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Biomedical subjects

D W Gray

Publications and source records attributed to D W Gray.

At least 73 records · Page 4Linked to original sources
PubMed1994

Differential effects of lithium on muscarinic cholinoceptor-stimulated CMP-phosphatidate accumulation in cerebellar granule cells, CHO-M3 cells, and SH-SY5Y neuroblastoma cells.

The ability of lithium to potentiate muscarinic cholinoceptor-stimulated CMP-phosphatidate (CMP.PA) accumulation has been examined in various cells in which muscarinic cholinoceptor agonists evoke a phosphoinositide response. Cell types examined include rat cerebellar granule cells, Chinese hamster ovary cells transfected to express the human muscarinic M3 receptor (CHO-M3 cells), and SH-SY5Y neuroblastoma cells. Neither carbachol (1 mM) nor lithium (10 mM) caused significant increases in CMP.PA accumulation in rat cerebellar granule cells; however, when added together for 20 min a linear 17-fold increase over basal levels was observed. The increase was dependent on the concentration of carbachol and lithium present, and the effect could be reversed by addition of exogenous myo-inositol (10 mM). Addition of carbachol alone to CHO-M3 cells caused a five-fold increase in CMP.PA accumulation. In the presence of lithium, a 70-fold increase was observed at 20 min after carbachol plus lithium addition. This latter response was concentration dependent and could be abolished by preincubation in the presence of 10 mM myo-inositol. In contrast, whereas carbachol elicited a three-fold increase in CMP.PA accumulation in SH-SY5Y neuroblastoma cells, which reached a plateau 10 min after agonist addition, the response could neither be augmented by addition of lithium nor inhibited by addition of myo-inositol. These results emphasise that the ability of lithium to affect agonist-stimulated CMP.PA accumulation is not simply a function of stimulus strength, but is also crucially dependent on the intracellular concentration of inositol.

Animals↗
PubMed1994

Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic glutamate receptor agonist 1S,3R-ACPD in neonatal rat cerebral cortex.

1. The effect of NMDA-receptor stimulation on phosphoinositide signalling in response to the metabotropic glutamate receptor agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) has been examined in neonatal rat cerebral cortex slices. 2. Total [3H]-inositol phosphate ([3H]-InsPx) accumulation, in the presence of 5 mM LiCl, in [3H]-inositol pre-labelled slices was concentration-dependently increased by 1S,3R-ACPD (EC50 16.6 microM) and, at a maximally effective concentration, 1S,3R-ACPD (300 microM) increased [3H]-InsPx accumulation by 12.8 fold over basal values. 3. [3H]-InsPx accumulation stimulated by 1S,1R-ACPD was enhanced by low concentrations of NMDA (3-30 microM), but not by higher concentrations (> 30 microM). [3H]-InsPx accumulations stimulated by 1S,3R-ACPD in the absence or presence of 10 microM NMDA were linear with time, at least over the 15 min period examined; however, in the presence of 100 microM NMDA the initial enhancement of 1S,3R-ACPD-stimulated phosphoinositide hydrolysis progressively decreased with time. 4. In the presence of a maximal enhancing concentration of NMDA (10 microM), the response to 1S,3R-ACPD (300 microM) was increased 1.9 fold and the EC50 for agonist-stimulated [3H]-InsPx accumulation decreased about 4 fold. The enhanced response to the metabotropic agonist was concentration-dependently inhibited by competitive and uncompetitive antagonists of NMDA-receptor activation. 5. 1S,3R-ACPD also stimulated inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) mass accumulation with an initial peak response (5-6 fold over basal) at 15 s decaying to a smaller (2 fold), but persistent elevated accumulation (1-10 min). 6. Co-addition of 10 or 100 MicroM NMDA enhanced the initial peak Ins(1,4,5)P3 response to 1S,3RACPD.However, the enhancing effect was only maintained over 10 min in the presence of 1O Micro MNMDA, whilst in contrast, 100 MicroM NMDA ceased to cause a significant enhancement of the metabotropic response by 5 min and completely suppressed lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation at 10 min.7. Both basal and 1S,3R-ACPD-stimulated Ins(1,4,5)P3 accumulations were reduced when slices were incubated in nominally Ca2"-free medium. Under these conditions only a concentration-dependent enhancement of the response was observed (EC50 for NMDA facilitation of lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation of 32 MicroM).8. These experiments have revealed that at low concentrations, NMDA can dramatically potentiate1S,3R-ACPD-stimulated phosphoinositide hydrolysis, probably by a Ca2"-dependent facilitation of agonist-stimulated phosphoinositide-specific phospholipase C activity. Higher concentrations of NMDA result in time-dependent inhibition of the metabotropic agonist-stimulated response. We believe the former effect could be fundamental in glutamate receptor 'cross-talk', whereas the latter may reflect a Ca2+-dependent neurotoxic effect of NMDA on the neonatal cerebral cortex slices.

2-Amino-5-phosphonovalerate↗
PubMed1993

Cefaclor vs amoxicillin in the treatment of acute, recurrent, and chronic sinusitis.

BACKGROUND: The treatment of acute, recurrent, and chronic sinusitis remains controversial because of the presence of a wide variety of aerobic and anaerobic bacteria in the sinuses. DESIGN: This double-blind, randomized trial compared cefaclor with amoxicillin in the treatment of acute, recurrent, and chronic maxillary sinusitis using clinical evaluation, roentgenography, and microbiologic evaluation of antral aspirates. SETTING: Outpatient office of five otorhinolaryngologists in Salt Lake City, Utah. PATIENTS: One hundred eight adult patients with acute, recurrent, or chronic maxillary sinusitis. INTERVENTION: Oral treatment with cefaclor (500 mg) twice daily or amoxicillin (500 mg) three times daily for 10 days. MAIN OUTCOME MEASURE: Clinical response to treatment with cefaclor vs amoxicillin. RESULTS: Fifty-six patients with acute sinusitis, 25 with recurrent sinusitis, and 15 with chronic sinusitis were evaluable. Although multiple organisms were common in each group, patients with acute sinusitis were more likely to have Haemophilus influenzae or Streptococcus pneumoniae, and patients with recurrent or chronic sinusitis were more likely to have anaerobes in sinus aspirate. Whether treated with cefaclor or amoxicillin, clinical improvement occurred in 86% of patients with acute sinusitis and 56% of patients with recurrent sinusitis. Patients with chronic sinusitis were too few to allow statistical analysis of the differences in outcome between them and patients with recurrent or acute sinusitis. Resistance of the cultured organisms to the study drug used was unrelated to treatment outcome. CONCLUSIONS: The rate of clinical improvement was high in patients with acute sinusitis but was less favorable in those with recurrent and chronic disease regardless of the study drug used. The susceptibility of organisms isolated to the study drugs was unrelated to outcome.

Acute Disease↗
PubMed1993

Two types of potassium channel regulated by ATP in pancreatic B cells isolated from a type-2 diabetic human.

Two types of K channel regulated by ATP were observed in pancreatic beta cells from a type-2 diabetic man. One type had a conductance of 67 pS at -70 mV in symmetrical 140 mM KCl and was inhibited by intracellular ATP with a half-maximal concentration of 40 microM. ATP inhibition was antagonised by ADP. Tolbutamide inhibited the whole-cell K currents half-maximally at 25 microM. This channel has properties similar to those found for the ATP-sensitive K channel in rodent and normal human beta cells. The second channel type observed was an ATP-activated K channel. It had a conductance of 37 pS at -70 mV in symmetrical 140 mM KCl and was activated half-maximally by 9 microM intracellular ATP. This channel was unaffected by 1 mM tolbutamide. In cell-attached patches, one beta cell out of four tested responded to 20 mM glucose with depolarization. The role of the ATP-activated K channel with respect to the (patho)physiology of the beta cell is uncertain.

Adenosine Diphosphate↗
PubMed1993

Variation in expression of endothelial adhesion molecules in pretransplant and transplanted kidneys--correlation with intragraft events.

Endothelial adhesion molecules are directly involved in the localization and migration of leukocytes from the circulation into tissues at sites of inflammation. We have compared the expression of PECAM-1 (CD31), ELAM-1, ICAM-1 (CD54), and VCAM-1 in pretransplant (n = 20) and needle-core biopsies from renal transplants obtained during different clinical circumstances (n = 42). PECAM-1 was consistently expressed on all endothelium in both pretransplant and transplant biopsies. In contrast, there was variation in endothelial expression of ELAM-1 and in proximal tubular expression of ICAM-1 and VCAM-1 between pretransplant biopsies. After transplantation induced expression of endothelial ELAM-1 and VCAM-1 and tubular induction of ICAM-1 and VCAM-1 was detected. Induced adhesion molecule expression was frequently associated with focal leukocyte infiltration, and there was a significantly higher level of CD45 and CD25 positive cell infiltration in biopsies with induced adhesion molecule expression. The induction of adhesion molecule expression is evidence of endothelial activation in these transplant biopsies. Comparison of adhesion molecule expression and HLA-class II antigen expression revealed that induced tubular class II antigens may be detected in the absence of induced adhesion molecule expression.

Antigens, Differentiation, Myelomonocytic↗
PubMed1993

A comparison of four solutions for cold storage of pancreatic islets.

Clinical pancreatic islet transplantation requires cold storage of islets for some hours. The best solution for cold storage will be that which maintains islet viability for the longest time. We have examined the viability of rat and human islet after storage at 4 degrees C for up to 6 days in Hanks' balanced salt solution, University of Wisconsin solution (UW), and 2 modified versions of this last solution, Sumimoto D (SD) and histidine-lactobionate (HL). The integrity of cold-stored rat and human islets of Langerhans has been examined using supravital stains and electron microscopy. In addition, the viability of cold-stored rat islets was tested by intraportal transplantation into syngeneic streptozotocin-induced diabetic recipients. The in vitro studies showed good preservation of islets stored in UW, SD, and HL for up to 72 hr. In comparison, storage for periods as short as 24 hr in HBSS markedly reduced islet integrity. The transplantation studies showed that rat islets cold stored in HBSS solution for 24 hr were not able to reverse experimental diabetes, whereas those stored in the other 3 solutions for 24 hr successfully reversed diabetes within 1 week of transplantation. After 48-hr cold storage, only islets preserved in HL solution were uniformly capable of producing functioning islet grafts. None of the tested solutions was able to maintain islet viability sufficiently to allow successful transplantation after more than 48 hr of cold storage. These experiments demonstrate that good islet viability is maintained for up to 24 hr of storage in UW, SD, and HL, and even after 48-hr cold storage in HL solution, whereas preservation in HBSS solution was deleterious to islet viability within 24 hr.

Adenosine↗
PubMed1993

Zinc-specific N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide as a selective nontoxic fluorescence stain for pancreatic islets.

Separation of the endocrine from the exocrine pancreatic tissue by fluorescence activated sorting has been limited by the lack of an ideal fluorescent label for islet tissue. Our studies indicates the zinc-specific stain N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ), has characteristics ideal for use as a fluorescent label for islet tissue. Dispersed rat pancreas cells stained with TSQ produced bright blue fluorescence when excited by UV light (peak emission wavelength at 480 nm, maximal excitation at 365 nm). The fluorescence was specific for islet tissue as confirmed by counterstaining with the islet-specific stain dithizone and there was minimal background staining of exocrine tissue. Stained tissue remained brightly fluorescent for 2 hr, with some fading by 4 hr. Injection of TSQ into rats at a concentration sufficient to produce staining of islets produced no toxicity discernible at 4 months. The viability of isolated rat islets stained with TSQ was maintained as shown by supravital staining, in vitro secretion of insulin, and reversal of diabetes after transplantation of stained islets into diabetic syngeneic recipients.

Aminoquinolines↗
PubMed1993

Clinical and socioeconomic benefits of serological HLA-DR matching for renal transplantation over three eras of immunosuppression regimens at a single unit.

The efficacy of HLA-DR matching in cadaveric renal transplantation is controversial in the cyclosporine (CsA) era. Reports have questioned both the reliability of serological HLA-DR typing as well as the benefit of matching in terms of improved graft survival. Analysis of 1,000 consecutive cadaver donor transplants performed at Oxford between 1975 and 1992 has shown that with improved immunosuppressive regimens and increased transplant success there has been a steadily diminishing influence of HLA-DR matching measured in terms of first graft outcome. For patients treated with azathioprine and prednisolone (n = 278) overall one-year first graft survival was 65%, but there was a 20% improvement associated with HLA-DR matching which has been maintained for up to 15 years. With the introduction of CsA, used either alone or in conjunction with low dose steroids (n = 96), one-year first graft survival was 69% and the difference between HLA-DR-matched and -mismatched transplants was 14%. Our current maintenance immunosuppressive protocol is triple therapy (N = 425) with an 81% one-year first graft survival for both matched and mismatched transplants. However, we do continue to find a marked correlation between HLA-DR matching and clinical course. HLA-DR-mismatched patients suffer more rejection episodes, spend a longer time in the hospital, and have higher creatinine levels at 3 months. This costs, on average, an extra 1,500 pounds for each mismatched transplant. The effect is most apparent in unsensitized males. For cadaveric regrafts, one-year graft survival for patients on triple therapy is 80% (n = 116) which does not differ from first graft survival rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Graft Rejection↗
PubMed1993

Routine use of arteriovenous fistula construction to dilate the venous outflow prior to insertion of an expanded polytetrafluoroethylene (PTFE) loop graft for dialysis.

For long-term haemodialysis to be successful an adequate length of vessel with correspondingly high flow is necessary, and the use of a peripheral arteriovenous fistula (AVF) between brachial artery and median cephalic vein is well described for long-term vascular access. However, the length of vessel available is often insufficient for dialysis and the time-lag between formation and availability for use may be prolonged. Primary insertion of a PTFE interposition graft is an alternative but may be technically difficult due to the small diameter of vein available for run-off, resulting in a significant rate of thrombosis. We advocate early AVF formation in most patients, even where the fistula is unlikely to prove usable for dialysis, with the express purpose of dilating the veins prior to PTFE graft insertion. The time-lag between AVF formation and PTFE graft insertion may be as short as 1 week. Although conversion of a functioning AVF to PTFE interposition graft has been described by others, we believe the routine use of AVF formation prior to PTFE insertion has not been previously advocated and gives a considerable advantage in patients with difficult dialysis access.

Arteriovenous Shunt, Surgical↗