Nutritional status following malaria control in a Vietnamese ethnic minority commune.

OBJECTIVE: To study whether control of malaria leads to catch-up growth or an increase of obesity in a marginally nourished population. SETTING: A Vietnamese ethnic minority commune in southern Vietnam. DESIGN: Repeated annual anthropometric surveys were performed from 1995 to 2000. Z-scores for height, weight and BMI for age and weight-for-height were determined by using NCHS 1978 and CDC 2000 reference tables and by the LMS method. INTERVENTION: Active malaria control that reduced the parasite carrier rate from 50% in 1994 to practically nil in 1998. RESULTS: Inhabitants were generally of short stature and very thin. Using the US reference tables, the prevalence of moderate/severe stunting among children was 53/24% and of wasting 27/9% in the first survey in 1995. Physical condition and normal daily activities of most inhabitants were normal. The repeated LMS-Z-scores uncovered a significant recovery of stunting, extending into preadolescence, including the development of a pubertal growth spurt for girls and enhancement of pubertal growth in boys, after control of malaria. The mean (95% CI) annual increase of Z-height-for-age was 0.11 (0.09-0.12) for boys and 0.14 (0.13-0.15) for girls (P<0.001). As a consequence, weight-for-age and BMI Z-scores decreased without indication of developing obesity. CONCLUSION: Catch-up growth, extending into preadolescent age, was observed in a Vietnamese ethnic minority population with a chronic state of low food intake, without indication of developing obesity. The control of malaria was probably the most significant contribution to this catch-up growth.

Control of malaria: a successful experience from Viet Nam.

OBJECTIVE: To follow malaria prospectively in an ethnic minority commune in the south of Viet Nam with high malaria transmission and seasonal fluctuation, during malaria control interventions using insecticide-treated bednets (ITBNs) and early diagnosis and treatment (EDT) of symptomatic patients. METHODS: From 1994 onwards the following interventions were used: distribution of ITBNs to all households with biannual reimpregnation; construction of a health post and appointment of staff trained in microscopic diagnosis and treatment of malaria; regular supply of materials and drugs; annual cross-sectional malaria surveys with treatment of all parasitaemic subjects, and a programme of community involvement and health education. Surveys were held yearly at the end of the rainy season. During the surveys, demographic data were updated. Diagnosis and treatment of malaria were free of charge. Plasmodium falciparum infection was treated with artesunate and P. vivax infection with chloroquine plus primaquine. FINDINGS: The baseline survey in 1994 recorded 716 inhabitants. Of the children under 2 years of age, 37% were parasitaemic; 56% of children aged 2-10 years, and 35% of the remaining population were parasitaemic. P. falciparum accounted for 73-79% of these infections. The respective splenomegaly rates for the above-mentioned age groups were 20%, 56%, and 32%. In 1999, the proportion of parasitaemic subjects was 4%, 7% and 1%, respectively, of which P.falciparum contributed 56%. The splenomegaly rate was 0%, 5% and 2%, respectively. CONCLUSIONS: A combination of ITBNs and EDT, provided free of charge, complemented by annual diagnosis and treatment during malaria surveys and community involvement with health education successfully brought malaria under control. This approach could be applied to other regions in the south of Viet Nam and provides a sound basis for further studies in other areas with different epidemiological patterns of malaria.

Nucleotide excision repair genes are upregulated by low-dose artificial ultraviolet B: evidence of a photoprotective SOS response?

Nucleotide excision repair is a major mechanism of defense against the carcinogenic effects of ultraviolet light. Ultraviolet B causes sunburn and DNA damage in human skin. Nucleotide excision repair has been studied extensively and described in detail at the molecular level, including identification of many nucleotide excision repair-specific proteins and the genes encoding nucleotide excision repair proteins. In this study, normal human keratinocytes were exposed to increasing doses of ultraviolet B from fluorescent sunlamps, and the effect of this exposure on expression of nucleotide excision repair genes was examined. An RNase protection assay was performed to quantify transcripts from nucleotide excision repair genes, and a slot blot DNA repair activity assay was used to assess induction of the nucleotide excision repair pathway. The activity assay demonstrated that cyclobutane pyrimidine dimers were removed efficiently after exposure to low doses of ultraviolet B, but this activity was delayed significantly at higher doses. All nucleotide excision repair genes examined demonstrated a similar trend: ultraviolet B induces expression of nucleotide excision repair genes at low doses, but downregulates expression at higher doses. In addition, we show that pre-exposure of cells to low-dose ultraviolet protected keratinocytes from apoptosis following high-dose exposure. These data support the notion that nucleotide excision repair is induced in cells exposed to low doses of ultraviolet B, which may protect damaged keratinocytes from cell death; however, exposure to high doses of ultraviolet B downregulates nucleotide excision repair genes and is associated with cell death.

Interspecies differences in the effect of pH on gallopamil protein binding to albumin and alpha 1-acid glycoprotein.

There is little information about the factors which influence drug protein binding between species. We have therefore investigated the role of pH on the binding of gallopamil, a calcium channel antagonist known to exhibit pH-sensitive binding, among four species, human, baboon, bovine, and canine. We used pure protein solutions of alpha 1 acid glycoprotein (AAG) (60 mg.l-1), albumin (45 gm.l-1), and their combination and three values of pH, 7.0, 7.4, and 8.0. Gallopamil protein binding was determined over a concentration range of 2.0 x 10(-7) mol.l-1 to 2.1 x 10(-3) mol.l-1 using equilibrium dialysis. Gallopamil binding in all solutions was best described using a two binding site model in the combination solution and a one binding site model in the pure solutions. pH did not affect the number of identical binding sites. However, the influence of pH on gallopamil binding was species specific. Increasing the pH from 7.0 to 8.0 influenced binding affinity differently between species. There were directionally similar changes in unbound fraction at a gallopamil concentration of 2 x 10(-7) mol.l-1 as pH increased, although there were species differences in the degree of change. In protein solutions containing both AAG and albumin a reduction in pH from 7.4 to 7.0 resulted in species-specific increases in the unbound fraction. Increasing the pH from 7.4 to 8.0 again resulted in species-specific reductions in the unbound fraction of gallopamil. Similar changes were seen when pure AAG or albumin solutions were used, indicating species variance in both gallopamil protein binding and the effect of pH on binding.

Effect of amiodarone on the disposition of acetaminophen in the rat.

Amiodarone has been demonstrated to form a cytochrome P-450Fe(II):metabolite complex. The administration of other agents which form this type of complex, such as troleandomycin, has been shown to deplete hepatic glutathione content. Depletion of glutathione will result in an increased synthesis of glutathione and an increased utilization of cysteine. Since inorganic sulfate and glutathione share cysteine as a common precursor, we postulated that amiodarone pretreatment may reduce the sulfation of drugs. To test this hypothesis, the effect of amiodarone pretreatment on acetaminophen disposition was examined in the rat. Acetaminophen (150 mg/kg) was administered to rats pretreated with amiodarone hydrochloride (100 mg/kg/d) or diluent for 5 d. There were no significant differences in the urinary recovery of acetaminophen sulfate or the partial clearance of acetaminophen to the sulfate metabolite between control and amiodarone-pretreated animals. There was a trend toward an increased urinary recovery of acetaminophen glucuronide in animals pretreated with amiodarone, but this did not reach statistical significance. Amiodarone pretreatment had no effect on the renal clearances of acetaminophen or its metabolites. These results suggest that amiodarone pretreatment does not alter the sulfation of drugs and that the formation of an amiodarone P-450Fe(II):metabolite complex is quantitatively insignificant.

Monthly variations in the pharmacokinetics of antipyrine in the rat: circannual rhythm or random variation?

We examined the pharmacokinetics of antipyrine in the rat over an 18 month period to determine whether or not the variations in pharmacokinetic parameters previously reported exhibited a circannual rhythm. While the clearance of antipyrine varied over the study period, no discernible rhythmic pattern was found. Comparing this data with previously published work also failed to demonstrate a rhythmic pattern of variability. Unlike previous investigations, we found only relatively small variations in antipyrine volume of distribution and half-life from month to month. These data indicate that the monthly variability in the pharmacokinetics of antipyrine in the rat are random and do not exhibit a circannual rhythm.

Dose-dependent effect of propafenone on in vivo drug metabolism in the rat.

The effect of propafenone, an investigational antiarrhythmic, on in vivo drug metabolism was examined in the rat using the model substrate antipyrine. Administration of a single oral dose of propafenone 100 mg/kg one hour prior to antipyrine administration resulted in a 23% reduction in antipyrine clearance. Similarly, administration of a dose of 200 mg/kg resulted in a 40% reduction in antipyrine clearance. These data indicate that propafenone, like other agents subject to substantial first-pass metabolism, is capable of inhibiting oxidative drug metabolism in vivo. The dose-dependency of this phenomenon suggests a competitive mechanism.

Effects of RNA and ribonuclease on the binding of estrogen and glucocorticoid receptors from MCF-7 cells to DNA-cellulose.

Effects of RNA and ribonucleases on the binding of estrogen- and glucocorticoid-receptor complexes from MCF-7 cells to calf thymus DNA-cellulose have been studied under cell-free conditions. Exogenous ribonucleases can increase binding of estrogen- and glucocorticoid-receptor complexes to DNA-cellulose. Purified RNA derived from MCF-7 cells can inhibit estrogen- and glucocorticoid-receptor binding to DNA-cellulose. Under low salt conditions, RNA appears to be associated with estrogen-receptor complexes from MCF-7 cells. These observations taken together suggest that there is an interaction between steroid hormone-receptor complexes and RNA. The implications of this interaction are discussed.

Estradiol-independent growth of a subline of MCF-7 human breast cancer cells in culture.

An estrogen-independent variant (R3) was selected by cloning wild type MCF-7 cells in soft agar in the presence of tamoxifen. R3 has a slightly slower growth rate under optimal growth conditions. Estradiol and tamoxifen have minimal effects on growth rate and thymidine incorporation as compared to wild type MCF-7 cells. R3 contains both cytoplasmic receptor and a receptor derived from crude nuclear extract with slightly higher numbers of cytosol receptor than wild type MCF-7. The same dissociation constant (Kd) and the same molecular weight (estimated by Sephadex chromatography) and sucrose density behavior for both cytoplasmic and nuclear estrogen receptor are seen in R3 and MCF-7. Estrogen receptor complexes were activated by salt and nucleotide and translocated to the nucleus equivalently in R3 and MCF-7. Relative binding affinities and extent of competition by estradiol and tamoxifen for cytoplasmic estrogen receptor are the same for MCF-7 and R3. Induction of progesterone receptor and nuclear estrogen receptor processing following treatment with estradiol in R3 is minimal compared with MCF-7. DNA affinity (as assessed by DNA cellulose chromatography) of estrogen receptor complexes from R3 and MCF-7 is different. R3 appears to represent a cell with a defect expressed in receptor function apart from the initial hormone-binding step.

Effects of temperature, nucleotides and sodium molybdate on activation and DNA binding of estrogen, glucocorticoid, progesterone and androgen receptors in MCF-7 human cancer cells.

We studied the effects of temperature, ribonucleotides and sodium molybdate on the activation and DNA cellulose binding of estrogen, glucocorticoid, progesterone and androgen receptor complexes in MCF-7 cells. Using DNA cellulose binding as a measure of receptor activation, we found that ribonucleotides activated all four of these receptor complexes. Temperature also activated glucocorticoid receptor complexes efficiently but activated progesterone and androgen receptor complexes less well. Temperature did not activate estrogen receptor complexes. Sodium molybdate blocked either ATP or temperature induced activation of glucocorticoid, progesterone and androgen receptor complexes but only partially blocked estrogen activation. Sodium molybdate also prevented the formation of multiple forms of estrogen and glucocorticoid receptor complexes seen on DEAE cellulose and hydroxylapatite chromatography of crude cytosol. The mechanism by which ribonucleotide enhances and molybdate inhibits activation are discussed.

Purification of estrogen receptors from MCF-7 human breast cancer cells.

We have partially purified human estrogen receptor from MCF-7 breast cancer cells in order to further characterize the chemical and biological properties of the receptor and to prepare specific receptor antibodies for radioimmunoassay. The estrogen receptor from MCF-7 cell cytosol was purified 1,166-fold (27% recovery) over starting cytosol by combining ammonium sulfate precipitation, affinity chromatography, and Sephadex G-100 gel filtration. The affinity resin consisted of estrone 17-(O-carboxymethyl)oxime:bovine serum albumin: Sepharose 4B. Under high salt conditions, the molecular weight of the purified receptor is 50,000 and is identical to that obtained on chromatography of crude cytosol. Sucrose density gradient centrifugation also revealed the purified receptor sedimenting at the same position as the crude cytosol receptor. The following methods to purify crude cytosol estrogen receptors are much less effective. (a) With DNA-cellulose chromatography, KCl elution revealed peaks at 0.04 M KCl (11-fold purification) and 0.22 M KCl (12.5-fold purification). This could not be combined sequentially with affinity chromatography because high salt conditions were required for affinity elution, and removal of salt by dialysis caused the receptor to adhere to the tubing. (b) With hydroxylapatite chromatography, phosphate elution revealed peaks at 0.12 M phosphate (1.1-fold purification) and 0.175 M phosphate (1.1-fold purification). (c) With phosphocellulose chromatography, KCl elution revealed only one peak at 0.18 M KCl (1.6-fold purification). (d) With diethylaminoethyl cellulose chromatography, KCl elution revealed 4 peaks at 0.025 M (1-fold purification), 0.12 M (1.27-fold purification), 0.14 M (1.28-fold purification), and 0.2 M (0.36-fold purification).