Primary health care in a multi-level perspective: towards a research agenda

The authors propose to view primary health care (PHC) from a multi-level perspective. Studying how PHC is conceived and implemented at different levels of social organization (e.g. in international agencies, national governments, regional centres of health care and local communities) will reveal which interests may be competing in the planning and execution of what broadly and conveniently is called 'PHC'. Mapping out these conflicting views and interests will contribute towards a better understanding of how PHC works or why it does not work and provide suggestions for a more effective and equitable PHC. Five themes are proposed for a multi-level research approach: (1) vertical versus horizontal organization of PHC: (2) the role of medical personnel in PHC; (3) the distribution of pharmaceuticals; (4) the integration of traditional medicine in PHC; and (5) family planning.     

Evaluation of the end-expiratory lung volume as an indirect index of bronchial constriction in asthma

The purpose of this study was to evaluate the merits of the end expiratory lung volume as an indirect ventilatory index of bronchial obstruction and to show an application of continuous monitoring of lung volume in asthmatic patients. The accuracy of the external measurements (IS) of functional residual capacity (FRC) was controlled by comparing them with the helium measurements (DS) obtained during nine methacholine tests (IS = 0.06 + 1.065 DS in litres: R2 = 0.99). Seven asthmatics (18-48 yr) were monitored by measuring rib cage and abdominal perimeter variations. This was done in basal condition, after methacholine-induced bronchoconstriction and after bronchodilation by either salbutamol or oxytropium bromide inhalation. All the subjects were investigated on two separate days and were their own control. Bronchoconstriction produced a significant increase (p less than 0.01) of tidal volume (VT: + 67%), external minute ventilation (VE: + 58%), mean inspiratory flow (VT/TI: + 78%) and FRC (+ 26.5%) while frequency (f) and fractional inspiratory time (TI/TT) fluctuated non significantly. In the group of seven tested subjects, there was a significant correlation (p less than 0.01) between forced expiratory volume in one second (FEV1) and VE, FEV1 and VT/TI, FEV1 and FRC. However, the individual regression line showed a significant relationship only between FEV1 and FRC (R2 = 0.80 +/- 0.04). We therefore conclude that the variation of the end expiratory level can be chosen as an indirect index of bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Iodomethylated fatty acid metabolism in mice and dogs

The myocardial uptake of fatty acids labeled with radioactive iodine and injected i.v. can only be evaluated with SPECT if their oxidation kinetics is slow enough. For this reason, we evaluated different iodomethylated fatty acids in mice and dogs to determine which of them shows the highest myocardial uptake and the slowest oxidation. The most suitable was found to be 16-iodo-3-methyl hexadecanoic acid (mono ) since its myocardial fixation was the same as that of the reference, i.e. 16-iodo-9-hexadecenoic acid (IHA), whereas it was degraded more slowly. Thirty min after injection of mono into dogs, the decrease in myocardial activity with respect to the maximum was two fold less than after IHA injection. The myocardial uptake of the two dimethylated fatty acids studied, i.e. 16-iodo-2,2-methyl hexadecanoic acid and 16-iodo-3,3-methyl hexadecanoic acid, was less than that of IHA in mice and dogs. In the latter, the myocardial uptake was so small that we were unable to study the time course of its activity. Consequently, these dimethylated fatty acids are not suitable for the study of the myocardial uptake of fatty acids in man.     

New enzyme immunoassays for sensitive detection of circulating Candida albicans mannan and antimannan antibodies: useful combined test for diagnosis of systemic candidiasis

Two standardized enzyme immunoassays for the serological diagnosis of candidiasis were developed. The first one detects antimannan antibodies, while the second one detects mannan with a sensitivity of 0.1 ng/ml. These tests were applied to 162 serum samples retrospectively selected from 43 patients with mycologically and clinically proven candidiasis caused by Candida albicans. Forty-three serum samples were positive for mannan, and 63 had significant antibody levels. Strikingly, only five serum samples were simultaneously positive by both tests. When the results were analyzed per patient, 36 (84%) presented at least one serum positive by one test. For 30 of them, positivity by one test was always associated with negative results by the other test for any of the tested sera. For six patients whose sera were positive for either an antigen or an antibody response, a balance between positivity by each test was evidenced by kinetic analysis of sera drawn during the time course of the infection. Controls consisted of 98 serum samples from healthy individuals, 93 serum samples from patients hospitalized in intensive care units, and 39 serum samples from patients with deep mycoses. The sensitivities and specificities were 40 and 98% and 53 and 94% for mannanemia or antibody detection, respectively. These values reached 80 and 93%, respectively, when the results of both tests were combined. These observations, which clearly demonstrate a disparity between circulation of a given mannan catabolite and antimannan antibody response, suggest that use of both enzyme immunoassays may be useful for the routine diagnosis of candidiasis.     

Fever-like thermal conditions regulate the activation of maturing dendritic cells

Fever is one of the most frequent clinical signs encountered in pathology, especially with respect to infectious diseases. It is currently thought that the role of fever on immunity is limited to activation of innate immunity; however, its relevance to activation of adaptive immunity remains unclear. Dendritic cells (DCs) that behave as sentinels of the immune system provide an important bridge between innate and adaptive immunity. To highlight the role of fever on adaptive immunity, we exposed murine bone marrow-derived lipopolysaccharide (LPS)- or live bacteria-maturing DCs over a 3-h period to 37 degrees C or to fever-like thermal conditions (39 degrees C or 40 degrees C). At these three temperatures, we measured the kinetics of cytokine production and the ability of DCs to induce an allogeneic mixed lymphocyte reaction. Our results show that short exposure of DCs to temperatures of 39 degrees C or 40 degrees C differentially increased the secretion of interleukin (IL)-12p70 and decreased the secretion of IL-10 and tumor necrosis factor alpha by maturing DCs. These fever-like conditions induced a regulation of cytokine production at the single-cell level. In addition, short-term exposed LPS-maturing DCs to 39 degrees C induced a stronger reaction with allogeneic CD4(+) T cells than maturing DCs incubated at 37 degrees C. These results provide evidence that temperature regulates cytokine secretion and DC functions, both of which are of particular importance in bacterial diseases.     

Gastrointestinal colonization and systemic dissemination by Candida albicans and Candida tropicalis in intact and immunocompromised mice.

Gastrointestinal colonization and systemic dissemination by Candida albicans and Candida tropicalis were compared in intact and immunocompromised mice. Five-day-old CFW mice were inoculated by the oral-intragastric route with 1.0 x 10(7) CFU of two C. albicans and two C. tropicalis strains isolated from the blood of patients with acute leukemia and with C. albicans 4918 and its cerulenin-resistant mutant 4918-10. C. albicans and C. tropicalis spread to the lungs, liver, and kidneys within 30 min postinoculation, and organ CFU of the two species were comparable over the following 10 days. Close association of blastoconidia with the villous surface of the small intestine resulted in lysis of microvilli and then progressive invasion of villi. Blastoconidia within villi were surrounded by a conspicuous zone of clearing. Persistent colonization of the small and large intestines by C. albicans blood isolates and strains 4918 and 4918-10 was similar for 31 days after inoculation, but consistently exceeded that of C. tropicalis. In mice colonized with C. albicans, immunosuppression with cortisone acetate and cyclophosphamide on days 30 and 33 after inoculation increased stomach CFU 40- to 370-fold and intestinal CFU 30- to 80-fold. In contrast, persistent colonization by C. tropicalis was undetectable before immunosuppression and only became apparent after treatment. C. albicans disseminated more frequently and with higher organ CFU than C. tropicalis. Despite this fact, 20% of mice infected with C. tropicalis died, compared with 4% infected with C. albicans blood isolates. Indirect immunofluorescence revealed penetrative growth by Candida hyphae exclusively in the mucosa and submucosa of the stomach from immunosuppressed, persistently colonized mice. Taken together, the data indicate that C. tropicalis appears to be more virulent than C. albicans and that factors responsible for gastrointestinal colonization, systemic dissemination, and mortality in immunocompromised mice may not be identical.     

Anti-HBs Cellular Immune Response in Kidney Recipients before and 4 Months after Transplantation

Patients with renal failure represent a population at risk for hepatitis B, since only 50 to 60% of them develop protective humoral responses after vaccination. As this could be due to an altered regulation of cellular immune responses, the objectives of the present study were to evaluate the proliferative abilities of lymphocytes from patients with chronic renal failure after stimulation in vitro with a mitogen (pokeweed mitogen [PWM]) or HBsAg. In order to differentiate between the immunodeficiency associated with renal failure and that due to immunosuppression posttransplantation, the same subjects were tested before and 4 months after kidney transplantation. The lymphoproliferation assay used was performed by flow cytometry, which is based on sequential analysis of the cell cycle and which allows analysis of cytokine production. Serologically, the group of 36 patients tested comprised 22% nonresponders, 30% poor responders, and 48% responders. Lymphocyte growth was observed for all patients after stimulation with PWM, indicating that these cells had the capacity to proliferate in vitro. The level of lymphoproliferation in response to PWM was significantly reduced after transplantation, yet both before and after transplantation, all serologic nonresponders developed cellular responses to at least two vaccines. No correlation between humoral and cellular responses was shown. Proliferating cells were lymphocytes, which mostly secreted interleukin 4 (IL-4) and IL-10 for the three serologic groups. This study suggests that even when repeated vaccination fails to induce significant antibody levels in patients with renal failure, specific HBs cellular responses develop, and these may prove to be efficient in protecting these patients against hepatitis B.     

Evidence for a fourth locus in Usher syndrome type I.

Usher syndrome type I (US1) is an autosomal recessive condition in which three different genes have been already localised (USH1A, USH1B, and USH1C on chromosomes 14q32, 11q13, and 11p15 respectively). The genetic heterogeneity of US1 has been confirmed in a previous study by linkage analysis of 20 French pedigrees. Here, we report the genetic exclusion of the three previously reported loci in two large multiplex families of Moroccan and Pakistani origin, suggesting the existence of at least a fourth locus in Usher syndrome type I.