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Biomedical subjects

M Richer

Publications and source records attributed to M Richer.

17 recordsLinked to original sources
PubMed2001

Re-emergence of epidemic sleeping sickness in southern Sudan.

A resurgence of sleeping sickness developed in southern Sudan during the past decade. Prevalence of confirmed Trypanosoma brucei gambiense infection in humans now exceeds 5% in several foci. From 1997 to 1999, trypanosomiasis control programmes in three counties of Western Equatoria Province detected 3785 new cases among 67 181 persons screened. A major contributing factor in the re-emergence of epidemic sleeping sickness was the lack of active case-finding throughout the 1990s. Although the situation is improving in sites where trypanosomiasis programmes have been recently implemented, co-ordination and additional international assistance are needed to bring sleeping sickness under control in Sudan.

Animals↗
PubMed2001

Developmental gene expression in Bacillus subtilis crsA47 mutants reveals glucose-activated control of the gene for the minor sigma factor sigma(H).

The presence of excess glucose in growth media prevents normal sporulation of Bacillus subtilis. The crsA47 mutation, located in the gene for the vegetative phase sigma factor (sigma(A)) results in a glucose-resistant sporulation phenotype. As part of a study of the mechanisms whereby the mutation in sigma(A) overcomes glucose repression of sporulation, we examined the expression of genes involved in sporulation initiation in the crsA47 background. The crsA47 mutation had a significant impact on a variety of genes. Changes to stage II gene expression could be linked to alterations in the expression of the sinI and sinR genes. In addition, there was a dramatic increase in the expression of genes dependent on the minor sigma factor sigma(H). This latter change was paralleled by the pattern of spo0H gene transcription in cells with the crsA47 mutation. In vitro analysis of RNA polymerase containing sigma(A47) indicated that it did not have unusually high affinity for the spo0H gene promoter. The in vivo pattern of spo0H expression is not predicted by the known regulatory constraints on spo0H and suggests novel regulation mechanisms that are revealed in the crsA47 background.

Bacillus subtilis↗
PubMed1999

Resurgence of sleeping sickness in Tambura County, Sudan.

Endemic foci of human African trypanosomiasis are present in southern Sudan. In 1996 and 1997, trypanosomiasis increased sharply in Tambura County. To define the magnitude and geographic distribution of the outbreak, we conducted a prevalence survey using population-based cluster sampling in 16 villages: 1,358 participants answered questions about routine activities and tsetse fly contact and received serologic testing. Seroprevalence in the surveyed area was 19.4% (95% confidence interval = 16.9%, 21.8%). We confirmed infection in 66% of seropositive persons who received one parasitologic examination and in 95% of those who had serial examinations of lymph node fluid and blood. Activities related to the civil war, such as temporary migration, were not associated with seropositive status. Since the previous population screening in 1988, the trypanosomiasis prevalence increased two orders of magnitude, and the proportion of villages affected increased from 54% to 100%. Our results suggest that there may be 5,000 cases in Tambura County. The absence of trypanosomiasis control for nearly a decade is a factor in the resurgence of the disease.

Adolescent↗
PubMed1998

Characterization of the cytotoxic factor(s) released from thymic dendritic cells upon human immunodeficiency virus type 1 infection.

We previously demonstrated that infection of primary human thymic dendritic cells (DCs) with laboratory strains of HIV leads to the release of soluble factor(s) which induced thymocyte killing. In the present paper, we extend the characterization of this process. Our results reveal that primary HIV-1 isolates are similarly able to induce the production of cytotoxic factor(s) from thymic DCs and that the release of such factor(s) is dependent on viral infection. Interestingly, we observed that CD4+ and CD8+ purified thymocyte subsets, and activated PBMCs are susceptible to the cytotoxic activity, whereas freshly isolated resting PBMCs are resistant to this effect. Cycloheximide treatment prevents the killing of thymocytes exposed to HIV-infected DC supernatant, revealing that this form of cell death is an active biological process requiring protein synthesis. Finally, our data suggest that FasL and TNF alpha could both participate in the killing process. These in vitro observations provide a plausible model, whereby HIV-infected DCs can play a role in vivo in the induction of uninfected thymocyte killing.

Animals↗
PubMed1998

Evaluation of the role of neurolinins and urecholine hypersensitivity in an animal model of infravesical outflow obstruction.

OBJECTIVES: To determine whether detrusor muscle strips from a male rat with infravesical outflow obstruction model demonstrate supersensitivity to parasympathomimetic and neurokinin NK-1 and NK-2 selective agonists. METHODS: Bladder instability developed after 6 weeks of partial urethral obstruction. The micturition frequency and voided volume were determined in unanesthetized animals. Detrusor hypertrophy was confirmed by evaluation of bladder weight. In vitro organ bath was used to compare the affinity and maximal activity of bethanechol and neurokinin NK-1 and NK-2 selective agonists on strips from the detrusor muscle of sham and obstructed rats. Bethanechol, N-Ac[Arg6, Sar9, Met(O2)]-SP(6-11), and [beta-Ala8]-NKA(4-10) were used to characterize cholinergic muscarinic, neurokinin NK-1 and NK-2 receptors. Results. No significant differences in affinities and maximal responses were found using 10-mg detrusor muscle strips with each of the three agonists. CONCLUSIONS: Bladder instability produced by outlet obstruction does not involve changes in the affinity or maximal activity of cholinergic muscarinic, neurokinin NK-1 and NK-2 receptors. Furthermore, detrusor supersensitivity to neurokinins or bethanechol was not seen. This suggests that bladder instability is not due to an increased affinity or maximal response to neurokinins or parasympathomimetics.

Animals↗
PubMed1996

Renal hemodynamics during norepinephrine and low-dose dopamine infusions in man.

OBJECTIVE: To characterize the effects of pressor doses of norepinephrine and low-dose dopamine (3 micrograms/kg/min) on renal hemodynamics in man, as well as to determine the clinical relevance of combining dopamine with norepinephrine. DESIGN: Prospective, single-blind, randomized study. SETTING: Clinical research unit of a tertiary care hospital. SUBJECTS. Six healthy male volunteers ranging in age between 20 and 28 yrs. INTERVENTIONS: The subjects were assigned randomly to four treatments (1 wk apart) in which renal hemodynamics and electrolyte excretion were assessed. Treatments consisted of 180-min infusions of the following: a) 0.9% sodium chloride (control); b) pressor doses of norepinephrine; c) dopamine at 3 micrograms/kg/min; and d) pressor doses of norepinephrine and dopamine at 3 micrograms/kg/min. Pressor doses of norepinephrine was defined as doses required to increase mean arterial pressure (MAP) by 20 mm Hg. MEASUREMENTS AND MAIN RESULTS: Glomerular filtration rate and renal blood flow were derived from inulin and para-aminohippurate clearances, respectively. Urine output and urine solute excretion were also determined. The mean norepinephrine dose required to increase MAP by 22 +/- 2 mm Hg was 118 +/- 30 ng/kg/min (range 76 to 164). After the addition of dopamine, similar doses of norepinephrine resulted in an MAP increase of 15 +/- 4 mm Hg. Glomerular filtration rate and urine output were comparable under all conditions. The infusion of norepinephrine decreased renal blood flow from 1241 +/- 208 to 922 +/- 143 mL/min/1.73 m2 (p = .03). The addition of dopamine returned renal blood flow to baseline values. The clearance of urine sodium increased significantly with the infusion of dopamine alone (p = .03). All subjects completed the four treatment periods. Adverse events, manifested mostly as palpitations and flushing, were rare and self-limiting. CONCLUSIONS: The addition of dopamine (3 micrograms/kg/min) to pressor doses of norepinephrine normalized renal blood flow in healthy volunteers. These hemodynamic changes were not reflected in urine output and glomerular filtration rate; hence, these monitoring parameters may be unreliable indicators of renal function in the setting of vasopressor therapy. In addition, systemic effects were observed with dopamine (3 micrograms/kg/min), as indicated by a decrease in MAP.

Adult↗
PubMed1996

Aprotinin.

OBJECTIVE: To review the clinical pharmacology of aprotinin in patients undergoing surgical procedures involving major blood loss, namely, coronary artery bypass graft (CABG). DATA SOURCES: A MEDLINE search was used to identify French- and English-language publications on aprotinin using the indexing terms aprotinin, cardiothoracic surgery, and hemorrhage. The MEDLINE search was supplemented by review of article bibliographies. Data also were obtained from the approved Canadian and US product labels. STUDY SELECTIONS: All abstracts and uncontrolled and controlled clinical trials were reviewed. DATA EXTRACTION: Study design, population, results, and safety information were retained. Efficacy conclusions were drawn from controlled trials. DATA SYNTHESIS: Aprotinin, a serine protease inhibitor isolated from bovine lung tissue, decreases bleeding after cardiac surgery by mechanisms including antifibrinolytic activity and preservation of platelet function. Several trials have shown that aprotinin reduced blood loss and transfusion requirements in patients undergoing CABG. Its use in other surgical procedures involving major blood loss has been reported. Aprotinin is well tolerated, with minor allergic reactions being the most frequently reported adverse effect. Although unsubstantiated, the possibility that aprotinin could create a prothrombic state leading to early graft occlusion and formation of microthrombi in renal and coronary vasculatures is of concern. CONCLUSIONS: Aprotinin is an effective hemostatic agent in CABG. Clear definitions of indications, dosing, safety, and repeated use remain to be investigated thoroughly.

Aprotinin↗
PubMed1995

Suction-induced blister fluid penetration of cefdinir in healthy volunteers following ascending oral doses.

The pharmacokinetics and suction-induced blister fluid penetration of cefdinir following single oral administrations of 200, 300, 400, and 600 mg were studied in 16 healthy young male volunteers according to a Latin square design. Plasma, blister, and urine samples were assayed by high-pressure liquid chromatography. We observed a nonlinear relationship (P = 0.02) between the dose and the maximum concentration in plasma as well as between the dose and the area under the concentration-time curve (AUC) in plasma (P < 0.001), which may be indicative of a limited absorption process. This resulted in a lower AUC value than expected as well as a smaller fraction of cefdinir excreted unchanged at a dose of 600 mg. Renal clearance decreased with increasing doses (P < 0.006; analysis of variance with the Latin square design and Games-Howell procedure). Maximal cefdinir concentrations in blister fluid were delayed compared with concentrations in plasma. Blister fluid penetration measured by the ratio of the AUC in blister fluid to the AUC in plasma was extensive (92.4 to 108.4%). Cefdinir concentrations in blister fluid remained equal to or higher than the concentrations in plasma from 6 to 12 h following cefdinir administration. On the basis of the concentrations in blister fluid and the in vitro MIC data, we estimated that cefdinir at 200 to 400 mg administered twice daily would be adequate to treat uncomplicated skin infections caused by Streptococcus pyogenes. Seven volunteers experienced episodes of light-to-moderate diarrhea. These adverse events occurred irrespective of dose.

Adult↗
PubMed1995

Fatal hepatotoxicity following oral administration of amiodarone.

OBJECTIVE: To report a case of fatal hepatotoxicity associated with the chronic use of oral amiodarone. CASE SUMMARY: Long-term administration of amiodarone for the control of intractable ventricular tachycardia was associated with fatal hepatotoxicity in a patient receiving amiodarone for 14 months. DISCUSSION: Although most hepatic adverse effects associated with amiodarone are transient and reversible with time, deaths resulting from amiodarone-induced hepatotoxicity have been reported. The relation of hepatotoxicity to cumulative dose and duration of therapy is debated. The histopathologic features of amiodarone-induced hepatotoxicity include Mallory bodies, steatosis, intralobular inflammatory infiltrates, fibrosis, and phospholipidosis. CONCLUSIONS: Evidence pertaining to both mild and severe amiodarone toxicity indicates that cumulative dose may correlate with overall toxicity and, therefore, maintenance doses should be kept as low as possible. Patients should be followed with monitoring of liver function test results every 3-6 months.

Administration, Oral↗
PubMed1994

Caffeine metabolism in cystic fibrosis: enhanced xanthine oxidase activity.

STUDY OBJECTIVE: To characterize the activities of the P450 mixed-function oxidase CYP1A2 as well as the cytosolic enzymes N-acetyltransferase and xanthine oxidase using caffeine as a probe in children with cystic fibrosis compared to age-matched healthy control subjects. METHODS: After administration of caffeine (cola beverage) to 12 children with cystic fibrosis (age range, 5 to 11 years) and 12 healthy control subjects (age range, 5 to 12 years), urine was collected for 4 hours. Caffeine metabolites were determined by HPLC, and urinary caffeine metabolite ratios were computed to determine liver enzyme activities. In addition, a blood sample was used to detect cystic fibrosis mutant alleles by polymerase chain reaction. RESULTS: The indexes for CYP1A2, N-acetyltransferase, and 8-hydroxylation were similar in both groups of subjects. In contrast, there was a significant difference in the frequency distribution of the xanthine oxidase activity between the two groups. Nine of 12 patients with cystic fibrosis but only one of 12 healthy volunteers had xanthine oxidase activities above 0.42 (Kolmogorov-Smirnov two-sample test, p < 0.01). CONCLUSIONS: Differences in xanthine oxidase may have clinical implications with regard to interindividual variation in xenobiotic biotransformation and the exposure to lung tissue-damaging oxygen radicals. Hepatic enzyme activities appear to be selectively altered in patients with cystic fibrosis.

Alleles↗
PubMed1993

Pharmacotherapy of sexual offenders.

OBJECTIVE: To review the definition, sociology, pathogenesis, diagnosis, medicolegal aspects, and pharmacologic treatment of sexual offenders, with emphasis on the antiandrogens, the luteinizing hormone-releasing hormone (LHRH) antagonists, and the serotonergics. DATA SOURCES: An English-language literature search using MEDLINE (1966-1991) yielded clinical trials, case reports, editorials, and review articles. STUDY SELECTION: Emphasis was placed on comparative trials and case reports discussing pedophilia, rape, and exhibitionism. DATA EXTRACTION: Data from controlled human studies were evaluated. The trials were assessed for sample size, duration of therapy, therapeutic response, and incidence of recidivism. CONCLUSIONS: The pharmacologic management of sexual offenders is controversial, and treatment is presently focused on psychotherapy and the use of antiandrogenic medications. Few well-controlled, blinded, efficacy trials with adequate sample sizes have been conducted. The populations studied are heterogeneous, and the subjects enrolled present with different sexually coercive behaviors. Consequently, the results of these studies are difficult to extrapolate to the treatment of other sexual offenders. No convincing evidence exists that pharmacologic treatment decreases the recidivism rate. Case reports describing the use of serotonergic drugs and LHRH antagonists hopefully will promote controlled clinical trials. A social consensus must be reached concerning the ethics of using these agents as a part of the treatment of sexual offenders.

Aggression↗
PubMed1993

A comparison of functional indexes, derived from screening tests, of chronic alcoholic neurotoxicity in the cerebral cortex, retina and peripheral nervous system.

Thirty abstinent alcoholics and 30 age-, education- and occupation-matched normal control subjects were tested with the Category test, the Lanthony-15 test of color discrimination and the Biothesiometer test of vibration detection threshold. Multivariate analysis of covariance revealed significant impairment of the alcoholics on these tasks (p < .007), but univariate analysis revealed that only the Category test yielded a significant difference (p < .001). Canonical correlation analysis, with age and education partialed out, was calculated on the alcoholics' data to determine whether duration, mean and maximum alcohol consumption, age of onset of alcoholism and duration of abstinence predicted performance on the tasks. The prediction was significant (p < .001). Multiple regression analysis revealed that vibration threshold, color preception and Category test performance were decreasingly predicted by the alcohol-related variables (p < .001, .006, .051, respectively). There was no higher incidence of hereditary dyschromatopsia in the alcoholic group than the control group. It was therefore concluded that all three functions (Category test performance, color discrimination, vibrotactile sensitivity) were impaired as a result of alcohol consumption.

Adult↗
PubMed1993

Hypoxia, arterial pH and theophylline disposition.

Theophylline is a bronchodilator used extensively in the management of obstructive pulmonary disease. Factors implicated in altered theophylline clearance include smoking, age, concomitant drug intake, liver disease and left ventricular heart failure. However, evidence now suggests that theophylline clearance may be altered by changes in severity of the pulmonary obstruction, hypoxia and variation in arterial pH. The in vitro disposition of theophylline has been evaluated in isolated rat livers and mouse hepatocytes. In vivo studies have assessed the metabolism of theophylline under hypoxia in rats, rabbits and dogs. In isolated mouse hepatocytes and rat livers, low oxygen concentrations resulted in higher theophylline concentrations, a longer elimination half-life and a decrease in the production of the metabolite 1,3-dimethyl uric acid, suggesting impaired metabolism of theophylline. In rabbits, hypoxia, hypercapnia and respiratory acidosis decreased total body clearance and increased plasma theophylline concentrations. On the other hand, experiments involving dogs showed no significant changes in theophylline concentrations or pharmacokinetic parameters with hypoxia. At present, animal studies remain inconclusive. This can be attributed to the use of different animal models and variations in study methodology, including the extent and duration of hypoxia and acidaemia, concurrent acid-base disorders such as hypercapnia, as well as the severity of pulmonary obstruction. Human studies assessing alterations in theophylline disposition secondary to the hypoxia present in pulmonary disease are few and include mostly case reports and observational studies. There is evidence suggesting decreased theophylline clearance and protein binding during acute illness and some consensus can be achieved using case reports and controlled studies. There is additional evidence that drug clearance decreases with age and that elderly patients may have a decreased theophylline clearance at baseline. However, the most obvious markers appear to be the severity of pulmonary disease and the rate of change in the patient's condition. Caution should be exercised when administering theophylline to elderly patients with chronic obstructive pulmonary disease presenting with acute exacerbations of a concomitant respiratory illness, as these patients appear to be most likely to exhibit altered theophylline metabolism. Therefore, they would be at increased risk for toxicity should conventional dosages be used during an acute respiratory event.

Acid-Base Imbalance↗
PubMed1992

Structure-function studies of peptides inhibiting the ribonucleotide reductase activity of herpes simplex virus type I.

Ac-Tyr298-Ala299-Gly300-Thr301-Val302-I le303-Asn304-Asp305-Leu306-OH (Ac-VZV R2-(298-306)) represents the acetylated form of the C-terminus of varicella-zoster virus (VZV) ribonucleotide reductase subunit 2 (R2). This peptide possesses a high degree of homology with the C-terminus nonapeptide of the herpes simplex virus (HSV) type I and II ribonucleotide reductase R2 protein and is 15 times more potent than the latter in its in vitro inhibition of HSV-1 reductase activity. Accordingly, a new series of analogues based on this structure was studied in vitro. The replacement of Asp305 by Asn, Glu, Gln, Ser, or Cys; of Asn304 by Gln or Ser; of Ile303 and Val302 by D-Val; and of Tyr298 by Cha induced an important loss of inhibitory potency. The substitution of Asn304 by Asp; of Thr301 by Cys, Ser, or Val; of Gly300 by Ala or Val; of Ala299 by Val; or of Tyr298 by homoPhe, 4'-fluoro-Phe, 4'-chloro-Phe, 3'-iodo-Tyr, Me-Tyr, or For-Trp led to a moderate decrease of the Ac-VZV R2-(298-306) potency. The replacement of Val302 by Ile; Ala299 by Cys, Ser, or Thr; or the insertion of a six- or eight-carbon chain between Tyr298 and the NH2 terminus either preserved or slightly increased the inhibitory potency of Ac-VZV R2-(298-306). Finally, the substitution of Tyr298 by Trp or the addition of 4'-nitro-Phe at the amino terminus resulted in a 3-fold increase of potency. Altogether, these results stress the importance of the structural integrity of the minimum active core 302-306 in preserving the inhibitory potency and suggest that further studies on monosubstitutions could be directed at the portion 298-301 of the peptide.

Amino Acid Sequence↗
PubMed1990

High level expression in 293 cells of the herpes simplex virus type 2 ribonucleotide reductase subunit 2 using an adenovirus vector.

The herpes simplex viruses (HSV-1 and HSV-2) encode a ribonucleotide reductase consisting of two non-identical subunits (RR1 and RR2) which associate to form the active holoenzyme. To facilitate the purification and subsequent biochemical characterization of this enzyme, we have cloned the small subunit 2 of the HSV-2 ribonucleotide reductase (RR2HSV-2) in a helper-independent adenovirus type 5 vector under the control of the adenovirus type 2 major late promoter. After infection of 293 cells with the recombinant virus, the amount of RR2HSV-2 protein produced was eightfold higher than in HSV-2-infected cells. The specific activities of the RR2HSV-2 recombinant subunit and the RR2HSV-2 protein in HSV-2-infected cells were determined by their mixing with saturating amounts of isolated RR1HSV-1 subunit. By comparison of the relative amount of each RR2HSV-2 subunit with its specific activity, we calculated that the recombinant protein intrinsic activity was similar to that of the protein produced in HSV-2-infected cells. These results demonstrated that the adenovirus expression vector is a good system to produce an active RR2HSV-2 subunit in fairly high amounts.

Adenoviridae↗
PubMed1981

Silver-Russell syndrome. A family with symmetric and asymmetric siblings.

Two siblings with Silver-Russell syndrome (SRS) were studied. Only one child had asymmetry. To our knowledge, this is the first report of the existence of both the "Silver" and "Russell" variants in a nuclear family, and provides additional evidence for considering SRS to be a single syndrome with a wide spectrum of clinical manifestations.

Abnormalities, Multiple↗