation. Studies examining the effects of forskolin on cannabinoid receptor mediated stimulation of adenyly cyclase also revealed differences among agonists in as much as forskolin enhanced the potency of HU-210 and CP-55,940 by approximately 100-fold but, by contrast, had no effect on the potency of WIN-55212-2 or anandamide. Taken together these findings demonstrate marked differences among cannabinoid receptor agonists in their activation of intracellular transduction pathways. This provides support for the emerging concept of agonist-specific trafficking of cellular responses and further suggests strategies for developing receptor agonists with increased therapeutic utility.

Adenylyl Cyclase Inhibitors↗
PubMed1997

Fat absorption after small intestinal transplantation in the rat.

BACKGROUND: Intestinal transplantation is now used for patients with severe malabsorption, however, little data exists quantifying the ability of the graft to absorb fat. This study tested the hypothesis that intestinal transplantation would not affect the lymphatic or venous uptake of fatty acids. METHODS: A syngeneic rat model of intestinal transplantation (SIT) with caval drainage of the graft was used. Control animals underwent intestinal division and reanastomosis (n=15 in each group). The animals were followed for 6 weeks, and fat absorption in vivo was quantified. The animals were anesthetized, sampling catheters were placed in the jugular and superior mesenteric veins and in the mesenteric lymphatic duct, and a feeding tube was passed into the duodenum. Animals were allowed to recover, and a steady-state duodenal infusion of lauric (C12:0) and palmitic (C16:0) fatty acid emulsion was begun. A radiolabeled pulse of lauric (C12:0) and palmitic (C16:0) fatty acid was then given, and the subsequent appearance in the lymphatic and venous systems was quantified. RESULTS: In vivo absorption of dietary fat was preserved, but after transplantation the mesenteric lymphatic flow and cumulative lymphatic appearance of both labels was significantly reduced (flow reduced from 4.8+/-1.1 in controls to 1.0+/-0.29 ml/hr in transplant animals, whereas lauric acid absorption was 33+/-11.4% in controls vs. 7.5+/-2.5% in transplant animals). There was a modest increase in the jugular venous appearance of the fatty acids (2.0+/-1.1% in transplant animals vs. 0.75+/-0.55% in controls for lauric acid; P<0.05 for all comparisons). Absorption of lauric and palmitic acids was very similar, and there was no preferential absorption detected in the portal venous system. Dye studies demonstrated lymphatic recannulization around the vascular anastomosis, into the retroperitoneum. CONCLUSIONS: These results suggest that in this model of SIT, fat absorption via the mesenteric duct is reduced, but that compensatory collaterals form into the retroperitoneal lymphatics. There was no evidence of any significant increase in portal venous uptake of fatty acids after SIT, nor of preferential absorption of medium-chain fatty acids. These results may have implications for patients after SIT.

Animals↗
PubMed1997

Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation.

Vertebrate organogenesis is initiated at sites that are often morphologically indistinguishable from the surrounding region. Here we have identified Pax9 as a marker for prospective tooth mesenchyme prior to the first morphological manifestation of odontogenesis. We provide evidence that the sites of Pax9 expression in the mandibular arch are positioned by the combined activity of two signals, one (FGF8) that induces Pax9 expression and the other (BMP2 and BMP4) that prevents this induction. Thus it appears that the position of the teeth is determined by a combination of two different types of signaling molecules produced in wide but overlapping domains rather than by a single localized inducer. We suggest that a similar mechanism may be used for specifying the sites of development of other organs.

Animals↗
PubMed1997

A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT1B/1D receptor antagonists.

The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives at vascular 5HT1B-like receptors is described. Several important auxiliary binding sites of the 5HT1B-like receptor have been proposed following various modifications to the 2-substituent and especially to the methylene- or ethylene-linked 5-side chain. Careful design of new molecules based on a proposed pharmacophoric model of the 5HT1B-like receptor has resulted in the discovery of ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(2, 5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate (40), a highly potent, silent, competitive, and selective antagonist which shows affinity at the vascular 5HT1B-like receptors only. Changes to the size of the 2-ester substituent have a significant effect on affinity at the 5HT1B-like receptor and other receptors. Prudent placement of the carbonyl substituent in the heterocycle of the 5-side chain is crucial for good affinity and selectivity over the 5HT2A and other receptors. Several key structural and electronic features were identified which are crucial for producing antagonism within a tryptamine-based series. An electron deficient indole ring system appears essential in order to achieve antagonism, and this is achieved by the inclusion of electron-withdrawing groups at the 2-position of the indole ring. The molecule displacement within the receptor resulting from the inclusion of the bulky 2-substituents also enhances antagonism as this results in the removal of the pi electron density of the indole ring from the region of the receptor normally occupied by the indole ring of 5HT. There also appears to be a structural requirement on the side chain incorporating the protonatable nitrogen, and this is achieved by the inclusion of the bulky 2-ester group which neighbors the 3-ethylamine side chain.

Animals↗
PubMed1997

Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development.

We present genetic and biochemical evidence that PAX6 is a key regulator of pancreatic islet hormone gene transcription and is required for normal islet development. In embryos homozygous for a mutant allele of the Pax6 gene, Small eye (Sey(Neu)), the numbers of all four types of endocrine cells in the pancreas are decreased significantly, and islet morphology is abnormal. In the remaining islet cells, hormone production, particularly glucagon production, is markedly reduced because of decreased gene transcription. These effects appear to result from a lack of PAX6 protein in the mutant embryos. Biochemical studies identify wild-type PAX6 protein as the transcription factor that binds to a common element in the glucagon, insulin, and somatostatin promoters, and show that PAX6 transactivates the glucagon and insulin promoters.

Alleles↗