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Biomedical subjects

S Murphy

Publications and source records attributed to S Murphy.

At least 253 records · Page 14Linked to original sources
PubMed1994

Cigarette smoking and bone mineral density in older men.

Cigarette smoking is cited as having a detrimental effect on bone mineral density (BMD), with associated increased fracture risk. Most of the data are from studies of women, with few studies of men. We examined the relationship between BMD and cigarette-smoking habit in a population-based study of men who were categorized by self-report as 'never smokers', 'current smokers' and 'ex-smokers'. BMD was measured using dual X-ray absorptiometry (DXA). We examined 453 men aged 65-76 years (mean 69.1). Non-smokers ('never' and 'ex' smokers) were heavier than current smokers (p = 0.05). There was no significant relationship between BMD and smoking habit at any site except the trochanter, where current smokers had significantly lower BMD than did non-smokers. However, after adjusting for age and weight there was no longer a significant relationship. BMD did not relate to pack-years of cigarette smoking. Current smokers consumed significantly more alcohol than non-smokers (p = 0.031), but adjusting for alcohol intake did not alter the BMD-smoking relationship. Cigarette smoking appears not to affect BMD in this group of older men.

Absorptiometry, Photon↗
PubMed1994

Reconstruction of major segmental loss of the proximal femur in revision total hip arthroplasty.

Reconstruction of major proximal femoral segmental defects is one of the most difficult challenges in revision total hip arthroplasty (THA). One technique that has been successful is the use of a modular, long-stemmed prosthesis, cemented to an allograft proximal femur and press-fit to the host bone. Since July 1989, the authors have used this technique in 30 hips (29 patients). The trochanteric slide approach was used in all cases. Sixty pounds of weight bearing was encouraged for six weeks, then full weight bearing as tolerated. The mean follow-up period was 22 months (range, two to 46 months). All but two grafts united to the host bone clinically and radiographically. Complications included five dislocations, one graft-host nonunion, one graft resorption, and one deep infection requiring resection arthroplasty. The latter patient was subsequently reconstructed successfully using the same technique. Although the follow-up period is short, the authors have been encouraged by the early success of these allograft-prosthetic composites. Advantages of this approach include rapid return to weight bearing, physiologic loading of the distal femur, and reconstitution of vital proximal bone stock.

Adult↗
PubMed1993

UTP activates multiple second messenger systems in cultured rat astrocytes.

In astrocytes, a number of second messenger systems are activated upon stimulation with ATP. Recently, UTP has been demonstrated to have effects similar to ATP in some cell types. To determine if this was also true in astrocytes, cultured cells were stimulated with UTP which was found to evoke thromboxane release, stimulate inositol phospholipid turnover and increase intracellular free calcium concentration. A 53 kDa protein was identified on astrocyte membranes by immunoblotting with an antibody raised against a putative rat fibroblast P2U receptor. These data indicate that astrocytes possess a UTP-sensitive receptor which may be distinct from the P2Y-purinergic receptor.

Adenosine Triphosphate↗
PubMed1993

Oxypurinol inhibits free radical release from the cerebral cortex of closed head injured rats.

Traumatic brain injury (TBI) is a significant cause of mortality and morbidity. Although the sequence of events underlying the resultant neuronal loss is still poorly understood, there are indications that oxygen-free radical generation is critically involved. Free radical generation in the cerebral cortex of closed head injury rats was monitored by measuring free radical release into cortical superfusates containing the spin trap agent 4-pyridyl-1-oxide-N-tert-butylnitrone (POBN, 100 mM). ESR analysis of the superfusates revealed six line spectra (alpha N = 15.4 G and alpha H beta = 2.5 G) characteristic of POBN-OH adducts. Administration of oxypurinol (40 mg/kg) 15 min prior to TBI prevented the formation of these radical adducts.

Animals↗
PubMed1993

Bradykinin and capsaicin stimulate cyclic GMP production in cultured rat dorsal root ganglion neurons via a nitrosyl intermediate.

Dorsal root ganglion (DRG) neurons express receptors for bradykinin and capsaicin, both algesic substances. Administration of bradykinin or capsaicin to neurons cultured from embryonic rat DRG stimulated the production of cyclic GMP but did not affect the production of cyclic GMP in nonneuronal DRG cultures. Bradykinin-evoked cyclic GMP production was mediated by B2 receptors and was unaltered by indomethacin. Both bradykinin- and capsaicin-stimulated cyclic GMP production required Ca2+ and was inhibited by methylene blue. Furthermore, methylene blue attenuated basal cyclic GMP production in DRG neurons, suggesting tonic cyclic GMP production in these cells. L-NG-monomethyl arginine inhibited both bradykinin- and capsaicin-stimulated cyclic GMP production as well as basal cyclic GMP production. These findings suggest the involvement of a nitrosyl compound in bradykinin- and capsaicin-stimulated cyclic GMP production and in tonic cyclic GMP production in DRG neurons.

Animals↗
PubMed1993

Cytokines regulate L-arginine-dependent cyclic GMP production in rat glial cells.

We have previously demonstrated that primary astrocyte cultures from neonatal rat cortex and C6 glioma cells express a calcium-independent nitric oxide synthase (NOS) on induction with bacterial endotoxin (lipopolysaccharide, LPS). One hypothesis regarding the mechanism of the LPS induction is that it causes release of cytokines from these cells which then induce the enzyme directly. Such cytokine induction of NOS has been demonstrated in many extraneural cell types. L-Arginine-dependent increases in cyclic GMP correlate with smaller increases in accumulation of nitrite, the major oxidation product of nitric oxide, and hence can serve as a more sensitive measure of nitric oxide production. Here we provide evidence that interferon-gamma (IFN-gamma), interleukin (IL)-1 beta and tumour necrosis factor-alpha induce L-arginine-dependent cyclic GMP synthesis in C6 cells and that a combination of IFN-gamma and IL-1 beta induce L-arginine-dependent cyclic GMP synthesis in astrocyte cultures, indicating that these cytokines induce NOS. In both cell types the induction by cytokines was less sensitive to inhibition by dexamethasone, IL-10 and IL-4 than was induction by LPS. These data suggest that cytokines can also induce a NOS in glial cells and that the mechanism of this induction may be more direct than that of LPS, since it is less sensitive to modulation by immunosuppressors. Due to the close associations of astrocytes with neurons and microvasculature, cytokine-induced NOS could have potentially important pathophysiological effects in the central nervous system.

Animals↗
PubMed1993

Increases in cytosolic Ca2+ in rat area postrema/mNTS neurons produced by angiotensin II and arginine-vasopressin.

It is well established that neurons in the dorsal medulla, including the area postrema and the medial nucleus tractus solitarius (mNTS), are involved in the central actions of circulating peptides such as angiotensin II (ANG II) and arginine vasopressin (AVP). This report describes a preparation that permits the identification and maintenance of area postrema/mNTS neurons in culture in which the cellular and potentially subcellular responses to neurotransmitters and neuropeptides on area postrema/mNTS cells can be investigated. Following 15-21 days in culture, the effects of ANG II and AVP on changes in intracellular Ca2+ concentration ([Ca2+]i) were examined. Both ANG II and AVP resulted in a rapid and transient increase in [Ca2+]i reaching maximum in 15 s and returning towards baseline values within 180 s. The ANG II-mediated increase in [Ca2+]i was almost completely abolished by the selective angiotensin AT1 receptor subtype antagonist, losartan (DuP 753). These results suggest that ANG II and AVP modulate area postrema/mNTS neuronal activity by increasing intracellular Ca2+.

Angiotensin II↗
PubMed1993

Purinergic P2Y receptors on astrocytes are directly coupled to phospholipase A2.

ATP stimulates arachidonic acid mobilization and eicosanoid production in cultured astrocytes via P2Y-purinergic receptors. To assist in determining the mechanism of phospholipase A2 activation and the role of calcium in eicosanoid production, cultures were pretreated with pertussis toxin (PTx). ATP-evoked eicosanoid release was inhibited by PTx in a concentration-dependent fashion. Inositol phospholipid hydrolysis was partially attenuated by PTx, but the concentrations required were approximately 50 times greater than those for inhibition of eicosanoid production, suggesting that phospholipase C activation is not necessary for eicosanoid synthesis. Stimulation of eicosanoid release by other P2Y-purinergic receptor agonists was also inhibited by PTx; however, PTx had no effect on eicosanoid release evoked by ionomycin or thapsigargin, nor did it affect ATP-stimulated calcium influx or mobilization from intracellular stores. Increases in intracellular free calcium concentration alone were insufficient to stimulate eicosanoid production, but maximal production was dependent upon the concentration of extracellular calcium. These results suggest that the P2Y-purinergic receptor is coupled to phospholipase A2 via a guanine nucleotide-binding protein, and that extracellular calcium may also be involved in the synthesis of eicosanoids by astrocytes.

Adenosine Triphosphate↗
PubMed1993

An immunohistochemical study of the innervation of the large intestine of the toad (Bufo marinus).

The distribution of intrinsic enteric neurons and extrinsic autonomic and sensory neurons in the large intestine of the toad, Bufo marinus, was examined using immunohistochemistry and glyoxylic acid-induced fluorescence. Three populations of extrinsic nerves were found: unipolar neurons with morphology and location typical of parasympathetic postganglionic neurons containing immunoreactivity to galanin, somatostatin and 5-hydroxytryptamine were present in longitudinally running nerve trunks in the posterior large intestine and projected to the muscle layers and myenteric plexus throughout the large intestine. Sympathetic adrenergic fibres supplied a dense innervation to the circular muscle layer, myenteric plexus and blood vessels. Axons containing colocalized calcitonin gene-related peptide immunoreactivity and substance P immunoreactivity distributed to all layers of the large intestine and are thought to be axons of primary afferent neurons. Five populations of enteric neurons were found. These contained immunoreactivity to vasoactive intestinal peptide, which distributed to all layers of the large intestine; galanin/vasoactive intestinal peptide, which projected to the submucosa and mucosa; calcitonin gene-related peptide/vasoactive intestinal peptide, which supplied the circular muscle, submucosa and mucosa; galanin, which projected to the submucosa and mucosa; and enkephalin, which supplied the circular muscle layer.

Animals↗
PubMed1993

A phase I trial of fazarabine in refractory pediatric solid tumors. A Pediatric Oncology Group study.

Fazarabine is a synthetic analog of cytosine arabinoside and 5-azacytidine that incorporates structural features of both compounds. Xenograft studies showed good activity against a variety of transplanted tumors. Initial studies in adults employed both a continuous infusion schedule and a daily bolus x 5 schedule. Myelotoxicity, especially neutropenia, was dose-limiting, with excessive myelotoxicity seen on the daily bolus x 5 at 72 mg/M2/day. Since short infusions may be administered in Ringer's lactate rather than either dimethylsulfoxide or dimethylacetamide required for continuous infusion, this study examined a daily x 5 schedule in children with refractory solid tumors. The initial dosage was 30 mg/M2/day, 80% of the maximum tolerated dosage in adults, with subsequent 30% dosage escalations. A total of 18 patients were enrolled, with a wide spectrum of pediatric solid tumors. Myelosuppression was the only significant toxicity, and was excessive at 78 mg/M2/day. Therefore, on this bolus regimen, 65 mg/M2/day for 5 days was the maximum tolerated dosage. One patient with medulloblastoma had stable disease for 65 days. No other responses were seen.

Antineoplastic Agents↗
PubMed1993

Intralobar pulmonary sequestration: a clinical and pathological spectrum.

Pulmonary sequestration is a mass of abnormal pulmonary tissue that does not communicate with the tracheobronchial tree and is supplied by an anomalous systemic artery. Whereas extralobar sequestration is clearly congenital, intralobar sequestration, which frequently presents in older children with pathological findings showing acute and chronic inflammation, may have an acquired origin secondary to frequent infections. Several large autopsy series support an acquired etiology of intralobar sequestration. Four cases of intralobar sequestration are presented that demonstrate a spectrum of inflammatory change that support its congenital, rather than acquired origin. Case 1 was a newborn who presented with tachypnea and a right lower lobe density. Resection at 3 weeks of age showed no inflammation in the sequestration specimen. Case 2 presented as a newborn infant with congestive heart failure. Pulmonary sequestration was confirmed by arteriogram. Resection at 3 months of age showed chronic inflammation. Case 3 presented at 7 months of age with chronic pneumonia. The resected specimen demonstrated moderately severe acute and chronic inflammation. Case 4 presented as a 6 year old. The operative specimen showed extensive bronchiectatic changes with marked acute and chronic inflammation. These cases support the congenital origin of intralobar sequestration and suggest a temporal progression from no inflammation to severe acute and chronic inflammation.

Bronchopulmonary Sequestration↗
PubMed1993

Synthesis of nitric oxide in CNS glial cells.

Attention has focused on particular neurons as the source of nitric oxide (NO) within the parenchyma of the CNS. In contrast, glial cells have been viewed mainly as potential reservoirs of L-arginine, the substrate for nitric oxide synthase (NOS), and as likely targets for neuronally derived NO because of their proximity and their expression of soluble guanylyl cyclase (sGC). However, it is becoming evident that astrocytes display both constitutive and inducible NOS activity under various conditions, and that activated microglia express an inducible NOS. The NO-producing capacity of oligodendrocytes is not yet known. Glial-derived NO has significant implications for CNS pathophysiology, given the anatomical location and abundance of these cells, and the wide variety of potential interactions that NO can have with cellular biochemistry. Our intention here is to evaluate the evidence for NO production from non-neuronal CNS sources and thus prompt discussion about potential 'nitrinergic' roles for glial cells.

Amino Acid Oxidoreductases↗
PubMed1993

Protein kinase C down-regulation in astrocytes: differential effects on agonist-stimulated inositol phosphate accumulation.

Prolonged phorbol ester treatment abolished protein kinase C (PKC) activity for over 48 h in cortical astrocyte cultures. Receptor-stimulated inositol phospholipid breakdown in these cultures subsequent to PKC depletion produced either enhanced, depressed or unchanged responses depending upon the agonist used. Noradrenaline-, ATP-, histamine- and glutamate-evoked [3H]-inositol phosphate accumulations were potentiated to varying degrees in PKC-depleted cultures whilst those evoked by carbachol and NaF were reduced and unchanged respectively. Analysis of the individual metabolites of inositol phospholipid metabolism formed in response to noradrenaline in PKC-depleted astrocytes revealed potentiated accumulations of radiolabelled glycerophosphoinositol (GPI), inositol monophosphate (IP1) and inositol bisphosphate (IP2) but not inositol trisphosphate (IP3) when compared to controls. Under the same conditions, accumulations of radiolabelled IP1 and IP2 were reduced and those of GPI and IP3 unchanged in carbachol-treated cultures. These results suggest that astrocyte receptors coupled to inositol phospholipid metabolism are differentially regulated by PKC.

Adenosine Triphosphate↗
PubMed1993

Sex hormones and bone mineral density in elderly men.

The aim of this study was to determine the relationships between sex hormones and bone mineral density (BMD) in older men. Community-dwelling men (n = 134, mean age (SD) 69.5 (3.1) years) were recruited from two general practices in Cambridge, UK. Plasma total testosterone and sex hormone binding globulin (SHBG) were assayed and a free androgen index (FAI) was derived as the ratio of total testosterone to SHBG (x 100). Spine and hip BMD were measured by dual energy x-ray absorptiometry using the Hologic QDR-1000. After adjusting for age and body mass index (BMI), the FAI correlated with femoral neck (r = 0.20, P = 0 0.03), intertrochanteric, trochanteric and Ward's Triangle BMD (r = 0.22, P = 0.01). Analysis of variance, with adjustment for age and BMI, showed a progressive upward trend of hip BMD with increasing quartiles of FAI. The findings suggest that free testosterone plays a role in determining bone mineral density in older men.

Absorptiometry, Photon↗
PubMed1993

Use of adrenocorticotrophic hormone analog to minimize brain injury.

STUDY OBJECTIVES: To investigate the effects of a vasoactive analog of adrenocorticotrophic hormone (GMM2) on time-dependent disturbances in regional cerebral blood flow, permeability-capillary surface area products, and intracranial pressure in a rat model of moderate concussion/brain injury. SETTING AND DESIGN: Regional permeability-capillary surface area products and cerebral blood flow were measured at two hours after trauma. Intracranial pressure was monitored for 120 hours after trauma. SUBJECTS: Male Wistar rats (330 to 430 g) (regional cerebral blood flow studies, n = 35; permeability-capillary surface area product studies, n = 36; intracranial pressure studies, n = 32). INTERVENTIONS: Post-traumatic subcutaneous administration of nanomolar concentrations of GMM2 (31 nmol per rat). MEASUREMENTS AND MAIN RESULTS: Untreated trauma acutely increased average brain permeability-capillary surface area products for sucrose and decreased average brain cerebral blood flow. Moreover, it produced marked and prolonged increases in intracranial pressure. Post-traumatic subcutaneous administration of nanomolar concentrations of GMM2 effectively reduced the early hypoperfusion, blood-brain barrier leakiness, and pathologic elevation of intracranial pressure. CONCLUSION: Post-traumatic administration of GMM2, in nanomolar amounts, can prevent or reverse significantly the serious cerebrovascular sequelae of moderate head injury in this animal model. In view of its potency, low toxicity, and other neuroprotective properties, in both rats and human beings, these data suggest that GMM2 may have considerable clinical benefits in the treatment of central nervous system trauma.

Adrenocorticotropic Hormone↗
PubMed1993

In vitro changes in platelet function and metabolism following increasing doses of ultraviolet-B irradiation.

Ultraviolet-B (UV-B) irradiation of platelet concentrates (PCs) may prevent the development of posttransfusion HLA alloimmunization. This study evaluated the effect of increasing doses of UV-B radiation on stored PCs. Pooled PCs were irradiated at UV-B doses of 600, 2400 or 10,000 mJ per cm2 and stored up to 96 hours under standard blood bank conditions. Compared to nonirradiated room-temperature and 37 degrees C controls, the irradiated units showed no significant changes in platelet count, white cell count, discharge of lactate dehydrogenase, release of beta-thromboglobulin, metabolism of ATP, ADP, ammonia, glutamine, glutamate, hypoxanthine, pCO2, or pO2 at any time of storage following any of the three UV-B doses. However, after a dose of 10,000 mJ per cm2, there were significant decreases in in vitro assays of platelet function-specifically, osmotic recovery and morphology score. Some metabolic systems were also affected by the 10,000 mJ per cm2 radiation dose, as shown by a decline in pH and bicarbonate and an increase in glucose consumption and lactate production (p < 0.05). The changes in these latter assays appeared only after 96 hours of postirradiation storage. Such changes were not seen in either the room-temperature or 37 degrees C control groups. Thus, heat generated during irradiation, per se, did not appear responsible for the observed in vitro changes in platelet function and metabolism. On the basis of the assays analyzed, it is concluded that UV-B irradiation of PCs at doses up to 10,000 mJ per cm2 does not induce significant metabolic or functional derangements following short-term storage (24-48 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1993

Roles of acetate and phosphate in the successful storage of platelet concentrates prepared with an acetate-containing additive solution.

The development of a synthetic medium for platelet storage is an important goal in transfusion medicine. Its use would make large volumes of plasma available for fractionation and might improve the quality of platelets after storage. Several investigators have described successful storage in media containing acetate. The previous work of the authors showed that platelet concentrates (PCs) can be stored successfully for 5 days at 22 degrees C by using an additive solution (Seto sol) to replace 80 to 95 percent of the plasma usually employed as a suspending medium. Seto sol contains 23 mM (23 mmol/L) sodium acetate and 25 mM (25 mmol/L) sodium phosphate. The roles of acetate and phosphate in achieving successful platelet storage were studied in the work reported here. The concentration of acetate decreased linearly for 7 days at 0.61 +/- 0.11 mumol per day per 10(9) platelets in parallel with the disappearance of 1-14C or 2-14C acetate. There was no disappearance of tritiated acetate from PCs or of 1-14C acetate from platelet-free mixtures of plasma and Seto sol, which suggests that the disappearance of 14C acetate from PCs reflected oxidation to CO2, which could leave PCs through the walls of the plastic container. Since O2 consumption was 1.47 mumol per day per 10(9) platelets, and the oxidation of a molecule of acetate requires 2 molecules of oxygen, acetate oxidation accounted for approximately 85 percent of oxygen consumption by platelets. The pH of PCs stored in Seto sol was nearly constant for 7 days, whereas, without acetate, it fell to 6.4 +/- 0.1 on Day 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗