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A Schapira

Publications and source records attributed to A Schapira.

At least 19 recordsLinked to original sources
PubMed2001

Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease.

Huntington's disease (HD) is one of 10 known diseases caused by a (CAG)(n) trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. We have developed stable inducible neuronal (PC12) cell lines that express huntingtin exon 1 with varying CAG repeat lengths under doxycycline (dox) control. The expression of expanded repeats is associated with aggregate formation, caspase-dependent cell death and decreased neurite outgrowth. Post-mitotic cells expressing mutant alleles were more prone to cell death compared with identical cycling cells. To determine early metabolic changes induced by this mutation in cell models, we studied changes in gene expression after 18 h dox induction, using Affymetrix arrays, cDNA filters and adapter-tagged competitive PCR (ATAC-PCR). At this time point there were low rates of inclusion formation, no evidence of mitochondrial compromise and no excess cell death in the lines expressing expanded compared with wild-type repeats. The expression profiles suggest novel targets for the HD mutation and were compatible with impaired cAMP response element (CRE)-mediated transcription, which we confirmed using CRE-luciferase reporter assays. Reduced CRE-mediated transcription may contribute to the loss of neurite outgrowth and cell death in polyglutamine diseases, as these phenotypes were partially rescued by treating cells with cAMP or forskolin.

Animals↗
PubMed1994

Hypoglycaemia in paediatric admissions in Mozambique.

We studied the incidence and clinical associations of hypoglycaemia in an acute medical paediatric service in Maputo, Mozambique. Of 603 children, 43 (7.1%) were hypoglycaemic. 16 of these with Plasmodium falciparum malaria had a shorter illness, and a higher incidence of convulsions and focal neurological signs than those with other diagnoses, but were less likely to die. Hypoglycaemia also complicated protein energy malnutrition, pneumonia, encephalitis, intestinal parasite infection, and nephrotic syndrome. 25 of the 603 children died: 7 (16.3%) of 43 with hypoglycaemia and 18 (3.2%) of 560 who were normoglycaemic, (relative risk of death 5.8 [95% confidence interval 2.25 to 14.93]). Hypoglycaemia is common in children in hospital in Mozambique, and should be suspected in any acutely-ill child regardless of the primary disease.

Child↗
PubMed1994

The influence of Maloprim chemoprophylaxis on cellular and humoral immune responses to Plasmodium falciparum asexual blood stage antigens in schoolchildren living in a malaria endemic area of Mozambique.

We examined the impact of chemoprophylaxis on the cellular and humoral immune responses to polypeptides of the asexual Plasmodium falciparum blood stage antigens, the glutamate rich protein GLURP and Pf155/RESA, both of which in previous field studies have been identified as potentially protective antigens. The study was carried out in the Escola Primária de Lingamo, a primary school in a suburban area of Maputo, Mozambique. A cohort of 392 schoolchildren (aged 7-12 years) was randomly allocated to two equal groups, one receiving chemoprophylaxis with dapsone/pyrimethamine (Maloprim), the other receiving placebo every week from December 1989 to November 1990. The groups were then followed until November 1991 without chemoprophylaxis. Cellular responses to immunodominant epitopes from Pf155/RESA and GLURP, and to non malaria antigens C. albicans and PPD, were assessed by lymphocyte proliferation assays in vitro. Anti-GLURP and anti-Pf155/RESA antibodies were detected by enzyme-linked immunosorbent assay (ELISA) and erythrocyte membrane immunofluorescence (EMIF), and total anti-P. falciparum antibodies were measured by indirect fluorescent antibody test (IFAT). Immunological reactivities were evaluated every six months, at the end of the rainy season and at the end of the dry season, both during the period of chemoprophylaxis and during the follow-up. The antibody response rate to the GLURP was lower in the Maloprim group than in the placebo group during the intervention phase. The lymphoproliferative response rate to the malaria antigens was significantly lower at the end of the rainy season than at the end of the dry season, but the difference between the experimental group and the control group of schoolchildren was not statistically significant. These results suggest that the antibody responses to the GLURP molecule and partly to the Pf155/RESA antigen in this study population were shortlived and dependent on frequent boostering, but whether these antigens play a role in the development of natural clinical immunity remains open. In the experimental group of schoolchildren weekly chemoprophylaxis successfully reduced the parasite rate during the rainy season from 43% to 4%, and during the dry season from 18% to 0%. Chemoprophylaxis may therefore have a useful role in combination with another partially effective malaria control measure such as insecticide-impregnated bed nets or a malaria vaccine.

Animals↗
PubMed1993

Malaria: living with drug resistance.

The epidemiological factors associated with the development and spread of drug-resistant malaria have been recently explored by Wemsdorfer in a paper in which he looked at parasite-drug-human-vector interactions that affect the occurrence and dynamics of drug resistance. The question that decision-makers must be asking themselves, as we face the 21st century, is: how will we live with drug resistance? Allan Schapira, Peter Beales and M. Elizabeth Halloran are ideally placed to consider this question. Extracting lessons from the past, they focus on drug-resistant Plasmodium falciparum in Africa. They propose a mathematical model, which will improve the conceptual basis for policy decisions and which has implications for drug development as well as for malaria-control programmes.

Journal Article↗
PubMed1992

Efficacy of dapsone with pyrimethamine (Maloprim) for malaria prophylaxis in Maputo, Mozambique.

In a randomized controlled study of malaria prophylaxis, dapsone-pyrimethamine at a weekly dosage of dapsone 50-100 mg with pyrimethamine 6.25-12.5 mg or placebo was administered to 166 school children for 17 weeks. Fortnightly parasitological controls revealed 28 infections in the placebo group and none in the dapsone-pyrimethamine group. It is concluded that weekly dapsone-pyrimethamine is effective for the prophylaxis of falciparum malaria in Mozambique.

Child↗
PubMed1990

The resistance of falciparum malaria in Africa to 4-aminoquinolines and antifolates.

Falciparum malaria cannot be eradicated from sub-Saharan Africa with present technology. The mainstay of malaria control in this situation is treatment of fever cases with chloroquine, aiming principally at reduction of mortality. The efficacy of this policy is now endangered because of the appearance and spread of chloroquine-resistance on the African continent. The present review examines laboratory and field research on the resistance of African P.falciparum to chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil and the combination sulfadoxine-pyrimethamine. Drug-resistance in malaria may be assessed with in vivo and in vitro technology. In vivo tests are simple, but the results are difficult to compare because of the influence of immunity. In vitro tests provide a more precise epidemiological tool, but their analysis should be undertaken with consideration of their technical limitations. For parasitological, immunological and epidemiological reasons, a one-to-one correlation between in vivo and in vivo grading of resistance is usually not found. Extended in vivo tests may be at least as sensitive as in vitro tests for detecting rare resistant parasites. On the other hand, the standardized grading of higher levels of in vivo resistance is arbitrary, and it is doubtful, whether such distinction has any clinical relevance. The 4-aminoquinolines (chloroquine and amodiaquine) presumably act by interfering with vital functions in the acid vesicles of parasites. Recent experiments indicate that resistance may be related to an increased rate of efflux of chloroquine from the parasite. It is caused by mutation, and at least three genetic levels of resistance have been identified. The blood stages of resistant plasmodia seem to have a biological advantage over sensitive ones, an observation that raises some hitherto unanswered questions. In the 1970s, a low degree of resistance to chloroquine was found in African P. falciparum in several localities. Resistance to the standard dose of chloroquine of 25 mg/kg was found in 1978 in tourists, who had sojourned in Kenya and Tanzania. Since then, chloroquine-resistance has spread centrifugally with increasing rapidity from an original focus in Northern Tanzania or Southern Kenya. The rate of increase in the proportion of resistant infections has generally been more rapid in the areas, where resistance has been introduced recently than in the original epifocus. The rate of increase is also generally more rapid in urban than in rural areas, an observation that can be ascribed to differences in drug pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminoquinolines↗
PubMed1990

[Comparative study of sulfadoxine-pyrimethamine and amodiaquine + sulfadoxine-pyrimethamine for the treatment of malaria caused by chloroquine-resistant Plasmodium falciparum in Maputo, Mozambique].

To compare the efficacy and side-effects of two therapeutic regimens for chloroquine-resistant falciparum malaria, a randomized study was carried out in 69 patients in Maputo Central Hospital in 1986-1987. The two treatments were sulfadoxine 25 mg/kg + pyrimethamine 1.25 mg/kg as a single dose (S + P) and amodiaquine 10 + 10 + 5 mg/kg over three days with sulfadoxine + pyrimethamine on the third day (A + S + P). The cure rate was 25/29 (86%) with S + P and 27/30 (90%) with A + S + P. No serious side-effects were observed. The probably slightly higher cure rate with the triple combination is hardly of clinical importance in semi-immune patients, but may theoretically help retard the development of resistance to sulfadoxine-pyrimethamine. This point and the question of the incidence of side-effects with the two regimens should be made the object of an epidemiological study.

Adult↗
PubMed1988

Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine.

As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p = 0.043). The side effects of both regimens were generally mild, but the combination of chloroquine phosphate with proguanil hydrochloride is recommended because it results in fewer side effects. As breakthroughs of malaria occurred at the earliest after seven weeks self treatment should not be recommended for travellers staying only a short time. Thick blood films are useful for diagnosis of suspected cases of malaria, can be prepared by non-specialists in Africa, and can be analysed successfully after long delays.

Adult↗
PubMed1988

The Plasmodium falciparum chloroquine in vivo test: extended follow-up is more important than parasite counting.

349 in vivo tests of the susceptibility of Plasmodium falciparum to chloroquine, 25 mg/kg, were analysed. In some surveys, standard in vitro tests were also carried out. The proportions of sensitive and resistant infections in different areas found by the 2 methods were similar, but, within a given area, correlation between the two methods was often poor. Two RI cases and one RII/RIII case were sensitive in vitro, and it is suggested that the extended in vivo test may sometimes be more sensitive than the in vitro test, and that even in endemic areas, where reinfection is possible, patency on day 14 will nearly always be due to resistance. Parasite density data were analysed by calculating the geometric mean of each day's parasite density as a percentage of the day 0 parasite density + 0.1. Most resistant and sensitive infections attained minimal values on day 4, and it is proposed that assessment of sensitivity based on parasite densities should use day 4 values. Contrasts between materials were more clearly defined statistically when comparisons were based on ranking in vivo test classifications, than when based on day 4 parasitaemia. It is therefore suggested that, for epidemiological purposes, extension of tests to at least 14 d is more important than parasite counting. Parasitaemia above 20-25% of the day 0 value on day 2 in a severely ill patient, or persistent patency on day 4 in a symptomatic patient, are both indications for a change of treatment.

Animals↗
PubMed1988

Hypovolemic stimuli and vasopressin secretion in man.

Different non-hypotensive hypovolemic stimuli were applied to 21 healthy and 20 uremic dialysis patients. The purpose was to study the effect on plasma arginine-vasopressin concentration, using orthostasis as a reference model. Orthostasis increased the plasma AVP level in healthy subjects as well as in uremic dialysis patients. In healthy subjects plasma AVP increased both when they were normohydrated and after they had been water-depleted. Lower body negative pressure (LBNP, -40 mmHg) was applied to 11 healthy males to induce a central blood volume decrease, equal to that induced by orthostasis. The plasma AVP increased in two subjects only who became hypotensive during the investigations. Ten hemodialysis patients were volume-depleted by isolated ultrafiltration. A flow directed Swan-Ganz catheter was used to measure the central intravascular pressures. Pulmonary capillary wedge pressure was reduced to normal or subnormal values during 1-2 h of ultrafiltration, without any significant changes in plasma AVP. Plasma AVP increased only in 2 patients, who became hypotensive during the investigations. Thus, of the present non-hypotensive volume stimuli only orthostasis was able to stimulate AVP secretion. Equal or even greater reductions in central blood volumes by other stimuli had no effect on AVP secretion. The results demonstrate that isolated stimulation of low-pressure volume receptors has no effect on the secretion of AVP in humans.

Adult↗
PubMed1988

Evaluation of four therapeutic regimens for falciparum malaria in Mozambique, 1986.

A randomized study on the effect of the following four treatment regimens on Plasmodium falciparum parasitaemia was carried out on 200 asymptomatic schoolchildren in Maputo, Mozambique: chloroquine (25 mg/kg body weight), amodiaquine (25 mg/kg), sulfadoxine-pyrimethamine (25 mg/kg and 1.25 mg/kg), or amodiaquine (25 mg/kg) + sulfadoxine-pyrimethamine (25 mg/kg and 1.25 mg/kg) administered on the third day of the study. The results of in vivo tests indicated that 94% of the infections were resistant to chloroquine, 76% to amodiaquine, and 16% to sulfadoxine-pyrimethamine. The cure rate with amodiaquine + sulfadoxine-pyrimethamine was 100%, which was not significantly different from that with sulfadoxine-pyrimethamine alone; the latter regimen was the most rapidly acting of the treatments studied. It is concluded that amodiaquine is not an appropriate substitute for chloroquine, but that the effect of the combination amodiaquine + sulfadoxine-pyrimethamine may be superior to that of sulfadoxine-pyrimethamine alone, although this requires further study.

Amodiaquine↗
PubMed1987

Plasmodium falciparum in vitro schizont maturation tests in Mozambique are not improved by removing immune parasite carriers' plasma.

To study the effect of immune parasite carriers' plasma on Plasmodium falciparum schizont maturation, peripheral blood stages were incubated for 24-40 h in RPMI medium with either 5% carrier's plasma + 5% non-immune AB serum or 10% non-immune serum. The number of schizonts per 200 asexual P. falciparum was lower in non-immune serum than in the presence of carrier's plasma in 19 of 26 cases, due to increased frequency of schizont rupture when carrier's plasma was absent. It is concluded that, under these test conditions, the replacement of immune plasma by non-immune serum makes schizont maturation tests, which are based on the proportion of schizonts among asexual P. falciparum as a measure of growth, more difficult to interpret.

Adolescent↗
PubMed1986

The susceptibility of Plasmodium falciparum to sulfadoxine and pyrimethamine: correlation of in vivo and in vitro results.

In 1982, 2 of 14 Plasmodium falciparum infections acquired in East Africa and diagnosed in Copenhagen were resistant to treatment with sulfadoxine plus pyrimethamine (Fansidar), while in 1983, 6 of 18 were so. The in vivo tests were supplemented by determinations of drug concentrations in serum, and 4 isolates from in vivo-sensitive cases and 6 from in vivo-resistant cases were selected for in vivo tests. These were performed in ordinary RPMI 1640 medium and in a medium with physiological p-aminobenzoic acid and folic acid concentrations. Pharmacokinetic aberrations were found to be of possible importance in only 2 of the in vivo-resistant cases. In vitro susceptibility to sulfadoxine was found to be uniformly low in all isolates. Testing with a combination of sulfadoxine and pyrimethamine in the medium with physiological concentrations of cofactors probably reflects the in vivo situation most accurately, but in all but 1 of the isolates studied in vitro the in vivo susceptibility to Fansidar would be predicted by in vitro susceptibility to pyrimethamine in either medium. The concentration of p-aminobenzoic acid in serum, quantitated by high performance liquid chromatography, was found to be subject to wide variation, and this may have implications for in vitro testing.

Adult↗