Comprehensive primary health care in South America: contexts, achievements and policy implications

This article summarizes an extensive review of South American experiences with primary health care since the Declaration of Alma-Ata. It aims to address the following specific questions: What are the enabling and constraining historical and structural conditions for primary health care policies and practices? How has health care reform supported or undermined primary health care? What evidence exists on the effectiveness of primary health care? What strategies are common to best practices? What evidence exists on the roles of citizen participation and intersectoral action? And finally, what are the policy lessons to be learned from these experiences? Narrative synthesis was used to identify and examine patterns in the data consistent with these questions. Conditions that were found to promote successful implementation of primary health care are outlined, together with features of effective primary health care systems that help create more equitable health services and health outcomes.     

Long-term surgical and visual outcomes in primary congenital glaucoma: 360 degrees trabeculotomy versus goniotomy.

PURPOSE: To compare the visual outcome and refractive status of children with primary congenital glaucoma who underwent 360 degrees trabeculotomy or goniotomy as an initial surgical procedure. METHODS: This retrospective study describes 24 eyes (15 patients) with primary congenital glaucoma that underwent 360 degrees trabeculotomy as the initial procedure and 40 eyes (23 patients) that underwent goniotomy as the initial procedure. Inclusion criteria were: (1) diagnosis of primary congenital glaucoma and initial angle surgery before 1 year of age, (2) no other ocular or systemic diseases, (3) 360 degrees trabeculotomy or goniotomy as the first surgical procedure, and (4) ability to obtain an Allen or Snellen visual acuity. A postoperative vision of 20/50 or better was considered good. Surgical success was defined as an intraocular pressure (IOP) less than 22 mm Hg with or without medication and without evidence of a progressive optic neuropathy. RESULTS: The IOP was successfully controlled in 92% of eyes in the trabeculotomy group and in 58% of eyes in the goniotomy group (P =.004). Of eyes in the trabeculotomy group, 79% had vision of 20/50 or better compared with 53% in the goniotomy group (P =.03). High myopia was more prevalent in the goniotomy group, but this difference was not statistically significant (P =.16). A poor visual outcome was associated with failure of the angle surgery or poor compliance with follow-up and amblyopia therapy. CONCLUSION: For primary congenital glaucoma, 360 degrees trabeculotomy is a highly effective procedure that results in excellent pressure control and is at least as successful as multiple standard procedures. In this study, 360 degrees trabeculotomy resulted in better vision than what is reported in the literature for standard angle procedures.     

Procoagulant activity may be a marker of the malignant phenotype in experimental prostate cancer.

Using a one-stage kinetic chromogenic assay, we studied the procoagulant activity (PCA) of prostatic tissue in an experimental model of prostate cancer in the rat. PCA was present in homogenates of rat prostate glands containing either benign or malignant tumours. The procoagulant activated factor X directly and was provisionally characterised as a tissue factor-factor VIIa complex. There was no significant differences in PCA between control rats and rats exposed to carcinogens that did not develop tumour. Levels in rats that developed tumours were significantly higher (P < 0.01) than all other groups and there was a positive correlation between tumour weight and PCA (r = 0.85, P < 0.001). Furthermore, prostatic PCA levels were higher in the metastasis (P < 0.02). We conclude that PCA reflects the malignant phenotype in this animals, the PCA of the primary tumour was compared with that of the corresponding secondary deposit and levels were higher in the metastasis (P < 0.02). We conclude that PCA reflects the malignant phenotype in this model of experimental prostate cancer and suggest that this parameter is worth evaluating as a potential tumour marker in the human disease.     

Survival of very young children with medulloblastoma (primitive neuroectodermal tumor of the posterior fossa) treated with craniospinal irradiation

Purpose: Very young children with medulloblastoma are considered to have a worse prognosis than older children. As radiotherapy remains an important part of the treatment, the adverse prognosis could be due to inadequate radiation treatment rather than biological factors. We analyzed the published literature to examine the impact of radiotherapy on survival in this group.

Methods and Materials: A Medline search was performed and we reviewed studies of treatment of medulloblastoma where radiotherapy was delivered using megavoltage equipment and the minimum follow-up allowed the calculation of 5-year survival rates.

Results: Thirty-nine studies were published between 1979 and 1996 with a treatment including craniospinal irradiation and boost to the posterior fossa. Eleven studies comprising 1366 patients analyzed survival by age at diagnosis. Eight of 11 studies showed a worse 5-year survival for the younger patient group which reached statistical significance in two. There is also a suggestion of a higher proportion of children with metastatic disease at presentation in the very young age group. The usual policy in younger children was to give a lower dose of radiotherapy to the craniospinal axis (CSA) and posterior fossa (PF) with reduction of dose in the range of 15 to 25% compared to standard treatment. As dose reduction to the posterior fossa is associated with worse survival and local recurrence is the predominant site of failure, the major determinant of worse survival in very young children with medulloblastoma may be suboptimal radiotherapy. Protocols including postoperative chemotherapy with delayed, omitted, or only local tumor irradiation do not reach survival rates of protocols with standard radiotherapy, also suggesting a continued importance for irradiation.

Conclusion: Very young children with medulloblastoma have a worse prognosis than older children. Inadequate radiation dose and technique to the primary tumor region may be a major contributing factor. Current chemotherapeutic regimes alone are not sufficient to compensate for reduced radiation doses and volumes.     

Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone bxsb mice

The diverse genetic backgrounds of lupus-prone murine models, which produce both quantitative and qualitative differences in disease expression, may be a valuable resource for studying the influence of environmental exposure on autoimmune disease in sensitive populations. We tested this premise by exposing autoimmune-prone BXSB and the nonautoimmune C57BL/6 mice to the heavy metal mercury. Although both strains express a nonsusceptible H-2 haplotype, exposure to mercury accelerated systemic autoimmunity in both male and female BXSB mice, whereas the C57BL/6 mice were resistant. The subclasses of antichromatin antibodies elicited in BXSB mice by mercury exposure were more consistent with the predominant Th1-type response of idiopathic disease than with the Th2-type response found in mercury-induced autoimmunity (HgIA). The appearance and magnitude of both humoral and cellular features of systemic autoimmunity correlated with the mercury dose. Furthermore, environmentally relevant tissue levels of mercury were associated with exacerbated systemic autoimmunity. These studies demonstrate that xenobiotic exposure can accelerate spontaneous systemic autoimmunity, and they support the possibility that low-level xenobiotic exposure enhances susceptibility to systemic autoimmunity in genetically susceptible individuals.     

Effects of academic examination stress on eating behavior and blood lipid levels

The influence of academic examination stress on eating behavior and lipid profiles and the moderating effect of dietary restraint, trait anxiety, and social support availability was assessed in university students. One hundred and seventy-nine students were divided into exam-stress groups (51 women, 64 men) and control groups (48 women, 16 men) and were assessed at baseline and then within 2 weeks of exams or an equivalent point for the control group. Perceived stress, emotional well-being, and fasting lipid profiles were measured, and dietary information was collected by interview. The exam-stress group reported significant increases in perceived stress and deterioration in emotional well-being at the exam sessions compared with baseline sessions. No general effects of exam stress on food intake were observed, and there was no interaction between stress and dietary restraint. However, students in the exam-stress group with high trait anxiety and low social support showed significant increases in total energy intake between baseline and exam sessions, whereas individuals with low trait anxiety and high social support showed a reduction in energy intake. Students with high trait anxiety and low social support showed increases between baseline and exam sessions in the amount of fat and saturated fat consumed. Women in the exam-stress group taking oral contraceptives showed a significant increase in total cholesterol between baseline and exam sessions. The results are discussed in relation to the effects of naturally occurring episodic stress on health behavior and on lipid profiles. Tessa M. Pollard now at the Department of Anthropology, University of Durham, England.     

Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes

The CAMPATH-1 (CD52) antigen is a 21–28 kDa glycopeptidewhich is highly expressed on lymphocytes and macrophages andis coupled to the membrane by a glycosylphosphatidylinositol(GPI) anchoring structure. The function of this molecule isunknown. However, it is an extremely good target for complement-mediatedattack and antibody-mediated cellular cytotoxicity. The humanizedCAMPATH-1H antibody, which is directed against CD52, is veryefficient at mediating lymphocyte depletion in vivo, and iscurrently being used in clinical trials for lymphoid malignancyand rheumatoid arthritis. It is therefore important to examinethe functional effects of this antibody on different lymphocytesub-populations. Because several other GPI-linked moleculesexpressed on the surface of T lymphocytes are capable of signaltransductlon resulting in cell proliferation, we have investigatedwhether the CAMPATH-1 antigen can also mediate these effects.In the presence of phorbol esters and cross-linking anti-lgantibodies, mAbs specific for CD52 induced proliferation andlymphokine production in highly purified resting CD4⁺ and CD8⁺T lymphocytes. The ret lgG2c YTH 361.10 anti-CD52 antibody,however, was able to activate resting CD4⁺ and CD8⁺ T cellsdirectly without cross-linking or phorbol myristate acetatein the absence of Fc-bearlng cells. Anti-CD52 antibodies alsoaugmented the anti-CD3 mediated proliferatlve response of CD4⁺and CD8⁺ T cells when the two antibodies were co-immobilizedonto the same surface or cross-linked in solution by the samesecond antibody. Both CD4⁺CD45RA and CD4⁺CD45RO T cells werestimulated to proliferate by anti-CD52 antibodies in the presenceof appropriate co-stimulatory factors. Antl-CD52 mAbs did not,however, synerglze with anti-CD2 or CD28 mAb to induce CD4⁺T cell proliferation. The activation of CD4⁺ T cells by antl-CD52antibodies was inhibited by cyclosporin A, suggesting a rolefor the calcineurin-dependent signal transduction pathways.Although CD52 could transduce a signal In T cells, anti-CD52antibodies did not inhibit antigen-specific or polyclonal Tcell responses, suggesting this molecule does not play an essentialco-stimulatory role in normal T cell activation.     

Cystic fibrosis and the use of pharmacogenomics to determine surrogate endpoints for drug discovery

Cystic fibrosis (CF) is caused by a mutation in the CFTR gene, encoding a chloride channel. For the most common mutation, Delta F508, the basis of the deficit is the failure of the mutant CFTR channel protein to traffic properly to the apical plasma membrane of the affected epithelial cell. The trafficking failure results in loss of the cyclic adenosine monophosphate (cAMP)-activated chloride channel function of the CFTR protein in the plasma membrane. The lung is the principal site affecting patient morbidity and mortality in CF. The main reason is that the CF airway epithelial cells also secrete high levels of the proinflammatory cytokine interleukin (IL)-8, resulting in massive cellular inflammation, infection, tissue damage and lung destruction. The relationship between the trafficking defect, the loss of chloride channel activity, and inflammation is not known. However, gene therapy of CF lung epithelial cells with the wild-type CFTR gene can repair the chloride channel defect, as well as suppress the intrinsic hypersecretion of IL-8. Repair of both defective channels and high IL-8 secretion can also be effected by treatment with the candidate CF drug CPX, which is in clinical trials in CF patients. CPX acts by binding to the mutant CFTR protein, and helps the protein to mature and gain access to the plasma membrane. CPX also suppresses the synthesis and secretion of IL-8 from CF epithelial cells, presumably by virtue of its repair of the trafficking defect of mutant CFTR. To guide pharmacogenomic experiments we have therefore hypothesized that the genomic signature of CF epithelial cells treated with CPX should resemble the signature of the same cells repaired by gene therapy. We have developed two algorithms for identifying genes modified by repair of CFTR defects. The GRASP algorithm uses a statistical test to identify the most profoundly changing genes. The GENESAVER algorithm allows us to identify those genes whose pattern of expression changes in-phase or out-of-phase with IL-8 secretion by CF cells. For the latter algorithm we modified IL-8 secretion from CF cells by treatment with wild-type CFTR, with CPX, or by exposure to bacteria. The results have supported the hypothesis, and have provided a basis for considering the common pharmacogenomic expression signature as a surrogate endpoint for CF drug discovery. Significantly, the nature of the hypothesis, as well as the algorithm developed for this study, can be easily applied to pharmacogenomic studies with other goals.     

Protection of cortical neurons against oxygen-glucose deprivation and N-methyl-D-aspartate by DIDS and SITS

The Cl(-) channel blockers, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) or 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) dose-dependently protected against oxygen-glucose deprivation in cultured rat cortical neurons. DIDS or SITS attenuated oxygen-glucose deprivation-induced increases in extracellular glutamate concentrations and intracellular Ca(2+). DIDS or SITS provided moderate protection against N-methyl-D-aspartate (NMDA) toxicity and decreased NMDA receptor-mediated increases in intracellular Ca(2+). Whole-cell NMDA receptor currents were attenuated 39+/-2% and 21+/-3% by 1 mM DIDS and SITS, respectively. Other Cl(-) channel blockers as equipotent as DIDS and SITS did not decrease oxygen-glucose deprivation- or NMDA-mediated neuronal Ca(2+) influx or toxicity. Neurotoxicity by exogenous glutamate was not prevented by SITS and was exacerbated by DIDS. Reductions in oxygen-glucose deprivation-induced increases in intracellular Ca(2+) levels underlie neuroprotection by DIDS and SITS. This was a reflection of lower extracellular [glutamate], direct inhibition of Ca(2+) influx through postsynaptic NMDA receptors, and possibly through other protective properties associated with DIDS and SITS.