The farnesyltransferase inhibitor FTI-277 suppresses the 24-kDa FGF2-induced radioresistance in HeLa cells expressing wild-type RAS.

In this paper, we describe the effect of the inhibitor of farnesyltransferase (FTI-277) on radioresistance induced by the 24-kDa isoform of FGF2 in human cells expressing wild-type RAS. Treatment with FTI-277 (20 microM) for 48 h prior to irradiation led to a significant decrease in survival of radioresistant cells expressing the 24-kDa isoform (HeLa 3A) but had no effect on the survival of control cells (HeLa PINA). The radiosensitizing effect of FTI-277 is accompanied by a stimulation of postmitotic cell death in HeLa 3A cells and by a reduction in G(2)/M-phase arrest in both cell types. These results clearly demonstrate that at least one farnesylated protein is involved in the regulation of the radioresistance induced by the 24-kDa isoform of FGF2. Furthermore, the radiation-induced G(2)/M-phase arrest is also under the control of farnesylated protein. This work also demonstrates that FTase inhibitors may be effective radiosensitizers of certain human tumors with wild-type RAS.

Radioresistance induced by the high molecular forms of the basic fibroblast growth factor is associated with an increased G2 delay and a hyperphosphorylation of p34CDC2 in HeLa cells.

The basic fibroblast growth factor-(bFGF) mediated signal transduction pathway has been implicated in cellular resistance to ionizing radiation. bFGF is synthesized from the same mRNA in four isoforms resulting from alternative initiations of translation at three CUG start codons (24, 21.5, and 21 kDa) and one AUG start codon (18 kDa). We analyzed the implication of high- and low-molecular forms of bFGF in radioresistance acquisition. For this, we transfected HeLa cells with retroviral vector containing either the CUG-initiated 24-kDa molecular form (HeLa 3A cells), the AUG-initiated 18-kDa molecular bFGF form (HeLa 5A cells), or the vector alone (HeLa PINA cells). A significantly increased radioresistance was obtained only in HeLa 3A cells (Dq = 810 +/- 24 cGy) compared with wild-type cells (Dq = 253 +/- 49 cGy) or HeLa PINA cells (Dq = 256 +/- 29 cGy; P < 0.001). This radioprotective effect was independent of an inhibition of radiation-induced apoptosis but related to an increased G2 duration after irradiation and to an hyperphosphorylation of p34cdc2 kinase. Knowledge of the high-molecular bFGF form-induced radioresistance pathway could offer novel targets for decreasing the radioresistance phenotype of tumors expressing high amounts of bFGF, such as glioblastoma.

Epidemiology training initiatives in the English-speaking Caribbean: preliminary evaluation - abstract

An important mandate of the Caribbean Epidemiology Centre, (CAREC) is the development of epidemiological capacity among member states. From 1979 to 1985, the Centre received a USAID grant for epidemiology training. However, migration, promotion and other demands led to a subsequent decline in overall epidemiological capacity. The call to renew training activities came from CAREC's Scientific Advisory Committee in 1990 and from Caribbean National Epidemiologists in 1991. Technical assistance was secured from the Emory School of Public Health, funded by the Fogarty International Center (NIH), while financial support was provided by the British Development Division in the Caribbean (BDDC), in late 1992. The resulting programme includes three operational objectives: to strengthen epidemiological skills for disease surveillance; outbreak investigation; evaluation of screening methods and to conduct community surveys; to increase knowledge of and facilitate experience with the design, organization and implementation of field research, questionnaire design data collection; and to increase microcomputer knowledge and skills for data analysis and interpretation. The programme applies adult education principles within a series of workshops and complementary field study activities. Trining activities commenced in the second quarter of 1993, and over 60 individuals had participated by the end of the year. Several evaluation instruments reveal positive outcomes in each of three sites to date. Major gains in knowledge have been demonstrated in pre/post-course testing. Multiple regression analysis reveals that the strongest predictor of post-course performance (including epidemiology, statistics, and computing) is pre-course performance in computing (AU)

Risk factors associated with the typhoid outbreak in Westmoreland, Jamaica in 1990 - abstract

The first wave of the typhoid epidemic started in July 1990, followed by a second wave in September 1990. One hundred and forty-five cases in the latter were studied to determine the risk factors associated with transmission of the Salmonella typhi in the three affected areas in Westmoreland. This was a case control study in which 145 cases were compared with 154 matched controls. The same questionnaire was administered to both groups. The mean age of the cases was similar to that of the controls (13.1 ñ 9.1 SD vs 13.2 ñ 7.9 SD). Sex distribution of the cases and controls was also similar (females: 44.8 percent vs 46.8 percent; males: 55.2 percent vs 53.2 percent). More than half of the cases (58.6 percent) and controls (64.9 percent were students). The purchase of two or more food items from vendors (odds ratio 2.5), piped water into the home (odds ratio 2.4), preparing food for the household (odds ratio 2.4) and the eating of ice-cream (odds ratio 2.2) were all associated with risk of typhoid fever. The results of the case control study were consistent with the possible spread of typhoid through the purchase of food items or ice-cream from vendors or through the piped water system but none of these associations could be established as causative factors on the basis of the case control study alone. Public health measures including health education were directed at controlling all possible modes of transmission of the typhoid epidemic (AU)

Bancroftian filariasis in coastal north Trinidad: the effects of mass chemotherapy using spaced doses of diethylcarbamazine citrate on human microfilaraemias and vector infection rates.

The effects of a mass chemotherapy programme using spaced doses of diethylcarbamazine citrate on Wuchereria bancrofti microfilaraemias and vector infection rates were studied in an isolated rural community of 650 people in north Trinidad where a microfilaria rate of 15% had previously been recorded. A single oral dose of 6 mg/kg body weight was given at monthly intervals for one year. After 6 months, 79% (52/66) of persons previously microfilaraemic had become negative. After 12 months the negative proportion had increased to 90% (63/70). The geometric mean microfilaria density of those still microfilaraemic was reduced from 19.7 to 4.6 per 100 mm3 of blood. Of 147 initially negative persons, none had become positive following treatment. Filarial infection rates in Culex quinquefasciatus from randomly sampled houses fell from 6.4% to zero; in houses where occupants with microfilaraemia had been identified before treatment, the rate was reduced from 15.8% to zero. In a supplementary study, however, weekly collections from one initially positive house showed a rapid decline in the vector infection rate from 43% to 2% after three months but an additional 3 months elapsed before the index reached zero. There was negligible microfilarial uptake by the vectors from residual low-density microfilaraemias (less than 10 microfilariae per 100 mm3 of blood) after chemotherapy.

Parasitological and clinical studies of Wuchereria bancrofti and Mansonella ozzardi in coastal north Trinidad, West Indies.

PIP: A parasitological and clinical survey of Wuchereria bancrofti and Mansonella ozzardi was conducted in Blanchisseuse, an isolated rural community of 650 people in coastal north Trinidad. W. bancrofti microfilariae were found in 15% of the resident population and the prevalence was higher in males (19%) than in females (12%). Microfilaraemias were undetected in children under 5 years of age but 12% of children and adolescents between 5 and 19 years of age were positive. Microfilaraemias were most common in males aged 40-59 years (34%) and in females in the same age group (21%). Whereas geometric mean microfilaria densities were generally higher in females than in males under 40 years old, in the older age groups the pattern was reversed, the difference being especially pronounced in the over 60s. There were more than 2 times as many males with M. ozzardi microfilariae (35%) than there were females (15%). The prevalence was low in children and young adults but increased with age thereafter. In the older age groups microfilaria densities followed a similar trend. Genital signs compatible with lymphatic filarial disease were seen in 29% of males; these included hydrocoele (15%) and elephantiasis of the scrotum (1%). Most signs were seen in persons over 50 years of age. 6% of females had lymphoedema of the leg(s), and in 4 cases (2.3%) this had progressed to elephantiasis. A positive association was found between M. ozzardi microfilaraemia and clinical history of articular pain. The findings suggest that both filarial species are of some public health significance in at least 1 rural area of Trinidad, and they provide a basis for the development of a lymphatic filariasis control strategy in the community.^ieng

Parasitological and clinical studies of Wuchereria Bancrofti and Mansonella Ozzardi in coastal North Trinidad, West Indies

A parasitology and clinical survey of Wuchereria bancrofti and Mansonella ozzardi was conducted in Blanchisseuse, an isolated rural community of 650 people in coastal north Trinidad. W. bancrofti microfilariae were found in 15 percent of the resident population and the prevalence was higher in males (19 percent) than in females (12 percent). Microfilaraemias were undetected in children under 5 years of age but 12 percent of children and adolescents between 5 and 19 years of age were positive. Microfilaraemias were most common in males aged 40-59 years (34 percent) and in females in the same age group (21 percent). Whereas geometric mean microfilaria densities were generally higher in females than in males under 40 years old, in the older age groups the pattern was reversed, the difference being especially pronounced in the over sixties. There were more than twice as many males with M. ozzardi microfilariae (35 percent) than there were females (15 percent). The prevalence was low in children and young adults but increased with age thereafter. In the older age groups microfilaria densities followed a similar trend. Genital signs compatiable with lymphatic filarial disease were seen in 29 percent of males; these included hydrocoele (15 percent) and elephantiasis of the scrotum (1 percent). Most signs were seen in persons over 50 years of age. Six per cent of females had lymphoedema of the leg(s), and in four cases (2.3 percent) this had progressed to elephantiasis. A positive association was found between M. ozzardi microfilaraemia and clinical history of articular pain (p<0.001). The findings suggest that both filarial species are some public health significance in at least one rural area in Trinidad, and they provide a basis for the development of a lymphatic filariasis control strategy in the community (AU)

Evaluation of a membrane (Nuclepore) filtration method using capillary blood for the detection of microfilariae

The efficacy of a membrane (Nuclepore) filtration technique using capillary blood (100 mm 3) for the detection of blood-circulating microfilariae was investigated during a prevalence survey for Wuchereria bancrofti and Mansonella ozzardi in north Trinidad by comparing results thus obtained with results from conventional thick smear preparations (25mm3) and from membrane (Nuclepore) filtration of venous blood (1 ml). Prevalence rates of W. bancrofti were 14 percent by thick smear, 17 percent by filtration of capillary blood and 6 percent by filtratioon of venous blood. For M. ozzardi the corresponding rates were 27 percent, 29 percent and 31 percent. A total of 389 persons was examined by all three methods. Microfilaria detection rates for both of the filtration techniques were significantly higher than by thick smear preparation, with the exception of results for M. ozzardi obtained by filtration of capillary blood. There was no significant difference between the number of positive persons detected by filtration of capillary blood and filtration of venous blood. Significantly higher microfilaria densities per unit volume of blood were recorded by thick smear preparation and filtration of capillary blood than by filtration of venous blood. Whereas results for the two capillary blood techniques were similar. In the detection of low density microfilaraemias, membrane filtration of capillary blood provides a practical and sensitive alternative to venous blood filtration and has the additional advantage of capilary blood collection rather than venepuncture.(AU)