Health status measurement in Toxic Oil Syndrome

Toxic Oil Syndrome (TOS) is a previously unreported condition which affected more than 20,000 people in Spain in 1981 and whose natural history is unknown. In 1993-94, a stratified random sample of 1400 survivors was drawn to measure their health status through clinical examination and their self-perception of well-being through the Nottingham Health Profile Questionnaire (NHPQ). Two-thirds of the sample population responded; indirect estimates suggest that selection bias was limited. Clear and intermediate signs of neuropathy were found in one-fifth and one-half of the patients, respectively. One-fourth and one-sixth showed some degree of scleroderma and contractures. All conditions were more frequent in women than in men and in age >50 than in younger ages. Although no concurrent control group was included in the study, prevalences of these conditions are well above expectations and are largely attributable to TOS. NHPQ scores increased with age in both sexes up to age 50, after which they reached a plateau (with values around 48 in men and 62 in women). Scores were associated to the occurrence of peripheral neurological changes, contractures, and scleroderma-like conditions. A multivariate analysis indicated age, sex, and severity of neurological conditions as major determinants of the NHPQ scores. This overall pattern of findings is peculiar to TOS and differs from the typical post-disaster nonspecific syndrome.     

Developmental expression of G proteins in a migratory population of embryonic neurons

Directed neuronal migration contributes to the formation of many developing systems, but the molecular mechanisms that control the migratory process are still poorly understood. We have examined the role of heterotrimeric G proteins (guanyl nucleotide binding proteins) in regulating the migratory behavior of embryonic neurons in the enteric nervous system of the moth, Manduca sexta. During the formation of the enteric nervous system, a group of approx. 300 enteric neurons (the EP cells) participate in a precise migratory sequence, during which the undifferentiated cells populate a branching nerve plexus that lies superficially on the visceral musculature. Once migration is complete, the cells then acquire a variety of position-specific neuronal phenotypes. Using affinity-purified antisera against different G protein subtypes, we found no apparent staining for any G protein in the EP cells prior to their migration. Coincident with the onset of migration, however, the EP cells commenced the expression of one particular G protein, Go alpha. The intensity of immunostaining continued to increase as migration progressed, with Go alpha immunoreactivity being detectable in the leading processes of the neurons as well as their somata. The identity of the Go alpha-related proteins was confirmed by protein immunoblot analysis and by comparison with previously described forms of Go alpha from Drosophila. When cultured embryos were treated briefly with aluminium fluoride, a compound known to stimulate the activity of heterotrimeric G proteins, both EP cell migration and process outgrowth were inhibited. The effects of aluminium fluoride were potentiated by alpha toxin, a pore-forming compound that by itself caused no significant perturbations of migration. In preliminary experiments, intracellular injections of the non-hydrolyzable nucleotide GTP gamma-S also inhibited the migration of individual EP cells, supporting the hypothesis that G proteins play a key role in the control of neuronal motility in this system. In addition, once migration was complete, the expression of Go alpha-related proteins in the EP cells underwent a subsequent phase of regulation, so that only certain phenotypic classes among the differentiated EP cells retained detectable levels of Go alpha immunoreactivity. Thus Go may perform multiple functions within the same population of migratory neurons in the course of embryonic development.     

Impact of HIV counselling and testing on HIV seroconversion and reported STD incidence among male factory workers in Harare, Zimbabwe

OBJECTIVES: To assess the impact of HIV counselling and testing on HIV seroconversion and incidence of reported sexually transmitted diseases (STDs) among male factory workers in Harare, Zimbabwe. DESIGN: Prospective, observational study among men recruited to participate in a future workplace based AIDS prevention intervention. METHODS: Participants provided STD histories and blood for HIV antibody testing at enrolment and six month intervals during visits to factories. Participants received HIV test results, post test counselling, and free STD services at the project clinic. RESULTS: Between March 1993 and June 1995, 2,414 men were enrolled with 85% follow up. Overall HIV sero-incidence was 2.60 per 100 person-years; the incidence of reported STDs was 10.19 per 100 person-years. Men who obtained their HIV test results had significantly higher HIV sero-incidence and incidence of reported STDs compared to men who did not obtain their results (IRRs: 1.87, 3.47, respectively). Among men who obtained their HIV test results, a non-significant 40% decrease in HIV sero-incidence was observed after obtaining test results compared to before obtaining results (p = 0.18). The incidence of reported STDs, however, increased by 30% after obtaining HIV test results (p = 0.10). CONCLUSIONS: Decreased HIV sero-incidence in the face of increased reported STD incidence suggests that timely treatment of STDs may decrease the risk of acquiring HIV even in the absence of behaviour change. In populations with high rates of HIV and STDs, the greatest benefit of HIV counselling and testing may be achieved by simultaneously offering STD screening and treatment services.     

Solid-phase microextraction applied to the analysis of pesticide residues in honey using gas chromatography with electron-capture detection

The possibilities of using solid-phase microextraction to determine residues of pesticides in honey have been examined. For this purpose, three types of fiber have been assayed: polyacrylate of 85 microns thickness, and polydimethylsiloxane of 7 and 100 microns thickness. They have been applied to the extraction of 21 pesticides of different chemical families. The effects of the temperature, extraction time and ionic strength on the microextraction have been studied, proposing the most adequate for each fiber. Under optimized conditions, precision, intervals of linearity and detection limits were evaluated.     

Hemodynamic, hormonal, and renal effects of intracerebroventricular adrenomedullin in conscious sheep

Adrenomedullin, the recently described vasodilator that exhibits potent hypotensive actions when administered systemically, is also found in the central nervous system, suggesting a role for adrenomedullin as a neurohormone. However, only a limited number of studies have examined the central effects of adrenomedullin. Therefore, we have examined the integrative hemodynamic, renal, and hormonal effects of intracerebroventricular (I.C.V.) adrenomedullin in conscious sheep. Eight surgically prepared sheep received I.C.V. infusions of adrenomedullin at two doses (2 ng/kg x min followed immediately by 20 ng/kg x min each for 90 min) in a vehicle-controlled study. Water deprivation for 48 h before control infusion resulted in sheep drinking 2617 +/- 583 ml in the 90-min period following reintroduction of water. On the adrenomedullin day, drinking was halved to 1392 +/- 361 ml (P < 0.05). Adrenomedullin had no significant effect on urinary volume and sodium excretion. Plasma adrenomedullin levels remained unchanged during control infusions but were elevated by the end of I.C.V. adrenomedullin infusions (P < 0.001). Plasma ANP levels were also increased approximately 50% (P < 0.05). Plasma levels of both ACTH and cortisol were also increased 3- to 4-fold in response to I.C.V. adrenomedullin (P < 0.05). There was no significant difference in arterial pressure, heart rate, or cardiac output between study days. In conclusion, adrenomedullin within the central nervous system may have at least two roles: modulation of the hypothalamo-pituitary-adrenal axis and protection against fluid overload.     

Adherence to guidelines for the prevention of HIV-related respiratory diseases

In this study we characterized the pattern of use of preventive therapies for specific respiratory diseases within a cohort of homosexual men and assessed the impact of targeted feedback on the level of compliance with guidelines for these diseases. All human immunodeficiency virus seronegative (HIV-) (n=169) and acquired immune deficiency syndrome (AIDS)-free human immunodeficiency virus seropositive (HIV+) (n=154) participants in our cohort, who completed four annual visits between October 1989 and December 1993, were identified. Information about the use of purified protein derivative (PPD) (tuberculin) testing, history of pneumococcal vaccinations, influenza vaccinations, use of Pneumocystis carinii pneumonia (PCP) prophylaxis, symptoms and CD4 counts was obtained yearly for each subject. In 1992, participating physicians were provided with feedback regarding the overall levels of compliance with contemporary guidelines for the prevention of respiratory disease. As part of this exercise, the guidelines were distributed and discussed. The percentage of HIV+ patients who underwent PPD testing increased from 43 to 65% during the study (p=0.001). Significantly more HIV+ than HIV- patients underwent PPD testing (p<0.001). A total of 144 (94%) HIV+ men received at least one influenza vaccination compared to 60 (35%) HIV- men (p<0.001). Utilization of influenza vaccination in the HIV+ group significantly increased from 78% in 1992 to 92% in 1993 (p<0.001). A total of 104 (68%) HIV+ men received pneumococcal vaccination compared to 2 (1%) HIV- men (p<0.001). Among HIV+ individuals whose absolute CD4+ count was less than 200 cells x mm(-3), the percentage of men who received primary PCP prophylaxis was 0, 86, 72 and 88 for the years 1990-1993, respectively. Among HIV+ patients whose only eligibility criterion for PCP prophylaxis was a CD4+ percentage <20%, compliance was 55, 30, 37 and 50% for the years 1990-1993, respectively. Among HIV+ subjects, increases in the compliance level were noted for all preventive therapies after targeted feedback was provided during the last quarter of 1992. However, only utilization of influenza vaccine exceeded a 90% compliance in 1993. These data demonstrate that a suboptimal level of compliance with current guidelines for the prevention of respiratory disease among human immunodeficiency virus-infected individuals can be significantly improved using targeted feedback. Although it is likely that similar effects could be achieved in other populations or the community at large, this remains to be demonstrated.     

Relevance of pheno- and genotyping in clinical drug development

Individual variability in the plasma concentration of a xenobiotic is a considerable problem in the clinical use as well as in the clinical development of a new drug. In clinics altered drug response and drug toxicity are predominant findings. In clinical development (especially in the early phases) problems with the interpretation of individual pharmacokinetics and appearance of unexpected drug reactions may occur. One major reason for the inter-and intraindividual variability is based on variations in the metabolism of the drug that are dependent on the genetic variations of the metabolising enzymes. However, while the first of these so-called polymorphisms has already been described in 1979 (for a review see [Daly 1995]) and knowledge of these polymorphisms are still growing, the impact on clinical practice as well on the selection and development of drug candidates in the pharmaceutical industry at present is still limited. This may change in the near future as recent advances in molecular biology and especially in the diagnosis of individual genomic characteristics will result in a better understanding of the basic principles of the polymorphisms. High throughput screening methods will reveal information on the distribution of these polymorphic alleles in the target population and enable the broad characterization of the drug candidate in in vitro systems. The early knowledge as to whether a polymorphic pathway is involved in drug metabolism/action and of its clinical relevance will lead to a reduction of time and costs in the development of a new drug.