COL1A1 Sp1 polymorphism predicts perimenopausal and early postmenopausal spinal bone loss.

Genetic factors play an important role in the pathogenesis of osteoporosis but the genes that determine susceptibility to poor bone health are defined incompletely. Previous work has shown that a polymorphism that affects an Spl binding site in the COLIA1 gene is associated with reduced bone mineral density (BMD) and an increased risk of osteoporotic fracture in several populations. Data from cross-sectional studies have indicated that COLIA1 Sp1 alleles also may be associated with increased rates of bone loss with age, but longitudinal studies, which have examined bone loss in relation to COLIA1 genotype, have yielded conflicting results. In this study, we examined the relationship between COLIA1 Sp1 alleles and early postmenopausal bone loss measured by dual-energy X-ray absorptiometry (DXA) in a population-based cohort of 734 Scottish women who were followed up over a 5- to 7-year period. The distribution of genotypes was as expected in a white population with 484 "SS" homozygotes (65.9%); 225 "Ss" heterozygotes (30.7%), and 25 "ss" homozygotes (3.4%). Women taking hormone-replacement therapy (HRT; n = 239) had considerably reduced rates of bone loss at the spine (-0.40 +/- 0.06%/year) and hip (-0.56 +/- 0.06%/year) when compared with non-HRT users (n = 352; spine, -1.36 +/- 0.06%/year; hip, -1.21 +/- 0.05%/year; p < 0.001 for both sites). There was no significant difference in baseline BMD values at the lumbar spine (LS) or femoral neck (FN) between genotypes or in the rates of bone loss between genotypes in HRT users. However, in non-HRT users (n = 352), we found that ss homozygotes (n = 12) lost significantly more bone at the lumbar site than the other genotype groups in which ss = -2.26 +/- 0.31%/year compared with SS = -1.38 +/- 0.07%/year and Ss = -1.22 +/- 0.10%/year (p = 0.004; analysis of variance [ANOVA]) and a similar trend was observed at the FN in which ss = -1.78 +/- 0.19%/year compared with SS = -1.21 +/- 0.06%/year and Ss = -1.16 +/- 0.08%/year (p = 0.06; ANOVA). The differences in spine BMD loss remained significant after correcting for confounding factors. Stepwise multiple regression analysis showed that COLIA1 genotype independently accounted for a further 3.0% of the variation in spine BMD change after age (4.0%), weight (5.0%), and baseline BMD (2.8%). We conclude that women homozygous for the Sp1 polymorphism are at significantly increased risk of excess rates of bone loss at the spine, but this effect may be nullified by the use of HRT.

Effect of zinc supplementation on the dietary intake, rate of weight gain, and energy cost of tissue deposition in children recovering from severe malnutrition.

Children recovering from severe malnutrition on a milk based diet have low plasma zinc concentrations: children recovering on a soya based diet have much lower plasma zinc concentrations, lower rates of weight gain, and higher energy costs of tissue deposition. However, they do not demonstrate the clinical features of anorexia, diarrhea, and skin lesions usually associated with zinc deficiency. We therefore supplemented 16 children with zinc acetate on the basis that a therapeutic response to zinc constitutes the best evidence of a preexisting zinc deficiency. Fourteen of the 16 children had an immediate and definite increase in their rate of weight gain with zinc supplementation. This was associated with a decrease in the energy cost of tissue deposition, regrowth of the thymus, and activation of the sodium pump. We conclude that the children were indeed zinc deficient. We suggest that the anorexia of zinc deficiency is related to an inability to metabolize nitrogen in the zinc deficient state, and that our children did not show an appetitive response because of the relatively low protein content of the diets we used. Based on the premise that the abnormalities seen in our children may have been secondary to mild zinc deficiency, we suggest that limitation of lean tissue synthesis, with resultant obesity, and a propensity to infection are the major features of a mild zinc deficiency. Children undergoing a period of "catch up" weight gain or growth should have supplemental zinc, particularly if they have had diarrhea or if the use of a soya based formula is contemplated.

Plasma zinc and the clinical features of malnutrition.

Human protein-energy malnutrition and zinc deficiency have common clinical features. These were related to the plasma zinc concentrations in 42 severely malnourished children. A low plasma zinc concentration was strongly associated with nutritional edema but not with the degree of edema or the plasma albumin concentration. In the absence of edema, there were significant relationships between plasma zinc concentrations and stunting, skin ulceration, and wasting. Infection was not necessarily associated with a lower zinc concentration. From these data it can be predicted that a malnourished child with edema, skin ulceration, stunting, or severe wasting, will have a low plasma zinc concentration.

The in vivo measurement of protein synthesis.

Methods of measuring in vivo protein synthesis are briefly reviewed. Methods involving incorporation of label into protein are more appropriate for mixed proteins. The major difficulty is the definition of the precursor pool for protein synthesis. The only data available on the effect of infection on protein synthesis are open to criticism on the grounds that the precursor pool was not sampled.

Plasma zinc, rate of weight gain, and the energy cost of tissue deposition in children recovering from severe malnutrition on a cow's milk or soya protein based diet.

Thirty-four malnourished children were rehabilitated on either a cow's milk or a soya protein based formula diet. The soya diet contained 25% less zinc than the cow's milk diet and 1.33 mmol/l phytic acid. When the marasmic children were given either of these diets they had a dramatic fall in their plasma zinc concentration. Children given the soya formula had an even more profound drop in plasma zinc, to levels associated with acrodermatitis enteropathica. Plasma zinc remained low throughout the phase of rapid weight gain, but rose when a mixed diet was given and the children ceased gaining weight. There was a negative correlation between the rate of weight gain and the plasma zinc concentration, the rate of new tissue synthesis being the predominant modulator of the plasma zinc concentration. The energy cost of tissue deposition was initially low on the cow's milk diet and relatively high on the soya diet. Later, the energy costs rose in the cow's milk fed children. The rate of weight gain was less on the soya diet; however, the appetite, as measured by the ad libitum dietary intakes, did not differ between the diets, or correlate with the plasma zinc concentration. This may be due to the relatively low protein content of the diets used. It is concluded that dietary zinc may limit the rate of weight gain during periods of recovery in body mass and may be a cause for the excessive deposition of adipose tissue.

Leucocyte sodium transport and dietary zinc in protein energy malnutrition.

Zinc supplementation of children who were just completing a period of rapid "catch-up" growth during recovery from severe malnutrition was found to stimulate sodium transport in their leucocytes. These results suggest that zinc status should be studied in the large number of serious illnesses, now known or thought to be associated with impaired sodium transport.

Peroxisomes and the fatty liver of malnutrition: an hypothesis.

Peroxisomes play a role in hepatic beta-oxidation of fat, a process that results in the production of hydrogen peroxide. The fatty infiltration of the liver that occurs in severely malnourished children remains unexplained. We observed an almost total absence of peroxisomes in the hepatocytes of these children. We suggest that lack of available peroxisomes could contribute to the development of fatty liver.

Epidemiological study of hip fracture in Shenyang, People's Republic of China.

The aim of this study was to investigate the incidence and epidemiology in 1994 of hip fracture in Shenyang, a large city in the northeast of The People's Republic of China, using register information and medical records collected from the 36 hospitals in Shenyang. The hip fracture data were restricted to cervical or trochanteric types. A subset (59% of total) of medical records of hip fracture was used to investigate the causes of hip fracture. The causes were classified as simple fall, fall from a bicycle during cycling, bicycle accident, car accident, and fall from a height. There was a total of 453 hip fractures (206 in women and 247 in men) in the population over 50 years of age. The age-adjusted 1 year cumulative incidence rate was 67/100,000 (95% confidence interval [CI] = 58-76/100,000) for women and 81/100,000 (95% CI = 71-91/100,000) for men. The standardized incidence rate against the 1985 U.S. population was 87/100,000 (95% CI = 77-97/100,000) for women and 100/100,000 (95% CI = 89-111/100,000) for men. The mean (+/-standard deviation) age of patients with a hip fracture was 67.5+/-9.8 years for men and 66.9+/-9.0 years for women. The overall male-to-female ratio of hip fracture was 1.21:1 for age-adjusted hip fracture incidence and 1.15:1 for standardized incidence. Simple fall accounted for 70% hip fractures in women but caused only 49% in men (chi2 = 11.2, degrees of freedom [df] = 1,p = 0.0008). The frequency of hip fractures caused by a fall from a bicycle was higher in men (28%) than women (10%) (chi2 = 13.0, df = 1,p = 0.0003). The results of this study indicate (1) a low incidence of hip fracture in a Chinese population compared with more affluent countries, and (b) a higher incidence in men than women that is related in part to a higher incidence of accidents, especially bicycle-related ones.

Coagulase-negative staphylococcal bacteremia in severely malnourished Jamaican children.

Immunosuppression increases the susceptibility to infection and changes the inflammatory response in children with severe protein-energy malnutrition. In this 5-year prospective study bacteremia was documented in 16% of 336 severely malnourished children, 2 to 34 months of age, who were hospitalized consecutively in the Tropical Metabolism Research Unit, Kingston, Jamaica. The 53 children had 60 episodes of nosocomial and community-acquired bacteremia with 69 blood isolates. Community-acquired bacteremia accounted for 72% (43 of 60) of bacteremic episodes. Thirty-five percent (24 of 69) of the strains were coagulase-negative staphylococci, 19% (13 of 69) were Staphylococcus aureus and 11% (8 of 69) were Streptococcus Group D. Seventeen episodes of coagulase-negative staphylococcal bacteremia were acquired in the community and 7 were nosocomial. These patients were more likely to have pneumonic consolidation than children with all other bacteremias combined (P < 0.02, Fisher's exact test). The bacteremia-related case fatality rate was 8% (5 of 60). Polymicrobial and Gram-negative septicemia were independent positive predictive factors for mortality when compared with single-agent and Gram-positive sepsis (P < 0.02). This 71% (49 of 69) prevalence of Gram-positive organisms suggests a change in the epidemiology from the predominant Gram-negative etiologies (76%) described in previous reports.

The effect of folic acid supplementation on plasma homocysteine in an elderly population.

BACKGROUND: Increased plasma homocysteine is associated with coronary artery disease, peripheral vascular disease and venous thrombosis. Folic acid is the most effective therapy for reducing homocysteine levels. The lowest effective supplement of folic acid is not known, particularly for the elderly who have the highest prevalence of these conditions. AIM: To explore the effects of daily supplements of 0, 50, 100, 200, 400 and 600 microg folic acid on plasma homocysteine in an elderly population. DESIGN: Randomized double-blind placebo-controlled trial. METHODS: Participants (n=368) aged 65-75 years were randomly allocated to receive one of the treatments for 6 weeks. Plasma homocysteine was recorded after 3 weeks and 6 weeks of supplementation. RESULTS: Only the 400 microg and 600 microg groups had significantly lower homocysteine levels compared to placebo (p=0.038 and p<0.001, respectively). Using multiple linear regression and each individual's total folic acid intake (diet plus supplement), a total daily folic acid intake of 926 microg per day would be required to ensure that 95% of the elderly population would be without cardiovascular risk from folate deficiency. DISCUSSION: A daily folic acid intake of 926 microg is unlikely to be achieved by diet alone. Individual supplementation or fortification of food with folic acid will be required to reach this target.

Muscle satellite cells in malnourished and nutritionally rehabilitated children.

Satellite cells were examined qualitatively and quantitatively in muscle biopsies from children when malnourished, during nutritional rehabilitation, and after clinical recovery. The proportion of satellite cell nuclei relative to myonuclei was significantly lower in malnourished subjects than in well-nourished age-matched controls (4.5 +/- 1% vs. 8.1 +/- 1.0%). The proportion of satellite cells remained low during the early period of "catch-up growth" but was significantly increased in the recovered subjects (10.5 +/- 1.0%). Satellite cells were small and their nuclei were heterochromatic in biopsies from the malnourished subjects. The cells were often partially segregated from the parent fiber by an external lamina. In recovering and recovered subjects many of the satellite cells enlarged, and the appearance of their nuclei and cytoplasmic organelles suggested a more active state. Intervention of external lamina between the satellite cell and the myofibre was uncommon in the recovered subjects.

Malnutrition: trials and triumphs.

Severe malnutrition is uncommon but often fatal, particularly in very young infants or when oedema is present. Another major contributor to mortality is undiagnosed infection. Three pilot studies have recently been performed in severely malnourished patients in therapeutic feeding centres in sub-Saharan Africa. In each, a practical management problem was addressed and a potential solution tested. Three conclusions were reached: young breastfeeding infants were best managed using a supplemented suckling technique; routine antibiotics from admission reduced mortality; and in adults with oedematous malnutrition, therapeutic diets with a lower-than-usual protein:energy ratio were effective in reducing mortality and permitting catch-up weight gain.

The rate of ingestion of Ascaris lumbricoides and Trichuris trichiura eggs in soil and its relationship to infection in two children's homes in Jamaica.

The rate of exposure to geohelminth infection of children living in 2 institutions in Jamaica, West Indies, was estimated from the product of their rates of ingestion of soil and the density of parasite eggs in the environment. The estimated mean rate of egg ingestion was 9-20 Ascaris lumbricoides eggs and 6-60 Trichuris trichiura eggs per year, although the distribution was highly overdispersed so that some individuals had an estimated annual exposure of several hundred eggs. The estimated individual rates of exposure correlated significantly with the observed worm burdens in children at one of the homes, but not at the other. It is suggested that the susceptibility of the children and the distribution of infective stages in the environment may be important in determining the relationship between exposure and the rate of acquisition of infection.

Quantitative assessment of geophagous behaviour as a potential source of exposure to geohelminth infection.

The most common form of pica, geophagy, has direct adverse nutritional effects and also exposes children to soil-borne infection. Existing methods for assessing geophagy are either inappropriate for field use (radiology) or unreliable (reporting). A new method is described, based on the measurement of soil-derived silica in stools. More than 90% of silica is excreted within one gut transit period of ingestion. The amount excreted is proportional to the amount ingested. Faecal levels of dietary silica (less than 2% dry wt stool) can be distinguished from levels due to geophagy (up to 25% dry wt stool). Studies in 2 children's homes in Jamaica showed that 33% and 66% of children were geophagous, ingesting up to 10 g soil day-1. The geophagy of less than 20% of the children accounted for greater than 60% of the total soil ingested. This overdispersion of exposure to soil-borne infection may contribute to the observed aggregation of geohelminth infection.

Predisposition of individuals and families in Mexico to heavy infection with Ascaris lumbricoides and Trichuris trichiura.

Stool specimens from 90% of the population of 2 marginal communities in Coatzacoalcos, Mexico, were examined by the Kato-Katz technique for the estimation of eggs per gram of faeces (epg). Average epg values for Ascaris lumbricoides and Trichuris trichiura were calculated for each family in the community, based on the arithmetic mean epg of family members for each parasite. 39 families were classified as either lightly or heavily infected with A. lumbricoides and infected members were treated with mebendazole. A. lumbricoides expelled following treatment were collected from the children 2-10 years of age, and reinfection was monitored monthly for 6 months. At the end of the reinfection interval, a final stool specimen was collected from all family members and those infected were treated. Again, A. lumbricoides expelled by the children 2-10 years of age were collected. There was a significant correlation between the number of A. lumbricoides expelled by the children at the first and second treatments as well as in epg values before the first and second treatments for both A. lumbricoides and T. trichiura in children (2-10 years) and adults (greater than 19 years). At the family level, there were significant correlations between the values of family mean epg before each treatment for both A. lumbricoides and T. trichiura.

Clustering of Ascaris lumbricoides and Trichuris trichiura infections within households.

A survey of 428 households in a shanty town in Coatzacoalcos, Mexico, revealed high prevalences of Ascaris lumbricoides and Trichuris trichiura. The data were analysed separately for A. lumbricoides and T. trichiura in order to investigate the spatial distribution of heavy infections through the town. Within each age class, those individuals with egg counts in the upper 20% of the range for that age were classified as "heavily infected". When the data were stratified by household size, it was found that the distribution of "heavily-infected" individuals was not random in the community. "Heavily-infected" individuals were found together in households; fewer household units had a single heavily-infected individual than would be expected by chance. Such a pattern could result either from genetic similarities among family members influencing their ability to mount an effective immunological response to infection, or focal transmission in the vicinity of the home, or both. This result may have important implications for the development of community control programmes.

Population dynamics and chemotherapeutic control of Trichuris trichiura infection of children in Jamaica and St. Lucia.

Population dynamical parameters of Trichuris trichiura infections in children were estimated from longitudinal intensity and prevalence data from a population (n = 23) in a children's home in Jamaica. The theoretical predictions of a deterministic model incorporating these parameters were approximated to observed horizontal-age prevalence data from a naturally infected population (n = 203) of children in a St. Lucian village, and a rough estimate of the basic reproductive rate (Ro = 8-10) of T. trichiura obtained. The findings suggest that T. trichiura populations are intrinsically more difficult to control by traditional mass-treatment chemotherapy (eradication requires greater than 91% of the population to be treated every 6 months for greater than 5 years) than are populations of Ascaris, but may be more susceptible to selective chemotherapy programmes which aim to treat only the most heavily infected individuals.

Population distribution of Trichuris trichiura in a community of Jamaican children.

The Trichuris trichiura worm burdens of 23 children living in a Place-of-Safety in Kingston, Jamaica, were assessed by stool collection for more than five days after treatment with mebendazole. This procedure was repeated after a seven-month period of natural re-infection. For both collections the maximum rate of worm expulsion was achieved on the fourth day after starting treatment. The worm population distributions were overdispersed and well described by the negative binomial probability model (k = 0.29) in each case. For any one individual, the number of worms passed on the first expulsion was unrelated, absolutely or relatively, to the number passed on the second. These data suggest that: knowledge of the time dependency of helminth expulsion is essential for the accurate estimation of worm burdens by this method; populations of Trichuris are more highly aggregated than those of Ascaris and may thus be more susceptible to control by selective rather than random chemotherapy; and the inherent predisposition of hosts to infection may be of minor importance in determining the distribution of worms in the population-heavily infected hosts appear no more or less likely to acquire large worm burdens on subsequent exposures.

Time-resolved fluorescence immunoassay (TRFIA) for the detection of Escherichia coli O157:H7 in apple cider.

An immunoassay based on immunomagnetic separation and time-resolved fluorometry was developed for the detection of E. coli O157:H7 in apple cider. The time-resolved fluorescent immunoassay (TRFIA) uses a polyclonal antibody bound to immunomagnetic beads as the capture antibody and the same antibody labeled with europium as the detection antibody. Cell suspensions of 10(1) to 10(8) E. coli O157:H7 and K-12 organisms per ml were used to test the sensitivity and specificity of the assay. The sensitivity of the assay was 10(3) E. coli O157:H7 cells with no cross-reaction with K-12. Pure cultures of E. coli O157:H7 (10(1) to 10(5) CFU/ml) in apple cider could be detected within 6 h, including 4 h for incubation in modified EC broth with novobiocin and 2 h for the immunoassay. When apple cider was spiked with 1 to 10(3) CFU/ml of E. coli O157:H7 and 10(6) CFU/ml of K-12, our data show that the high level of K-12 in apple cider did not impede the detection of low levels of O157:H7. The minimum detectable numbers of cells present in the initial inoculum were 10(2) and 10(1) CFU/ml after 4- and 6-h enrichment. The TRFIA provides a rapid and sensitive means of detecting E. coli O157:H7 in apple cider.

Protein-energy interactions in the management of severe malnutrition.

The three syndromes of childhood malnutrition are contrasted with respect to protein. It is concluded that stunting and wasting are the outcomes of protein deficiency, and that kwashiorkor is not due to protein deficiency, rather it is related to unopposed oxidant stress. Formula for the energy and protein requirements are derived and contour plots of the amounts needed to sustain high rates of weight gain at different body compositions generated. It is suggested that all nutrients be expressed with energy as the denominator. No more than 12.5% of protein energy is required to sustain maximum likely rates of weight gain. Using this approach to design a diet, high rates of weight gain are achieved under field conditions in refugee camps.