PRRT2 mutations and paroxysmal disorders.

In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.

Antibodies to HTLV-I p24 in African and Portuguese populations.

Using a radioimmunoassay to detect HTLV-I protein antibodies of molecular weight 24,000, we screened populations from Algeria (140 subjects), Tunisia (442), Mali (69), Senegal (415), Uganda (135), the Central African Republic (77), the Congo (360), and Madagascar (193). Only four subjects were positive (1 from Senegal, 1 from Uganda, 2 from the Congo). This is a much lower figure than that found by others in Africa by the enzyme-linked immunosorbent assay technique. In addition, 319 Portuguese blood donors (46 of whom have lived in Angola or Mozambique) were screened using the same radioimmunoassay. All were negative.

Reevaluation of the relative risk for susceptibility to celiac disease of HLA-DRB1, -DQA1, -DQB1, -DPB1, and -TAP2 alleles in a French population.

In a population of 46 children with CD recruited in the Paris area of France, an excess of DRB1*03 and DRB1*07 alleles and of DR3/DR7, DR3/DR3 and DR11(or 12)/DR7 phenotypes was found (RRs of 6.3, 9.3, 24.6, 15, and 15.1, respectively), which is reminiscent of the markers of susceptibility observed in southern rather than in northern European celiac patients. More importantly, the highest association with CD was not found in individuals expressing the DQA1*0501-DQB1*0201 heterodimer in single dosage (RR = 24.9) or in homozygous state, but in people co-expressing one copy of DQA1*0501-DQB1*0201 on one haplotype and a second copy of DQB1*0201 on the second haplotype (RR = 35.7). This suggests that in our population either DQB1*0201 or a gene closely linked to DQB1*0201 influences the susceptibility to CD conferred by the DQA1*0501-DQB1*0201 heterodimer. Significant positive or negative RRs conferred by some TAP2 or DPB1 alleles were found. However, they were moderate compared to the RR conferred by the expression of a second copy of DQB1*0201. Moreover, they were no longer significant when patients were compared with HLA-DR matched controls. This suggests that associations of CD with TAP2 and DPB1 alleles are secondary to linkage disequilibria and argues against the contribution of these alleles in resistance and/or susceptibility to CD. Thus the "raison d'être" of a "DQB1*0201 second haplotype effect" in susceptibility to CD remains to be elucidated.

Frequency of cytokine-producing T cells in HIV-infected patients treated with stavudine, didanosine, and ritonavir.

To assess prospectively the influence of the control of viral replication on the frequency of cytokine-producing T cells, and to correlate these changes with immune activation, we conducted a 15-month follow-up study of IFN-gamma- and IL-2-producing CD4+ and CD8+ T cells at a single-cell level in 12 previously untreated patients receiving highly active antiretroviral therapy (HAART). At baseline we observed a strikingly high proportion of IFN-gamma-producing CD8+ T cells. The treatment-induced decrease in the proportion of IFN-gamma-producing CD8+ T cells ran parallel to the decrease in HLA-DR+ and CD38+CD8+ T cell subsets and was associated with the reduction in HIV RNA level. IL-2-producing cells were mainly CD4+. As a consequence of CD4+ T cell loss, the number of IL-2-producing CD4+ T cells was lower in patients than in control subjects (52 vs. 171 cells/microl), but the proportion of these cells was unchanged (22.4 vs. 19.3). During therapy the proportion of CD4+ IL-2-producing cells was initially stable and then fell markedly at month 5, followed by a gradual return to previous values. The reduction in viral load was associated with the fall in the proportion of CD4+ activated subsets. Intracellular cytokine assays are a new approach to the assessment of T cell function in HIV infection. Our results suggest that the functional capacity of CD4+ T cells is probably less severely altered than previously thought on the basis of conventional assays. CD8+ T cells exhibit an increased capacity to produce IFN-gamma that is associated with an increase in activation marker expression. These alterations decrease partially and in parallel under treatment.

Predictors of short- and long-term survival in HIV-infected patients admitted to the ICU.

STUDY OBJECTIVES: To evaluate the prognosis of HIV-infected patients admitted to ICUs and to identify factors predictive of short- and long-term survival. DESIGN: A prospective study from January 1, 1990, to December 31, 1992, including all consecutive HIV-infected patients admitted to our ICU for the first time. ICU survivors were followed up until January 1, 1994. SETTING: An 18-bed infectious diseases ICU in a 1,300-bed university hospital in Paris. PATIENTS: Four hundred twenty-one HIV-related admissions were recorded during the study period (33.5% of 1,258 admissions to ICU); 354 HIV-infected patients were first ICU admissions and were analyzed. MEASUREMENTS AND RESULTS: Predictive factors on univariate and multivariate analyses (logistic regression and Cox model) for short- and long-term mortality were performed. Respiratory failure was the main cause of admission (49.2%), followed by neurologic disorders (26.8%), sepsis (10.2%), heart failure (4.5%), and miscellaneous disorders (9.3%). For these groups, in-ICU and in-hospital mortality rates were as follows: 16.7% and 33.9%; 23.2% and 41.1%; 38.9% and 58.3%; 25% and 68.8%; and 12.1% and 24.2%, respectively. In-ICU and in-hospital mortality rates were significantly different across the groups (p=0.026 and 0.002, respectively). Multivariate analysis showed that the in-hospital outcome was significantly associated with functional status (p=0.05), time since AIDS diagnosis (p=0.04), HIV disease stage (0.016), simplified acute physiology score (SAPS I) (p=0.06), need for mechanical ventilation (p<0.000001), and its duration (p=0.0001). In the 281 patients who were discharged alive from the ICU, cumulative survival rates were 51%+/-38% at 6 months, 28%+/-38% at 12 months, and 18%+/-30% at 24 months. Median and crude mean+/-SD survival times were 199 days and 316+/-343 days. Multivariate analysis showed that the long-term outcome was significantly associated with functional status (p=0.000001), weight loss (p=0.00001), the CD4 count (p=0.00001), the HIV disease stage (p=0.01), the duration of AIDS (p=0.001), the admission cause group (p=0.03), and the SAPS I at admission (p=0.00001). CONCLUSIONS: The short-term (in-ICU and in-hospital) outcome of HIV-infected patients was mainly related to the severity of the acute illness (SAPS I, cause of admission, need for and duration of mechanical ventilation), and to the preadmission health status, based on functional status and weight loss. Some of these parameters, in particular the SAPS I and preadmission health status, also influenced the long-term outcome. Whereas HIV-related variables had little impact on the in-ICU outcome, they were closely related with the in-hospital outcome and even more strikingly with the long-term outcome. Thus, the life expectancy of HIV-infected patients, which depends primarily on the natural history of the HIV infection, is the most powerful determinant of the long-term prognosis. Our results confirm that ICU support for HIV-infected patients should not be considered futile.

Seroepidemiology of hepatitis B in a population of children in central Tunisia.

The prevalence rate of HBV markers in the overall population was 18.0%. The prevalence rates of HBsAg and anti-HBs were 3.3% and 12.2% respectively. 2.5% of the children were negative for these markers but positive for anti-HBc alone. Of the 17 HBsAg positive children, 10 were HBeAg positive and four were anti-HBe positive. The statistical study using multifactorial correspondence analysis and the chi 2 test showed a positive relationship between the prevalence rate of anti-HBs and age, and a negative relationship between the prevalence rate of 'absence of markers' and age. The male sex and urban dwelling were related to higher prevalence rates of HBsAg and anti-HBc alone and to a lower prevalence rate of 'absence of markers'. No relationship was found between geographical zone, father's education and HBV markers. The implications of these results in terms of prevention are discussed.

Demographic factors associated with HTLV-1 infection in a Gabonese community.

An epidemiological study of human T-lymphotropic virus type 1 (HTLV-1) and syphilis has been carried out in a multiethnic community of seven neighbouring villages located in eastern Gabon on 1240 subjects over 5 years old (82.7% of the population in this age range). Antibodies to HTLV-1 (anti-HTLV-1) were detected by ELISA with confirmation by Western Blot and antibodies to syphilis by Venereal Diseases Research Laboratory assay with confirmation by the Treponema pallidum haemaglutination assay. The prevalence rate of anti-HTLV-1 was 8.5% and increased from 3.7% in the 5-14 years age group to 23.8% in the over 60 years age group. Logistic regression showed that the positivity for anti-HTLV-1 was associated with age, ethnic group and sex (higher prevalence in females). The seroprevalence rate of syphilis was 8.2%. Seropositivity for syphilis and HTLV-1 were related but age was a confounding variable in this relationship. This study showing a highly heterogeneous distribution of HTLV-1 in a geographically limited area suggests the role of environmental and behavioural factors in HTLV-1 transmission.

Serologic survey of human hydatid disease in high risk populations from central Tunisia. Preliminary results.

The annual surgical incidence rate of hydatid disease in central Tunisia varies from 11.1 to 30.1 per 100,000 population depending on the district. In order to obtain more comprehensive data, we conducted a serologic survey in the district with the highest rate, using hemagglutination-inhibition to test 480 workers from a state farm and 190 inhabitants of villages in the neighborhood. The overall prevalence rate was 1.3% (9/670). Echotomography revealed liver cysts in all cases and the diagnosis was confirmed in the eight subjects who underwent surgery. If these preliminary results are confirmed by further surveys, mass screening might be considered in high risk districts.

Echotomographic and serologic screening for hydatidosis in a Tunisian village.

Echotomographic and serologic screening for hydatidosis was carried out in 1,650 subjects aged over 5 years in a village located in a high risk region of central Tunisia. Echotomography detected liver cysts in 6 subjects (prevalence rate: 3.6 per 1,000). These 6 cases were among the 7 positive cases detected by ELISA. In all 6, the diagnosis of liver cysts was confirmed. No other localization was found in any of the subjects including one with a positive ELISA and a normal echotomographic examination. This work demonstrates the high feasibility of echotomography in the field and confirms the high prevalence rate of hydatidosis in the community.

Population-based study of serum hepatitis B virus DNA in Gabon.

The prevalence of serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) was measured in a Gabonese community at high risk for HBV infection. Among 698 subjects 5 to 24 years old, the prevalence of HBsAg was 11.1% vs. 57.9% for anti-HBs and 7.2% for anti-HBc alone. The prevalence of HBeAg among HBsAg-positive subjects was 26.5% vs. 59.5% for anti-HBe. The prevalence of HBV DNA tested by a hybridization spot test was 2.1% in the overall population and 18.7% among HBsAg-positive subjects. HBV DNA was found in 15 of 21 HBeAg-positive subjects but in none of the subjects positive for anti-HBe or negative for both HBeAg and anti-HBe. HBV DNA was not detected in any HBsAg negative subjects. The prevalence of HBV DNA decreased with age. This low prevalence of HBV DNA contrasts with the high level of endemicity in the study population.

Echotomographic and serological population-based study of hydatidosis in central Tunisia.

A population-based echotomographic (ECT) and serological survey of hydatidosis was carried out in a high risk community located in Central Tunisia. 1434 subjects over 5 years of age (93.3% of the population in this age range) underwent an abdominal echotomography (ECT) and a serological test (ELISA with confirmation by counterelectrophoresis). The ECT prevalence rate was 3.5% and increased with age reaching 7.7% in the over 39 years age group. Most subjects (96.0%) had liver cyst(s). The serological prevalence rate was 2.9%. A strong agreement was found between ECT and serological results (Kappa test = 0.449). Taking ECT as a reference, the relative specificity and sensitivity of serology were 99.3 and 62.0 respectively. Most ECT positive seronegative subjects had calcified cysts. These results confirm the presence of highly endemic foci of hydatidosis in Central Tunisia, show a good agreement between serological and ECT results at a population level and demonstrate the high feasibility of ECT as a screening technique.

Distribution of surgical hydatidosis in central Tunisia (1982-1985).

The mean annual surgical incidence rates (MASIR) of hydatidosis were measured for the 1982-1985 period in central Tunisia in order to investigate the natural history of human hydatidosis and provide baseline data for the evaluation of future prevention campaigns. 986 cases were identified from surgical records of regional hospitals to which cases from central Tunisia are mandatorily referred. The overall MASIR was 19.3 per 10(5) inhabitants. The MASIR according to district varied from 0 to 56.6 per 10(5), was higher in women than in men (22.6 versus 15.8 per 10(5] and increased with age (maximum 53.0 per 10(5) in the 50-59 age group for women and 27.1 per 10(5) in the 40-49 group for men). Among the 940 cases with single organ hydatidosis, liver ranged first (55.3%, 545/940), then lung (32.4% 320/940), kidney (2.7%) and spleen (1.8%). Among the 865 subjects with single lung or liver hydatidosis, liver was more often involved in women (349 out of 503) than in men (196 out of 362) (chi 2 = 20.9, p less than 0.001). In both sexes, the lung/liver ratio decreased with age. These data reveal the existence of highly endemic foci of hydatidosis within central Tunisia. The predominance of infection in women might be due to sex related behavioral differences. The causes of liver predominance in women and variation of lung/liver ratio are open to question.

Pulmonary function at 1 year of age in survivors of neonatal respiratory distress: a multivariate analysis of factors associated with sequelae.

We studied pulmonary function 1 year after neonatal respiratory distress (RD) in 54 infants who had been treated at birth in the same neonatal intensive care unit. RD was related to hyaline membrane disease in 36 cases (group I) and to other causes in 18 cases (group II). Compared with predicted values, dynamic lung compliance (CL) was lower (less than -2 SD) and total pulmonary resistance (RL) was higher (+2 SD) in 18 (33%) and 12 (22%) infants, respectively. The relationships between these functional abnormalities at 1 year of age and the characteristics of the neonatal respiratory disease were assessed using a multifactorial analysis (multiple correspondences analysis). We found that elevated RL (greater than +2 SD) at 1 year of age was very significantly related with hyaline membrane disease, involving both high rate of positive pressure ventilation and prolonged intubation, and with the presence of both tachypnea and abnormal chest X rays at the time of discharge. Compared with elevated RL, the relationships between low CL (less than -2 SD) and the same neonatal characteristics were less significant; in particular, there was no strong link between low CL and hyaline membrane disease. Finally, birth before 30 weeks gestation was an index of severity.

Respiratory frequencies of sleeping infants during the first months of life: correlations between values in different sleep states.

This study was carried out on 57 normal infants: 22 full-term newborns, examined in the hospital laboratory, and 35 2-18-wk-old infants, examined in two resident nurseries. Polygraphic records, including 1-3 complete sleep cycles, were performed during the morning. The tracings were analyzed by 20-sec epochs. Three to 10% of active sleep states (AS) and 0.8-4% of quiet sleep states (QS) included greater than or equal to 3 sec respiratory pauses. There were minimal, non-significant differences between respiratory frequencies (RF) in total and in no-pause tracings. Our results confirmed that RF was higher in AS in all ages, when compared with QS (P less than 0.02). During the transition (TS) from one to another well-defined sleep state, the respiratory rate showed an intermediate level (AS greater than TS greater than QS): the transition from AS to QS showed progressive slowing of RF, while the transition from QS to AS occurred abruptly, with sudden acceleration of RF. There was a significant slowing of RF during the couse of QS, while the RF in AS was more variable without significant differences between the beginning, the middle and the end of AS state. In this material RF was higher in 2-5-wk and 6-10-wk age groups, compared to newborns and to 11-18-wk-old infants. At all ages, there was a high degree of correlation (P less than 0.01) between RF found in different sleep states for given individuals: some infants breathed more rapidly and other more slowly in all sleep states. A review of the literature showed that the differences between normal RF.

The pharmacokinetics of chloroquine in healthy and Plasmodium chabaudi-infected mice: implications for chronotherapy.

The schizogony of malarial parasite is a typical cyclic phenomenon where the different stages of parasite development appear at regular time intervals. Each of the stages is specifically sensitive to different antimalarial drugs. Knowledge of the details of the cycle, drug susceptibility and the pharmacokinetics of drugs, could allow the improvement of drug action by the chronotherapeutic approach: treatment at the time of appearance of the drug sensitive stage with a drug that displays rapid pharmacokinetics. Since murine malarias serve as preferable models for in vivo drug testing, the pharmacokinetics of subcutaneously (sc) administered chloroquine (CQ) were tested in the whole blood of healthy mice and in animals slightly (1.5-3.5% parasitemia) or heavily infected (21-25% parasitemia) with Plasmodium chabaudi chabaudi. The half-time of absorption was around 5 min and almost independent of parasitemia. The apparent half-time of drug concentration decay was around 40 min in healthy animals, about 90 min at low parasitemia and about 410 min in heavy infection, indicating that the concentration of CQ is a typical spike, that is prolonged by asymptomatic disease, and considerably more by the active accumulation of CQ in infected cells. The latter is confirmed by the 3-fold higher peak blood [CQ] at the trophozoite stage and < 1.5-fold increase during schizogony. In conjunction with our previous experiments which showed that a single sc injection of 5 mg/kg CQ is sufficient to eliminate the drug susceptible mid-term trophozoite stage, the present results seem to justify to propose the chronotherapeutic approach for the treatment of malaria.

[Epidemiologic interrelation among intestinal protozoans by direct count. Statistical analysis of 9,471 examinations and a comparison with the literature]. / Interrelations épidémiologiques entre protozoaires intestinaux a contage direct. Analyse statistique de 9,471 examens et comparaison avec la littérature.

A statistical study of the results of coprological analysis allows us to appreciate the prevalence of the different parasites, depending on the geographic origin of the outpatients of a hospital situated in the suburbs of Paris. The multifactorial analysis shows, besides other problems, the epidemiological relations between these parasites or, in the contrary, the oppositions which can appear. These results are compared with those published since two decades; their study empowers to set the problem of the fiability of some statistics and, therefore, of the possibilities of an efficient epidemiological research.

[Epidemiology of HTLV-I infection in its hyperendemic foci (Japan, tropical Africa, Caribbean)]. / Epidémiologie de l'infection par HTLV-I dans ses foyers d'hyperendémie (Japon, Afrique intertropicale, Caraïbes).

HTLV-1 infection is endemic in Japan, black Africa, the Caribbean and several regions of South America. In these foci, the infections is very heterogeneously distributed (variations from village to village, intrafamilial clustering). The virus is transmitted from mother to child, and breast feedings seems to play a major role. Sexual transmission is usually from man to woman. The frequency of transmission by blood transfusion must not be underestimated. It justifies the systematic detection of HTLV-1 infection in areas where it is economically feasible.