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Biomedical subjects

R Knight

Publications and source records attributed to R Knight.

At least 19 recordsLinked to original sources
PubMed1992

Changing perspective on gastrointestinal complications in patients undergoing cardiac surgery.

There has been a documented shift towards increasing age and severity of illness in the patient population undergoing cardiac surgery. To determine if there was a coincident change in frequency, gastrointestinal (GI) complications were prospectively recorded in a consecutive series of 5,438 patients undergoing cardiac surgery from 1983 to 1991. There were 73 complications in 69 patients (incidence = 1.4%) defined as any GI condition that required transfer to an acute care unit, surgical intervention, blood transfusion, or treatment that prolonged the hospital course. Fourteen patients died, a mortality rate of 20% for patients with GI complications (p less than 0.001 versus patients without GI complications). The most frequent complications were those of gastric ulceration despite routine use of H2-receptor blocking agents. Thirty-six patients had upper GI (UGI) bleeding from gastric ulceration with 4 patients requiring operative intervention to control hemorrhage and 6 fatalities in patients with UGI bleeding. Two additional patients died of septic complications following gastroduodenal perforation or penetration. Six patients experienced bowel obstruction or prolonged bowel dysfunction (three Ogilvie's syndrome) with two requiring laparotomy. There were four cases of cholecystitis, two cases of pancreatitis, and the remaining cases were equally divided among common septic complications (diverticulitis and ischemic injury among others). Three patients with massive intestinal infarction died. GI complications were significantly associated with older patients (p less than 0.01) and valve surgery (p = 0.002) but were not more common in women. When considered as a separate group, patients with acid-peptic complications had longer perfusion times, increased use of vasopressors, and more frequent utilization of the intra-aortic balloon pump. In contrast to prior studies, this investigation indicates that GI complications associated with acid-peptic erosion of the UGI tract tend to occur in a different patient group than those with other GI complications. Older patients and/or those with a prior history of peptic ulcer symptoms, as well as those who experience prolonged perfusion times, low cardiac output, or prolonged ventilatory support, should be under rigorous gastric pH surveillance and receive aggressive prophylactic treatment with high-dose H2 antagonists, antacids, and/or sucralfate.

Aged↗
PubMed1992

Pharmacokinetic strategies for cyclosporin therapy in organ transplantation.

Marked interindividual variations in cyclosporin (CsA) produce disparate clinical results in organ transplant recipients. In an attempt to eliminate marked deviations of insufficient or excessive CsA concentrations consequent to the administration of uniform drug doses, test dose pharmacokinetics were performed on each potential organ transplant candidate. An intravenous 3 mg/kg test dose delivered over 3 h proved to be readily performed, namely 53% perfect studies, and relatively reliable, namely 73% of observed concentrations within 10% of the predicted values. Furthermore, the use of CsA doses predicted by pretransplant studies reduces the incidence of delayed graft function, early rejection episodes and transplant loss. The oral test dose study predicted a suitable amount of CsA to achieve sufficient gastrointestinal absorption but was less accurate than the iv prediction method: namely, 40% of observed post-transplant concentrations were within 10% of the predicted target value. Furthermore, patients who received oral doses predicted by the test dose strategy showed no improvement in the incidence of acute rejection episodes between 7 and 60 days, and only modestly improved serum creatinine values. The lower accuracy of predictions from oral test dose studies may reflect the impact of non-linear oral (as opposed to iv) drug pharmacokinetics, of variable diet, and/or of altered postoperative gastrointestinal function.

Administration, Oral↗
PubMed1992

A trial of the prostaglandin E1 analogue, enisoprost, to reverse chronic cyclosporine-associated renal dysfunction.

Cyclosporine (CYA) reduces the renal synthesis of prostaglandins of the E series (PGE). Analogue of PGE1 have been shown to mitigate the vasoconstriction and abnormal renal function of experimental acute CYA nephrotoxicity. We examined the hypothesis that the orally bioavailable PGE analogue enisoprost (EP) would improve renal function in renal transplant recipients chronically exposed to CYA. In a randomized double-blind study, 40 patients at two centers who were being monitored for 3 to 30 months after renal transplantation, were allocated to receive either EP 100 micrograms orally four times daily or placebo (P) for 2 weeks. CYA dosing was fixed at existing levels. There could be no evidence of concurrent acute renal injury, including that of acute rejection. Glomerular filtration rate (GFR) was measured by the clearance of radiolabeled DTPA, while effective renal plasma flow (ERPF) was measured as the clearance of p-aminohippuric acid (PAH). The acute effects of EP were examined twice, by comparing immediate postdose to predose values for GFR and ERPF on day 1 and again on day 14. Chronic effects were examined by comparing baseline (predose) values only for GFR and ERPF between days 1 and 14 and by an examination of creatinine clearances (CCR) on days 0, 14, and 21. At enrollment, patients were well matched for renal function (CCR:EP 47 +/- 5 v P 49 +/- 4 mL/min/1.73 m2; P = NS). Baseline demographics were similar, although patients treated with EP were older (46 +/- 2 v 36 +/- 3 years, mean +/- SEM, P = 0.003). CYA doses and blood levels did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The ability of pretransplant test-dose pharmacokinetic profiles to reduce early adverse events after renal transplantation.

Pretransplant test-dose pharmacokinetic profiles were used to determine individual cyclosporine drug bioavailability and clearance rates in renal transplant patients. Assuming a linear relation between dose and area under the concentration curve (AUC), starting i.v. and p.o. CsA doses were computed from the test-dose results. Target values were 400 ng/ml steady-state concentration (Css) during continuous intravenous infusion, and 500 ng/ml average drug concentration (Cavss = AUC/dosing interval) after oral administration, based upon measurements with the specific monoclonal antibody 3H-tracer radioimmunoassay. The outcomes after dose individualization with a 1-(n = 32), 2-(n = 38), or 3-(n = 41) hr i.v. infusion test dose and a p.o. test dose (n = 111) were compared with 228 historical control patients who received a uniform protocol of CsA i.v. at 2.5 mg/kg/day and p.o. at 14 mg/kg/day. The observed Css after i.v. CsA was within 10% of the target concentration in 73% of recipients tested with the 3-hr protocol, a significantly greater fraction than achieved with either the uniform dose (14%), or the 1-(34%) and 2-(25%) hr protocols. Patients in the 3-hr protocol group showed reduced incidences of delayed graft function, early graft loss, and rejection episodes, and a lower mean serum creatinine value, particularly at 7 but also at 30 days posttransplantation. Administration of the predicted oral dose produced a peak concentration of greater than or equal to 700 ng/ml drug absorption in 60% of recipients at 3 days, 90% at 5 days, and 98% at 7 days. The test-dose method less effectively predicted the appropriate oral CsA dose to produce target Cssav and failed to reduce the 90-day rejection incidence. Despite its limitations with the more-complicated p.o. route, the test-dose method successfully predicts i.v. CsA doses, thereby reducing the incidence of early adverse events.

Administration, Oral↗
PubMed1992

Protozoan infections and HIV-1 infection: a review.

Reactivation of latent infection is the principal mechanism relating Toxoplasma gondii and Pneumocystis carinii to HIV. Less common is reactivation in Leishmania donovani, Trypanosoma cruzi, and microsporidian infections. An impaired primary immune response occurs in all these infections, and also with Cryptosporidium and Isospora belli. Association of HIV infection with gut parasites including Giardia lamblia and Entamoeba histolytica, and also with Trichomonas vaginalis infection is likely to be related to sexual modes of contact that favour both HIV and the parasite. The severity of malaria is not definitely associated with HIV, but Plasmodium falciparum infection may favour more rapid evolution of the HIV infection. Both malaria and trichomoniasis favour HIV transmission; the former by necessitating blood transfusion, and the latter by enhancing viral transmission during sexual contact.

AIDS-Related Opportunistic Infections↗
PubMed1991

Simple empirical assessment of beta-cell function by a constant infusion of glucose test in normal and type 2 (non-insulin-dependent) diabetic subjects.

The plasma insulin or C-peptide response to a 90-min constant glucose infusion 5 mg.kg ideal body weight-1.min-1 provides Beta-cell assessment comparable to more intensive methods. In 14 diet-treated Type 2 (non-insulin-dependent) diabetic subjects and 12 non-diabetic subjects, plasma insulin and C-peptide concentrations gave near linear plots against simultaneous glucose values. The 'glucose-insulin and glucose-C-peptide vectors' (G-I and G-C vectors), could be extrapolated to predict insulin and C-peptide levels during a 12 mmol/l hyperglycaemic clamp. Predicted concentrations correlated with clamp concentrations, r = 0.94 and r = 0.98 respectively, p less than 0.001, validating the vectors as empirical glucose dose-response curves. The vector slopes correlated highly with %Beta, a mathematical model-derived measure of Beta-cell function using constant infusion of glucose model assessment, Spearman r = 0.95 and 0.93 for insulin and C-peptide, respectively. G-I vector slopes in 21 diet-treated Type 2 diabetic subjects with fasting glucose (mean + 1 SD) 7.5 +/- 2.3 mmol/l, were lower than in 28 non-diabetic subjects, (geometric mean, 1 SD range, 8.4 pmol/mmol (3.3-21.0) and 25.1 pmol/mmol (14.3-44.1), p less than 0.001, respectively), indicating an impaired Beta-cell response. The G-I vector slopes correlated with obesity in both groups (r = 0.54 p less than 0.02 and 0.72, p less than 0.001 respectively), and, in 15 non-diabetic subjects, correlated inversely with insulin sensitivity as measured by a euglycaemic clamp (r = -0.66, p less than 0.01). Thus, Beta-cell function needs to be interpreted in relation to obesity/insulin resistance and, taking obesity into account, only 4 of 21 diabetic patients had Beta-cell function (G-I vector slope) in the non-diabetic range. The fasting plasma glucose in the diabetic subjects correlated inversely with the obesity-corrected G-I and G-C vector slopes (partial r = -0.57, p less than 0.01 and -0.86, p less than 0.001, respectively). The insulin or C-peptide response to the glucose infusion provides a direct empirical measure of the Beta-cell function, which can be interpreted in relation to obesity or to insulin resistance to assess underlying pancreatic responsiveness.

Blood Glucose↗
PubMed1991

Chronic changes in the brain Mg2+ concentration after forebrain ischemia in the rat.

Brain Mg2+ ion concentrations, [Mg2+], were evaluated in three groups of animals subjected to either 8 minutes (n = 10), or 12 minutes (n = 10) of near-complete forebrain ischemia, or sham operation (n = 10), from their 31P NMR spectra. No significant differences were observed in [Mg2+] among sham operated animals prior to or at any time point after surgery. In the 8-min ischemia group, mean [Mg2+] were significantly lower at 48 (0.28 +/- 0.06 mM, p = 0.014) and 72 (0.29 +/- 0.07 mM, p = 0.005) hours post-ischemia when compared to their mean pre-ischemia levels (0.39 +/- 0.08 mM). [Mg2+] was restored to pre-ischemia values at 96 hours after induction of ischemia. In the 12 min ischemia group, [Mg2+] were lower at all time points post-ischemia when compared to their pre-ischemia levels. Our data shows that forebrain ischemia causes a chronic decline of cerebral Mg2+ concentration, and the observed reduction of this cation can be partially attributed to concurrent brain tissue alkalosis.

Animals↗
PubMed1991

Test-additivity experiments: different procedures, different results.

Test-additivity experiments reveal the combination rules for separate contributions to visual detection. The measured degree of additivity and the shape and symmetry of the additivity function have been used to design or evaluate theories about the underlying visual pathways. However, all these characteristics can be distorted if measured by means of a variable-proportion procedure, in which the amount of one primary is held constant while the amount of the other is varied in order to measure threshold. A fixed-proportion procedure, in which the amounts of each primary are varied together in constant proportion in order to measure threshold, is preferable. These differences in results were found by using the method of adjustment but may also apply to the method of limits and other psychophysical procedures.

Color Perception↗
PubMed1991

A mutation in the second nucleotide binding fold of the cystic fibrosis gene.

The discovery last year of the deletion of a phenylalanine residue at amino acid position 508 of the cystic fibrosis (CF) gene has meant that approximately 70% of mutant chromosomes associated with CF can be accounted for. We report the finding of a substitution at nucleotide position 4041 of the CF gene, resulting in a change from asparagine to lysine at amino acid position 1303. We believe that this is a disease-causing mutation, as it involves a nonconservative amino acid change and has only been found on CF chromosomes with a consistent haplotype background. The mutation was detected using direct sequencing of PCR-amplified genomic DNA and was confirmed by dot hybridization to both normal and mutant allele-specific oligonucleotides. The mutation was detected on three chromosomes from four individuals but not on any normal chromosome. Its presence in the heterozygous state is not correlated with the clinical status of the individual patients.

Adult↗
PubMed1991

Effects of experimental sarin intoxication on the morphology of the mouse diaphragm: a light and electron microscopical study.

A sublethal dose of sarin (GB, isopropyl methylphosphonofluoridate) was administered to mice. The animals were killed up to 28 days after dosing. Following excision, diaphragms were divided into two halves and used for ultrastructural examination and light microscopy. Planar sections of diaphragm showed muscle fibre degeneration and predominantly mononuclear infiltration, notably at 24 h. Semithin toluidine blue-stained sections and ultrastructural studies demonstrated hypercontraction with gross disruption of sarcomeres including loss of Z and A bands, which appeared to be associated with neuromuscular junctions. All changes were rapidly regressing by 7 days.

Animals↗
PubMed1990

Comparison of bretylium and lidocaine in the prevention of ventricular fibrillation after aortic cross-clamp release in coronary artery bypass surgery.

The authors compared bretylium and lidocaine for reducing the incidence and persistence of ventricular fibrillation following aortic cross-clamp release performed during coronary artery bypass surgery. Thirty-three adult patients scheduled for elective bypass surgery were randomly assigned in a double-blind fashion to receive a bolus of bretylium, 10 mg/kg, lidocaine, 2 mg/kg, or saline, in equal volumes prior to the release of the aortic cross-clamp. Coronary artery bypass surgery was conducted using standard cardiopulmonary bypass (CPB) procedures with systemic cooling to 24 degrees to 28 degrees C. Temperature, arterial blood gases, and electrolytes were recorded. After clamp release, the first electrical rhythm was noted. Abnormal rhythms (ventricular fibrillation) were allowed to persist for 1 to 2 minutes, and if spontaneous conversion to a supraventricular rhythm did not occur, defibrillation with internal DC countershocks was applied. Patients were compared with respect to occurrence of ventricular fibrillation, need for DC countershocks, antiarrhythmic drugs, and inotropic support. There was no significant difference among the groups with respect to age, sex, preoperative medications, past medical histories, ejection fractions, average number of bypasses, cross-clamp times, or temperatures during bypass. The incidence of ventricular fibrillation after aortic cross-clamp removal was: saline 91%, lidocaine 64% (P less than 0.01), and bretylium 36% (P less than 0.01). The number of countershocks required to defibrillate, while lower in the bretylium group, did not reach statistical significance. After cardiopulmonary bypass, cardiac output and systemic vascular resistance were comparable. Bretylium warrants further study in this setting.

Aged↗
PubMed1990

Geographical distribution of cases of Creutzfeldt-Jakob disease in England and Wales 1970-84.

Two hundred and sixty seven patients with a definite or probable diagnosis of Creutzfeldt-Jakob disease (CJD) were identified in an attempt to ascertain all cases of the disease in England and Wales in the period 1970-84. No evidence of space-time clustering of dates and places of onset was found for these cases. Two age- and sex-matched controls were selected for 72 of the 122 cases diagnosed in the period 1980-84 and life histories of places of residence were obtained for these cases and the controls. No evidence was found that cases had lived closer to each other than had controls at any time in their lives, except that there was an excess of cases born in London. The study does not provide supportive evidence for case-to-case transmission of CJD being an important component in the aetiology of the disease.

Adult↗
PubMed1990

Chronic cerebral intracellular alkalosis following forebrain ischemic insult in rats.

We measured cerebral intracellular pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy during 1 week after forebrain ischemia or sham operation in eight and seven rats, respectively. Mean maximum pH was significantly higher (p less than 0.003) in the ischemic group than in the sham-operated group (7.34 +/- 0.03 and 7.19 +/- 0.02, respectively). The difference between mean maximum pH and baseline pH (7.08 +/- 0.01 in each group) was significantly greater (p less than 0.02) in the ischemic group than in the sham-operated group. In the ischemic group, alkalosis occurred primarily after 48-72 hours of recirculation. We speculate that brain tissue alkalosis occurring chronically after ischemia is associated with delayed ischemic neuronal death.

Alkalosis↗
PubMed1989

Percutaneous toxicity of ethylene glycol monomethyl ether and of dipropylene glycol monomethyl ether in the rat.

The subacute percutaneous toxicity of dipropylene glycol monomethyl ether (DPM) in male rats dosed 5 days/week for 4 weeks under both occluded and unoccluded conditions has been assessed and compared to the percutaneous toxicity of ethylene glycol monomethyl ether (EGM). DPM caused no significant changes in the clinical chemistry, haematology, or pathology, whereas EGM caused changes in the haematology and clinical chemistry, and both testicular and bone marrow damage at doses of 1000 mg/kg per day.

Administration, Topical↗
PubMed1989

The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat: comparison to normothermia and hyperthermia.

The metabolic effects of graded whole body hypothermia on complete global cerebral ischemia and recirculation was investigated in the cat. Hypothermia was induced to one of three levels prior to ischemia; T = 26.8 degrees +/- 0.5 degrees C (n = 4), T = 32.1 degrees +/- 0.2 degrees C (n = 5), and T = 34.6 degrees +/- 0.3 degrees C (n = 6), and maintained constant throughout 16 min of ischemia and 1.5-2 h of recirculation. Intracellular cerebral pH and relative concentrations of high-energy phosphate metabolites were continuously monitored, using in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. Except for the first 4 min of ischemia, no significant differences were detected in the response of adenylate intensities and intracellular pH to ischemia and recirculation between the hypothermic groups. The three hypothermic groups were then pooled into one group, and the data compared to previously published data from a normothermic group, T = 38.4 degrees +/- 0.6 degrees C (n = 14), and a hyperthermic group, T = 40.6 degrees +/- 0.2 degrees C (n = 9), subjected to the identical ischemic and NMR measurement protocols. The hypothermic animals exhibited a statistically significant reduction of cerebral intracellular acidosis, both during ischemia and recirculation, as well as a more rapid return of adenylate intensities during recirculation, compared to the normothermic or hyperthermic groups. The data thus suggest that mild hypothermia has an ameliorative affect on brain energy metabolism and intracellular pH under conditions of complete global cerebral ischemia and recirculation.

Animals↗