[Structured care for stroke patients: 'stroke units' and 'ambulatory stroke services'].
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Ambulatory Care↗
Biomedical subjects
S Thomas
Publications and source records attributed to S Thomas.
Membrane association, localization and topology of rat inositol 1,4,5-trisphosphate 3-kinase B: implications for membrane traffic and Ca2+ homoeostasis.
We previously reported the isolation of a rat cDNA clone encoding a protein with significant sequence homology to the B isoform of human myo-inositol 1,4,5-trisphosphate 3-kinase (IP3 3-kinase B); this protein was thus designated rat IP3 3-kinase B [Thomas, Brake, Luzio, Stanley and Banting (1994) Biochim. Biophys. Acta 1220, 219-222]. However, no IP3 kinase isoform had been shown to generate the physiologically important isoform of inositol tetrakisphosphate, i.e. inositol 1,3,4,5-tetrakisphosphate. We now present direct evidence that the putative rat IP3 3-kinase B is genuinely an IP3 3-kinase. We also show that the enzyme exists both as a peripheral membrane protein tightly associated with the cytosolic face of the extended endoplasmic reticulum network, and as a cytosolic protein. Association of the IP3 3-kinase with membranes is not affected by treatment with brefeldin A, Na2CO3 (pH 11.5), 2 M NaCl, or alteration of [Ca2+]. However, treatment of isolated membranes with 4 M urea leads to dissociation of the kinase from the membrane, implying that membrane association involves specific, conformation-dependent protein-protein interactions. The fact that IP3 3-kinase B is localized exclusively to membranes of Ca2+ stores, is consistent with a model where this kinase plays a role in IP3-dependent Ca2+ release.
Amino Acid Sequence↗
[3H]R-terazosin binds selectively to alpha1-adrenoceptors over alpha2-adrenoceptors - comparison with racemic [3H]terazosin and [3H]prazosin.
Most tissue sources for adrenoceptors contain a mixed population of alpha1- and/or alpha2-adrenoceptor subtypes; thus studies using non-specific radioligands are complicated by receptor heterogeneity. The examination of alpha1-adrenoceptor radioligand binding by radiolabeled terazosin and its enantiomers was simplified by using mouse fibroblast cells, which are thymidine kinase mutant (LTK-), transfected with cloned alpha1a-, alpha1b-, and alpha1d-adrenoceptor subtypes. [3H]Terazosin and its enantiomers were equipotent at the alpha1b-adrenoceptor. [3H]R-Terazosin was significantly less potent than [3H]terazosin and [3H]S-terazosin at the alpha1a- and the alpha1d-adrenoceptors. Using tissue derived alpha-adrenoceptors prepared in cold 25 mM glycyl-glycine buffer, [3H]prazosin, [3H]terazosin and [3H]S-terazosin bound to two sites in the rat neonatal lung preparation consistent with the presence of both alpha1- and alpha2B-adrenoceptors. The relative binding potencies of these radioligands at these two sites correlated with low affinity binding to the alpha2B-adrenoceptor and high affinity binding to an alpha1-adrenoceptor. [3H]R-Terazosin, on the other hand, bound to a single site in the rat neonatal lung membrane preparation, most likely an alpha1-adrenoceptor. Thus, [3H]R-terazosin may be useful as a selective alpha1-adrenoceptor radioligand for establishing the functional role of adrenoceptors in tissues expressing multiple subtypes.
Adrenergic alpha-Antagonists↗
[Summary of the updated guideline 'Gastric Complaints' of the Dutch College of General Practitioners].
The Dutch College of General Practitioners recently updated its guideline 'Gastric complaints'. The main change concerns Helicobacter pylori infection diagnosis and treatment. In cases of functional dyspepsia with Helicobacter infection antibiotic eradication treatment is not advised. In patients with gastric complaints, three working diagnoses are presented: aspecific gastric complaints, ulcer complaints, reflux complaints. Endoscopy is given a more prominent role than in the previous version of the guideline. Criteria are given for discontinuation of unmotivated long-term use of antacid medication.
Antacids↗
Harmonizing European patent practice.
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Biotechnology↗
Finite change analysis of glycolytic intermediates in tuber tissue of lines of transgenic potato (Solanum tuberosum) overexpressing phosphofructokinase.
Genetically engineered organisms overexpressing phosphofructokinase (PFK), a supposed 'regulatory' step of glycolysis, often show little or no measurable change in glycolytic or respiratory flux, although the concentrations of glycolytic intermediates may change. We have used the finite change theory of Metabolic Control Analysis (MCA) to analyse the concentrations of glycolytic metabolites in aged disks of tuber tissue from four lines of transgenic potatoes expressing different amounts of PFK that, under aerobic conditions, showed statistically indistinguishable rates of respiration. The constancy of the metabolites' concentration deviation indices for different increases in PFK expression indicated that the metabolite changes from a graded series, excluding the possibility of anomalous behaviour that might be observed in a single transgenic line. Consequently we were able to use the finite change method to validate the results of an MCA model of tuber glycolysis [Thomas, Mooney, Burrell and Fell (1997) Biochem. J. 322, 119-127]. Furthermore the metabolite changes with PFK activity are evidence that near-equilibrium steps do not transmit increased substrate concentrations down the pathway without attenuation. Our results support the view that flux increase by activation of a single enzyme early in the pathway will, contrary to expectations, be of limited effectiveness in achieving flux increases.
Energy Metabolism↗
Metabolic Control Analysis of glycolysis in tuber tissue of potato (Solanum tuberosum): explanation for the low control coefficient of phosphofructokinase over respiratory flux.
We have applied Metabolic Control Analysis (MCA) in an attempt to determine the distribution of glycolytic flux control between the steps of glycolysis in aged disks of potato tuber under aerobic conditions, using concentrations of glycolytic metabolites in tuber tissue from a range of transgenic potato plants and published enzyme kinetic data. We modelled the substrate and effector kinetics of potato tuber phosphofructokinase (PFK) by reanalysing published results. Despite the scarcity of reliable kinetic data, our results are in agreement with experimental findings namely that, under the conditions described, PFK has little control over glycolytic flux. Furthermore our analysis predicts that under these conditions far more control lies in the dephosphorylation of phosphoenolpyruvate and/or in the steps beyond. We have validated the results of our analysis in two ways. First, predictions based on calculated concentration control coefficients from the analysis show generally good agreement with observed metabolite deviation indices discussed in the preceding paper [Thomas, Mooney, Burrell, and Fell (1997) Biochem. J. 322, 111-117]. Second, sensitivity analysis of our results shows that the calculated control coefficients are robust to errors in the elasticities used in the analysis, of which relatively few need to be known accurately. Experimental and control analysis results agree with previous predictions of MCA that strong co-operative feedback inhibition of enzymes serves to move flux control downstream of the inhibiting metabolite. We conclude that MCA can successfully model the outcome of experiments in the genetic manipulation of enzyme amounts.
Electron Transport↗
Spectral analysis of heart rate variability during heat exposure and repeated exercise.
This study examined indices of parasympathetic (PNS) and sympathetic (SNS) nerve activity during exposure to heat and/or two successive bouts of exercise. Seven healthy males [age = 27.1 (3.6) years; mean (SD), maximum oxygen consumption (VO2max) = 48.1 (7.6) ml x kg(-1) x min(-1)] were assigned to each of four experimental conditions according to a randomized-block design. While in a thermoneutral (23 degrees C) or heated (40 degrees C, 30% relative humidity) climatic chamber subjects performed exercise on a cycle ergometer (two 30-min bouts at approximately 50% VO2max, separated by a 45-min recovery period, (CEx and HEx, respectively) or remained seated (CS and HS, respectively) for 2 h. The R-R intervals of the subjects' ECGs were analyzed for selected near-steady-state time periods [termed Phase I (25-40 min) and Phase II (100-115 min)] according to the method of Yamamoto and Hughson (J Appl Physiol 71:1143-1150, 1991). Total (P(T)), low-frequency (P(LF) = 0-0.15 Hz) and high-frequency (P(HF) = 0.15-0.5 Hz) power spectra were calculated using coarse-graining spectral analysis. Heat exposure alone did not alter autonomic balance or levels of circulating catecholamines significantly. Exercise in both environmental conditions induced a significant decrease in an index of PNS tone (PHF:PT) [PNS indicator for CS = 0.084 (0.04) vs CEx = 0.023 (0.015) and HS = 0.065 (0.027) vs HEx = 0.015 (0.009)], with an increase in catecholamine concentrations. Although the index of SNS activity (P(LF):P(HF)) tended to rise with exercise in both environmental conditions, increments reached levels of significance only during exercise in the heat [SNS indicator for CS = 8.22 (5.58) vs CEx = 34.06 (21.73) and HS = 8.94 (5.49) vs HEx = 54.29 (49.80)]. The relative magnitudes of SNS and PNS indicators did not differ significantly between the first and second bouts of exercise. These results indicate the substantial contribution of vagal withdrawal and catecholamine secretion to the increase in heart rate that occurs during repeated moderate exercise at room temperature and the additional contribution from SNS activity during such exercise in the heat.
Adult↗
Developmental skills of children with spastic diplegia: functional and qualitative changes after selective dorsal rhizotomy.
OBJECTIVE: This study examined changes in muscle tone, passive range of motion, stability, and mobility in developmental skills at 6 months and 1 year after selective dorsal rhizotomy (SDR). DESIGN: Prospective outcome study of a consecutive sample. SETTING: Private children's hospital. PATIENTS: Twenty-six children with spastic diplegia: 13 independent and 13 dependent ambulators (assistive devices). RESULTS: A decrease in spasticity was seen at 6 months after SDR, with no further decrease at 1 year. Increases in passive range of motion of the hip and ankle were seen at 6 months after SDR. The ability to assume and maintain developmental positions with improved alignment and stability was seen more frequently at 6 months after SDR, whereas an improvement in the ability to perform transitional movements was seen more frequently at 1 year after SDR. CONCLUSION: SDR decreases spasticity and increases lower extremity range of motion in children with spastic diplegia and appears to be associated with the ability to assume a greater variety of developmental positions with improved alignment, thus greater stability. Improvements in the ability to perform difficult transitional movements at 1 year after SDR are most likely the result of the combined effect of maturation, SDR, and intensive therapeutic intervention.
Activities of Daily Living↗
Overseas mobility of U.K. based nurses.
This paper examines trends in international mobility of U.K. nurses. Inflow and outflow of qualified nurses from the U.K. are assessed, and source and destination countries identified. The reasons for mobility are also examined. The paper reveals that mobility of nurses to and from the U.K. has declined in the 1990s, after having increased markedly in the late 1980s. Mobility to and from North America and Australasia has reduced significantly, as a result of organisational change and reduced career opportunities, whilst inflow and outflow to and from other European countries has remained more static, but at a lower level.
Adult↗
The safety of fetal pulse oximetry in parturients requiring fetal scalp blood sampling.
OBJECTIVE: To determine whether maternal or fetal morbidity is increased in association with fetal pulse oximetry monitoring using an atraumatic intrapartum transcervical fetal oxisensor. METHODS: In a prospective cohort study from January 1993 to June 1996, 196 fetuses were monitored during the intrapartum period with a fetal oximetry sensor placed between the uterine wall and the presenting fetal part. The oxisensors were in position for a median duration of 134 minutes. A total of 101 monitored fetuses underwent intrapartum fetal scalp blood sampling because of nonreassuring heart rate tracings. For a control group, we selected all cases during the same period in which fetal blood sampling was performed in the intrapartum period (n = 949) without pulse oximetry monitoring. Data for maternal and fetal morbidity were evaluated and tested for significant differences by the Mann-Whitney U test. RESULTS: There was no significant difference in gestational age, birth weight, duration of labor, fetal outcome parameters, cesarean rate, operative vaginal deliveries, episiotomy rate, or perineal injuries between the study and control groups. Similarly, the percentages of neonatal intensive care unit admissions, neonatal resuscitations, and neonatal infections were not statistically different in the two groups. A rare complication in the group with pulse oximetry monitoring was a transient impression of the oxisensor probe on the fetal cheek. The rates of postpartum maternal infections, anemia, or secondary wound disruptions were identical in both groups. CONCLUSION: There was no increased fetal or maternal morbidity associated with the use of an atraumatic intrapartum fetal pulse oxisensor.
Female↗
In vitro effects of glucose polymer-containing peritoneal dialysis fluids on phagocytic activity.
Commercially available peritoneal dialysis fluids (PDFs) are known to impair peritoneal cellular defense mechanisms. We have investigated the influence of glucose polymer-containing PDFs on phagocytic function in vitro. Polymorphonuclear neutrophils (PMNLs) and monocytes (MNs) from 10 continuous ambulatory peritoneal dialysis patients and 10 healthy donors were incubated in PDFs containing either 7.5% icodextrin (glucose polymer) or 1.5% glucose at original pH and pH 7.4. Chemiluminescence response and H202 production were measured following stimulation with preopsonized Staphylococcus epidermidis or phorbol myristate acetate. Phagocytosis of radiolabeled bacteria and killing capacity of the cells were determined. A comparison of the impact of glucose polymer versus glucose-containing solutions at their original pH on the oxidative metabolism of the cells showed a highly significant difference (P < 0.0001) in favor of glucose polymers for H202 production of PMNLs (7.78 +/- 4.5 nmol cytochrome C reduction/10(6) cells/min v 1.11 +/- 0.67 nmol cytochrome C reduction/10(6) cells/min) and MNs (7.66 +/- 3.6 nmol cytochrome C reduction/10(6) cells/min v 1.29 +/- 0.86 nmol cytochrome C reduction/10(6)cells/min). Correspondingly, PMNLs and MNs incubated in glucose polymers showed a significantly higher chemiluminescence response irrespective of the stimulant used (P < 0.0001). Applying the killing assay on PMNLs also revealed a significantly higher percentage of inactivated bacteria (45.5% +/- 11.0% v 29.2% +/- 15.5%; P < 0.05). After adjustment of pH to 7.4, a significant difference could only be found for H202 production of PMNLs in favor of glucose polymers (16.73 +/- 6.98 nmol cytochrome C reduction/10(6) cells/min v 11.65 +/- 5.37 nmol cytochrome C reduction/10(6) cells/min; P < 0.05). In addition, we compared the glucose-polymer solution to an otherwise equally composed equiosmolar solution that contained 0.274% glucose instead of glucose polymers. No significant differences were detected with any of the tests applied. Our data suggest that glucose polymer solutions are comparatively less suppressive to phagocytic function than currently used glucose-containing PDFs. This effect may be attributed to the low osmolarity of these solutions.
Adult↗
Attenuation of the locomotor activating effects of D-amphetamine, cocaine, and scopolamine by potassium channel modulators.
1. Locomotor activating effects of D-amphetamine, cocaine, and scopolamine were determined alone and after pretreatment with K-channel modulators in mice. 2. When administered alone, D-amphetamine (1.0- 30 mg/kg) and cocaine (3.0- 56 mg/kg) produced inverted U-shaped dose-effect curves characteristic of psychomotor stimulant drugs. 3. When administered alone, scopolamine (3.0-56 mg/kg) also produced dose-dependent increases in locomotor activity but these effects plateaued with similar increases in locomotor activity induced by 10-56 mg/kg of scopolamine. 4. Pretreatment with the K-channel blockers 4-aminopyridine (0.3-1.7 mg/kg), quinine (30-100 mg/kg) or apamin (0.3-1.0 mg/kg) attenuated the locomotor increases induced by d-amphetamine, cocaine, and scopolamine. 5. Like the K-channel blockers, pretreatment with the K-channel openers cromakalim (1.0-3.0 mg/kg) and pinacidil (3.0-10 mg/kg) also attenuated the locomotor increases induced by D-amphetamine and scopolamine but did not modify the locomotor activating effects of cocaine. 6. These results demonstrate that K-channel modulation modifies the effects of D-amphetamine, cocaine, and scopolamine. 7. The results also demonstrate that K-channel openers can differentially alter the behavioral effects of cocaine and D-amphetamine.
4-Aminopyridine↗
A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors.
CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level 8 (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T1/2 = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vdss 376 L/m2.
Adult↗
Superoxide, nitric oxide, peroxynitrite and cytokine combinations all cause functional impairment and morphological changes in rat islets of Langerhans and insulin secreting cell lines, but dictate cell death by different mechanisms.
We have shown that nitric oxide treatment for 30-90 min causes inhibition of insulin secretion, DNA damage and disturbs sub-cellular organization in rat and human islets of Langerhans and HIT-T15 cells. Here rat islets and beta-cell lines were treated with various free radical generating systems S-nitrosoglutathione (nitric oxide), xanthine oxidase plus hypoxanthine (reactive oxygen species), 3-morpholinosydnonimine (nitric oxide, super-oxide, peroxynitrite, hydrogen peroxide) and peroxynitrite and their effects over 4 h to 3 days compared with those of the cytokine combination interleukin-1beta, tumour necrosis factor-alpha and interferon-gamma. End points examined were de novo protein synthesis, cellular reducing capacity, morphological changes and apoptosis by acridine orange cytochemistry, DNA gel electrophoresis and electron microscopy. Treatment (24-72 h) with nitric oxide, superoxide, peroxynitrite or combined cytokines differentially decreased redox function and inhibited protein synthesis in rat islets of Langerhans and in insulin-containing cell lines; cytokine effects were arginine and nitric oxide dependent. Peroxynitrite gave rare apoptosis in HIT-T15 cells and superoxide gave none in any cell type, but caused the most beta cell-specific damage in islets. S-nitroso-glutathione was the most effective agent at causing DNA laddering or chromatin margination characteristic of apoptotic cell death in insulin-containing cells. Cytokine-induced apoptosis was observed specifically in islet beta cells, combined cytokine effects on islet function and death most resembled those of the mixed radical donor SIN-1.
Journal Article↗
Nurses' reflections on problems associated with decision-making in critical care settings.
The present study investigated nurses' perceptions of the problems associated with their decision-making in critical care settings. This paper reports a survey of 230 Australian practising critical care nurses. In responses to a set of structured questions concerning various difficulties in making decisions, it was found that between 22 and 56% of nurses reported to be experiencing difficulties on a weekly or more frequent basis "due to knowledge base', "lack of time to make decisions', "lack of time to implement decisions', and "personal values conflicts with other staff'. Nearly one-third (30.3%) of the respondents indicated that they disagreed with other staff who were responsible for making decisions in their units on at least a weekly basis. The nurses were also invited to comment in writing on their concerns in a variety of areas. Major sources of nurse dissatisfaction included: treatment decisions for patients with poor prognoses; disharmony with medical staff concerning decision autonomy issues, especially with junior doctors; time constraints on nursing care: the demands of new intensive care technology upon the nurses' knowledge bases; and the need for in-service education to address this problem. The paper concludes with arguments for the use of in-depth interviews to further study these issues.
Adult↗
Replacement of isoleucine-47 by threonine in the HPr protein of Streptococcus salivarius abrogates the preferential metabolism of glucose and fructose over lactose and melibiose but does not prevent the phosphorylation of HPr on serine-46.
Phosphorylation of HPr on a serine residue at position 46 (Ser-46) by an ATP-dependent protein kinase has been reported in several Gram-positive bacteria, and the resulting intermediate, HPr(Ser-P), has been shown to mediate inducer exclusion in lactococci and lactobacilli and catabolite repression in Bacillus subtilis and Bacillus megaterium. We report here the phenotypic properties of an isogenic spontaneous mutant (G22.4) of Streptococcus salivarius ATCC 25975, in which a missense mutation results in the replacement of isoleucine at position 47 (Ile-47) by threonine (Thr) in HPr. This substitution did not prevent the phosphorylation of HPr on Ser-46, nor did it impede the phosphorylation of HPr on His-15 by EI or the transfer of the phosphoryl group from HPr(His-P) to other PTS proteins. However, the 147T substitution did perturb, in glucose-grown but not in galactose-grown cells, the cellular equilibrium between the various forms of HPr, resulting in an increase in the amount of free HPr at the expense of HPr(His-P)(Ser-P); the levels of HPr(His-P) and HPr(Ser-P) were not affected. Growth on melibiose was virtually identical for the wild-type and mutant strains, whereas the generation time of the mutant on the other sugars tested (glucose, fructose, mannose, lactose and galactose) increased 1.2- to 1.5-fold. The preferential metabolism of PTS sugars (glucose and fructose) over non-PTS sugars (lactose and melibiose) that is observed in wild-type cells was abolished in cells of mutant G22.4. Moreover, alpha- and beta-galactosidases were derepressed in glucose- and fructose-grown cells of the mutant. The data suggest that HPr regulates the preferential metabolism of PTS sugars over the non-PTS sugars, lactose and melibiose, through the repression of the pertinent catabolic genes. This HPr-dependent repression, however, seems to occur solely when cells are growing on a PTS sugar.
Adenosine Triphosphate↗
Angiotensin II-receptor blockade further reduces afterload safely in patients maximally treated with angiotensin-converting enzyme inhibitors for heart failure.
Combined therapy with an angiotensin-II type I receptor (AT1) antagonist and an angiotensin-converting enzyme (ACE) inhibitor results in more complete suppression of the renin-angiotensin system. Accordingly, the blood-pressure response and safety of combining AT1-receptor blockade with losartan for ACE inhibition were evaluated in patients with congestive heart failure who were already treated with maximally recommended or tolerated doses of an ACE inhibitor. Forty-three patients with symptomatic congestive heart failure were evaluated biweekly for 1 month before addition of losartan and weekly during administration of losartan at a daily dose of 25 mg for the first week and 50 mg for the second week. Systolic blood pressure, which remained unchanged before addition of losartan, decreased from 122 +/- 18 mm Hg to 112 +/- 17 and 107 +/- 17 mm Hg (p < 0.001) after 1 week of 25 mg and 1 week of 50 mg losartan, respectively. Diastolic blood pressure also significantly decreased. The decreases in blood pressure were well tolerated by all patients, even by those in whom symptomatic hypotension developed during uptitration of ACE inhibition. Serum potassium and sodium and parameters of renal function remained unchanged. Combining AT1-receptor blockade with losartan to maximally recommended or tolerated ACE inhibition appears safe and leads to further vasodilatation in symptomatic patients with congestive heart failure.
Aged↗