Malaria vaccines

Significant progress has been made in the development of the malaria vaccine during the last 20 years. Ninety percent of the 300–500 million clinical cases of malaria per year worldwide occur in Africa. Thus, research must be directed toward the 1 million African children under 5 years of age who die every year of malaria. An asexual blood-stage vaccine, capable of reducing severe and complicated malaria and malaria-related mortality, is therefore an important public health tool in these countries. Although knowledge of the parasite's biology is incomplete, research has allowed insight into some of the mechanisms that the parasite uses to evade host immunity. This is the basis for adopting an antigenic cocktail approach toward obtaining a synthetic or recombinant subunit vaccine such as the synthetic Colombian Malaria vaccine SPf 66. During the development of Spf66, field trials under both low and high malaria endemicity areas in Latin America and Africa have been carried out. The results from these studies showed a protective efficacy ranging between 38.8 and 60.2% againstPlasmodium falciparum malaria. Given the characteristics of the normal immune response to malaria (relatively short-lived and not completely effective), it is understandable that the main goal is to try to increase the host's natural immunity. The best candidates for designing a malaria vaccine are the proteins required for parasite survival, those with low mutation rates and conserved epitopes. Because these proteins play an important role in multiple or alternative steps during the invasion process, they should be the targets against which a protective immune response should be elicited. The interaction between the malaria parasite and its host is complex. It is therefore crucial to define new ways of improving the immune response—such as directly modifying the chemical structure of epitopes or using new adjuvants or DNA immunization techniques—to produce novel vaccines against this disease.     

Practical office management of male sexual dysfunction

A discussion of the importance of the close relationship between patient and physician in the office. Emphasis on detailed history of the patient to include; physical examination, laboratory work and any additional tests if necessary.Evaluation and diagnosis of Impotence and the ability to separate organic from psychological disorders is outlined. A Sexual Function Questionnaire is attached. Treatment and success of the office approach can be obtained in a large majority of patients.     

Entrepreneurial systems. Do it yourself for profit and pleasure

You don't have to have a degree in computing or a 1 m pounds budget to create a system that improves efficiency or saves money. Gren Manuel introduces a special report which celebrates the small-scale initiatives devised and implemented by health staff armed only with a personal computer.     

Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients.

BACKGROUND: OSI-774 is an inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK) currently in clinical development. In preclinical models, the antitumor activity of OSI-774 was directly related to its ability to inhibit the EGFR-TK. On the basis of these data, we hypothesized that inhibition of the EGFR-TK will be required for this agent to be effective in the clinic. This study evaluated the pharmacodynamic effects of OSI-774 in normal skin tissues collected from patients treated with the agent in a Phase I study. METHODS: Patients with advanced cancer who were treated in a Phase I study of OSI-774 underwent a biopsy of normal skin epidermis at baseline and after the last dose of drug in the first course of treatment. The expression and activation of the EGFR, downstream signaling extracytoplasmatic-regulated kinase (Erk), and cell cycle regulator p27 were determined in paraffin-embedded skin tissues using an immunohistochemical method (IHC). The IHC data were analyzed using both a semiquantitative scoring system and an automatic absorbance quantitative IHC method. The number of cells with nuclear staining of p27 per 500 cells was determined. Plasma samples were collected to quantitate OSI-774 plasma concentrations. RESULTS: A total of 56 skin specimens was collected from 28 patients treated with OSI-774 at doses ranging from 25 to 200 mg/day. There was a significant decrease in phospho-EGFR (Tyr 1173) expression as determined semiquantitatively with OSI-774 treatment [2.75 +/- 0.51 (mean +/- SD) pretreatment versus 2.36 +/- 0.76 after treatment, pair comparison P = 0.01]. The quantitative ratio [(phopho-EGFR/EGFR) x 100] of phospho-EGFR (Tyr1173) decreased from 64.16 +/- 36.58 pretreatment to 48.87 +/- 35.37 post-treatment (pair comparison, P = 0.02). No significant differences were observed in phospho-Erk (Thr202/Tyr204) expression. The mean number of cells with nuclear staining for p27 increased from 185 +/- 101 (mean +/- SD) pretreatment to 253 +/- 111 post-treatment (pair comparison P = 0.02). A total of 12 (42.8%), 7 (25%), and 14 (50%) patients had >25% variation in the ratio of phospho-EGFR (Tyr1173), phospho-Erk (Thr202/Tyr204), and p27 expression, respectively. Only changes in p27 expression were related to the administered dose of OSI-774. CONCLUSIONS: OSI-774 exerted pharmacodynamic effects in skin tissues of 30-50% of patients treated with the agent. Up-regulation of p27, which is a downstream effect of EGFR inhibition, was dose related. Although there was a significant decrement in phospho-EGFR (Tyr1173), it was not related to the administered dose of OSI-774. On the basis of these findings and the relatively simple and reliable method to measure p27 expression, this biomarker appears to be the most promising and is being evaluated in Phase II studies as a predictor of clinical outcome.