Studies on autoantibodies to poly (adenosine diphosphate-ribose) in SLE and other autoimmune diseases.

Sera from 41 patients with systemic lupus erythematosus (SLE), 87 controls with various diseases, and 30 normal subjects were examined for poly (adenosine diphosphate-ribose) and ds DNA binding. Elevated levels of poly (ADP-ribose) binding were found in 73% of the SLE patients compared with 58% who had raised ds DNA binding. In a further study of 160 sera from 27 patients with SLE, levels of antipoly (ADP-ribose) antibodies were shown to correlate with clinical activity better than either anti-ds DNA or ss DNA antibodies.     

Emergency peripartum hysterectomy in a tertiary London hospital

Objective The objective was to review all emergency peripartum hysterectomies performed at a tertiary hospital in London, UK, and to identify the risk factors for emergency peripartum hysterectomy.Method A retrospective case control study. The cases consisted of all women who had emergency peripartum hysterectomy between 1 January 1993 and 31 December 2003. Controls were women who delivered immediately before and after the indexed case. Demographic data, medical and surgical histories, pregnancy, intrapartum and postpartum data were collected. Differences between cases and controls were compared with ², Fisher exact and Student t tests. Multiple logistic regression analysis was performed to identify independent risk factors for emergency peripartum hysterectomy.Results There were 15 cases of emergency peripartum hysterectomy in 31,079 deliveries, giving a rate of 0.48 per 1,000. Women who had emergency peripartum hysterectomy were significantly older (mean age 37 years vs. 29 years, P<0.001) and multiparous (P=0.02). More of the cases had a history of uterine surgery (67 vs. 30%, P=0.01), placenta praevia (60 vs. 3%, P<0.0001) and were delivered by caesarean section (86.7 vs. 30%, P=0.003). Eighty percent of the hysterectomies were performed in the daytime and all were done by consultants. Haemorrhage due to placenta praevia was the main indication for emergency peripartum hysterectomy (47%). Independent risk factors for emergency peripartum hysterectomy were older age (odds ratios [OR] 1.2, 95% confidence interval [95% CI] 1.2–1.6), multiparity (OR 2.6, 95% CI 1.3–10.2), history of previous caesarean section (OR 13.5, 95% CI 2.7–65.4), caesarean delivery in index pregnancy (OR 11.6, 95% CI 2.1–68.6) and caesarean delivery in index pregnancy for placenta praevia (OR 18, 95% CI 3.6–69).Conclusion Caesarean deliveries, especially repeat caesareans in women with placenta praevia, significantly increase the risk of emergency peripartum hysterectomy.     

Effects of sub-chronic oral cyanide on endothelial function in rabbit aortic rings

We have investigated how the endothelium affects vascular responses following sub-chronic low dose cyanide administration. Cyanide exists in low levels in cassava foods, which are widely consumed in tropical Africa. Adult rabbits were administered 0.38 mg/kg per day KCN po for 25 days, and responses of the isolated aortic rings to noradrenaline (NA), calcium chloride (Ca2+) and acetylcholine (ACh) were measured in vitro in the presence and absence of the endothelium. In order to establish that the dose was not toxic, animal weight, some haematological indices, plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. Results show that endothelium denudation significantly (P <0.05) attenuates NA-induced contraction in rings from cyanide-treated rabbits. There was a similar reduction in response in Ca2+-depleted NA-precontracted endothelium-denuded aortic rings from cyanide-treated rabbits. Endothelium-denuded rings from cyanide-treated rabbits showed significantly (P <0.05) enhanced relaxation to ACh. In rings from control animals, the responses to NA and Ca2+ were not significantly altered, whether in the presence or absence of the endothelium. There were no significant changes in the studied toxicological indices. We conclude that endothelial compromise is necessary for low-dose sub-chronic cyanide-induced to alter vascular reactivity to NA and ACh.     

Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist

Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.5 to 8 mg. A total of 6,834 taranabant plasma concentrations from 187 healthy and 385 obese subjects were used to develop the population model in NONMEM. A standard covariate analysis using forward selection (α = 0.05) and backward elimination (α = 0.001) was conducted. A three-compartment model with first-order absorption and elimination adequately described plasma taranabant concentrations. The population mean estimates for apparent clearance and apparent steady-state volume of distribution were 25.4 L/h and 2,578 L, respectively. Statistically significant covariate effects were modest in magnitude and not considered clinically relevant (the effects of body mass index (BMI) and creatinine clearance (CrCL) on apparent clearance; BMI, age, CrCL, and gender on apparent volume of the peripheral compartment and age on apparent intercompartmental clearance). The pharmacokinetic profile of taranabant can adequately be described by a three-compartment model with first-order absorption and elimination. Clinical dose adjustment based on covariates effects is not warranted.Key words: NONMEM, obesity, pharmacokinetics, population, taranabant     

Mutation analysis and description of sixteen RSH/Smith‐Lemli‐Opitz syndrome patients: Polymerase chain reaction–based assays to simplify genotyping

We report the clinical and molecular data of 16 patients with RSH/Smith‐Lemli‐Opitz syndrome (RSH/SLOS) with varying phenotypic severity, for which we have identified mutations in both alleles. RSH/SLOS is an autosomal recessive malformation syndrome caused by mutations in the gene encoding the sterol Δ⁷‐reductase. This protein catalyzes the reduction of 7‐dehydrocholesterol to cholesterol in the last step of cholesterol biosynthesis via the Kandutsch‐Russell pathway. In addition to previously reported mutations (T93M, L109P, G147D, W151X, T154M, R242C, A247V, T289I, IVS8‐1G→C, Y408H, and E448K), we have identified six previously undescribed mutations (321G→C, W177R, R242H, Y318N, L341P, and C444Y). We also report rapid polymerase chain reaction (PCR)–based assays developed to detect four of the recurring mutations (T93M, W151X, V326L, and R404C) and six other RSH/SLOS mutations (321G→C, L109P, T154M, T289I, Y318N, and L341P). The purpose of this article is to correlate detailed clinical information with molecular data in order to improve our understanding of the genotype–phenotype correlation of RSH/SLOS and to report the development of PCR‐based assays that will allow more rapid mutation analysis. Am. J. Med. Genet. 94:214–227, 2000. Published 2000 Wiley‐Liss, Inc.     

Caregiver–proxy reliability of the Igbo-culture adapted Maleka Stroke Community Reintegration Measure: a validation study

Objectives: This study was designed to determine the caregiver–proxy reliability of the Igbo-culture adapted urban version of the Maleka Stroke Community Reintegration Measure (I-MSCRIM).

Methods: This was a validation study involving 74 consenting stroke survivors and their 74 primary informal caregivers consecutively recruited from selected tertiary hospitals in South-East Nigeria (Igboland). The I-MSCRIM was researcher-administered to the participants. Obtained data was analyzed using frequency counts, percentages, range, mean, standard deviation, Spearman rank order correlation, Mann–Whitney U test, Kruskal–Wallis test and Intra-class Correlation Coefficient. Alpha level was set at 0.05.

Results: The mean ages of the stroke survivors (55.4% males) and their primary informal caregivers (41.9% males) were 50.14 ± 12.24 and 31.93 ± 10.9 years respectively. There was no significant difference in the community reintegration (CR) scores as rated by stroke survivors and their primary informal caregivers (p > 0.05). The correlations between stroke survivors’ and primary informal caregivers’ rated CR scores were all adequate and acceptable (ICC = 0.602–0.917). The discrepancy in the total CR scores between the two ratings was significantly influenced by primary informal caregivers’ educational attainment (k = 13.15; p < 0.01).

Conclusion: The I-MSCRIM has acceptable caregiver–proxy reliability among Igbo stroke survivors in South-East Nigeria. This suggests that primary informal caregivers of stroke survivors can reliably estimate the CR of their care recipients when I-MSCRIM is administered to them. This will be useful when a stroke survivor cannot respond to I-MSCRIM.     

<Emphasis Type="Italic">In-vitro</Emphasis> evaluation of antioxidant potential of <Emphasis Type="Italic">rauwolfia vomitoria</Emphasis> root extract and its inhibitory effect on lipid peroxidation as indication of aphrodisiac properties

Rauwolfia vomitoria (RV) Afzel (Apocynaceae) is a medicinal plant used in traditional medicinal practice for the treatment of hypertension. This research is devoted to phytochemical constituents, in particular, some specific alkaloids present in the RV root extract. The phytochemical evaluation revealed the presence of alkaloids, tannins, saponins, and flavonoids in this extract. The antioxidant activity of the RV root extract was also evaluated in a series of in vitro assays involving free radicals. The extract exhibited significant hydrogen peroxide scavenging effect relative to ascorbic acid (p < 0.05, IC₅₀ = 98 μg/ml), nitric oxide scavenging effect (50.37 ± 0.4% after 150 min), and metal chelating activity (89.08 ± 2.62%). In addition, it exhibited significant ferric reducing power relative to ascorbic acid (p < 0.05). The total content of phenolic substances was 233.3 ± 2.9 mg/g. The extract was also studied for its inhibitory capacity on lipid peroxidation as a possible mechanism of its aphrodisiac effect, by measuring thiobarbituric acid reactive substances in various male-cow tissues incubated in a 5% solution of the RV root extract, distilled water, and antioxidant vitamins C and E upon keeping the samples frozen for 35 days. Tissues incubated in the test solution had lower levels of malondialdehyde (MDA) compared to those in the samples incubated in distilled water. Results obtained from this study indicate that the RV root extract can be a potential source of natural antioxidants.