Differentiation of osmotic and secretory diarrhoea by stool carbohydrate and osmolar gap measurements

Clinical features and laboratory tests that determine carbohydrate in faeces were evaluated to determine which was best able to distinguish between osmotic and secretory diarrhoea in infants and children. For this purpose 80 boys aged 3 to 24 months, with acute watery diarrhoea, were studied prospectively. The faecal osmolar gap (FOG) was calculated as: serum osmolarity-[2 x (faecal sodium + potassium concentration)]. Fifty eight patients were classified as having predominantly osmotic diarrhoea (FOG > 100 mosmol/l), and 22 as having predominantly secretory diarrhoea (FOG < or = 100 mosmol/l). The two groups were comparable in their clinical features on admission, in the results of blood and urine tests, and in the evolution of their diarrhoeal illness. Evidence of steatorrhoea (by positive Sudan III test) and of acid faecal pH on admission were significantly more frequent in patients with osmotic diarrhoea. Mean (SD) faecal osmolarity was not significantly different between the two groups (319 (80) mosmol/l in secretory diarrhoea v 361 (123) mosmol/l in osmotic diarrhoea). Tests for reducing substances in faeces such as Benedict's test--with and without hydrolysis--and glucose strip, all showed a positive and significant association with osmotic diarrhoea (p < 0.05, < 0.025, < 0.05, respectively). The presence of excess reducing substances (Benedict's test with hydrolysis > 2+) on admission was the most sensitive and specific test with the best predictive value for differentiating between the two types of watery diarrhoea.     

Annual summary of vital statistics--1996

Several recent trends in the vital statistics of the United States continued in 1996, including an increase in life expectancy and declines in infant mortality, births to teenage mothers, age-adjusted death rates, and death rates for children and adolescents. In 1996, there were an estimated 3 914 953 births in the United States. The preliminary birth rate remained unchanged at 14.8 births per 1000 population, and the fertility rate, births per 1000 women 15 to 44 years of age, was essentially the same at 65.7. Fertility rates rose slightly for most racial and ethnic groups except black women, for whom the rate hit a historic low of 70.8. Overall, fertility remains particularly high for Hispanic women, although there is considerable variation within this heterogenous group. For the fifth consecutive year, birth rates dropped for teenagers. Birth rates for women >/=30 years of age continued to increase. The birth rate for unmarried women declined 1% in 1996 to 44.6 births per 1000 unmarried women, continuing the decline noted in 1995 for the first time in 2 decades. The percentage of women who began prenatal care in the first trimester rose in 1996 to 81.8%, whereas the percentage with late (third trimester) or no care dropped to 4.1%. The rise in timely prenatal care was greatest for black and Hispanic women. The percentage of low birth weight (LBW) infants reached 7.4% in 1996, its highest level since 1975. The very low birth weight rate remained unchanged at 1.4%. The rise in LBW occurred primarily among white women, whereas the LBW rate for black women dropped to 13.0%, the lowest rate reported since 1987. The rise among white women is only partially a result of increases in multiple births, because LBW rates have also risen among white singleton births. The multiple birth ratio rose again in 1996 by 2%, as it has since 1980. The rise was particularly large for higher-order multiple births. Infant mortality reached an all time low level of 7.2 deaths per 1000 births, based on preliminary 1996 data. Neonatal and postneonatal rates declined, as did rates for both black and white infants. National birth weight specific mortality rates are reported here for the first time. In 1995, 63% of infant deaths occurred to the 7.3% of the population that was born LBW. The four leading cause of infant death were congenital anomalies, disorders relating to short gestation and unspecified birth weight, sudden infant death syndrome, and respiratory distress syndrome, accounting for more than half of infant deaths in 1996. Despite the declines in infant mortality, the United States continues to rank poorly in international comparisons of infant mortality. Expectation of life at birth reached a new high in 1996 of 76.1 years for all gender and race groups combined. Age-adjusted mortality rates declined in 1996 for diseases of the heart, malignant neoplasms, cerebrovascular diseases, accidents and adverse effects, chronic liver disease and cirrhosis, and suicide. They rose, as in the past several years, for chronic obstructive pulmonary diseases, diabetes mellitus, and pneumonia and influenza. For the first time since human immunodeficiency virus infection was created as a special cause-of-death category in 1987, death rates for human immunodeficiency virus infection declined from 15.6 in 1995 to 11.6 in 1996. The homicide rate also declined, as it has since 1991. Death rates for children between 1 and 19 years of age declined in 1996, with an estimated 29 183 deaths to children. Unintentional injury mortality has dropped by approximately 50% among children and adolescents since 1979, although it remains the leading cause of death for all age groups of children from 1 to 19 years. Homicide was the fourth leading cause of death for children 1 to 4 and 5 to 9 years of age, the third leading cause for children 10 to 14, and the second leading cause for 15 to 19 year olds.     

Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis

OBJECTIVE: To study the effect of highdose prednisone on intracranial pressure (ICP), cranial computed tomographic (CT) findings, and clinical outcome in young children with moderate to severe tuberculous meningitis (TBM). STUDY DESIGN: Prospective, controlled, randomized study. METHODS: Continuous lumbar, cerebrospinal fluid pressure monitoring and contrasted CT scanning were performed in 141 consecutive children with TBM at admission. All children were then randomly allocated to a nonsteroid group (71 children) or a steroid group (70 children) who received prednisone (first 16 children, 2 mg/kg per day; next 54 children, 4 mg/kg per day) for the first month of treatment. ICP monitoring and CT scanning were repeated regularly, and clinical outcome was assessed after 6 months of antituberculosis treatment. RESULTS: No statistically significant difference in ICP or the degree of hydrocephalus (as demonstrated by CT scan) was found between the steroid and nonsteroid groups after the first month of treatment. Basal ganglia infarcts developed in 16% of children in the steroid group and 24% in the nonsteroid group during the first month of treatment. Neither this incidence nor the eventual size of infarcts present at admission differed significantly between the two treatment groups. Single or multiple tuberculomas were seen on the first CT scans of 7 children (5%), whereas tuberculomas developed in 11 children (8%) at treatment. Both the response of the tuberculomas to treatment and the incidence of new tuberculomas were significantly improved by steroid therapy. Basal enhancement was also significantly less in the steroid group after 1 month of treatment. Steroids lowered mortality in stage III TBM significantly. Similarly, more surviving children in the steroid group had IQs of greater than 75 than did the those in the nonsteroid group. No significant difference was found in the incidence of motor deficit, blindness, or deafness. CONCLUSIONS: Corticosteroids significantly improved the survival rate and intellectual outcome of children with TBM. Enhanced resolution of the basal exudate and tuberculomas by steroids was shown by serial CT scanning. Corticosteroids did not affect ICP or the incidence of basal ganglia infarction significantly.     

Physiologically based pharmacokinetic modeling of 1,3-butadiene, 1,2- epoxy-3-butene, and 1,2:3,4-diepoxybutane toxicokinetics in mice and rats

1,3-Butadiene (BD) is a more potent tumor inducer in mice than in rats. BD also shows striking differences in metabolic activation, with substantially higher blood concentrations of 1,2:3,4-diepoxybutane (butadiene diepoxide; BDE) in BD-exposed mice than in similarly exposed rats. The objective of this study was to develop a single mechanistic model structure capable of describing BD disposition in both species. To achieve this objective, known pathways of 1,2-epoxy-3-butene (butadiene monoepoxide; BMO) and BDE metabolism were incorporated into a physiologically based pharmacokinetic model by scaling rates determined in vitro. With this model structure, epoxide clearance was underestimated for both rats and mice. Improved simulation of blood epoxide concentrations was achieved by addition of first-order metabolism in the slowly perfused tissues, verified by simulation of data on the time course for BMO elimination after i.v. injection of BMO. Blood concentrations of BD were accurately predicted for mice and rats exposed by inhalation to constant concentrations of BD. However, if all BD was assumed to be metabolized to BMO, blood concentrations of BMO were overpredicted. By assuming that only a fraction of BD metabolism produces BMO, blood concentrations of BMO could be predicted over a range of BD exposure concentrations for both species. In vitro and in vivo studies suggest an alternative cytochrome P-450-mediated pathway for BD metabolism that does not yield BMO. Including an alternative pathway for BD metabolism in the model also gave accurate predictions of blood BDE concentrations after inhalation of BD. Blood concentrations of BMO and BDE observed in both mice and rats are best explained by the existence of an alternative pathway for BD metabolism which does not produce BMO.      

Retention of conjugated linoleic acid in the mammary gland is associated with tumor inhibition during the post-initiation phase of carcinogenesis

Conjugated linoleic acid (CLA) has been reported to have significant activity in inhibiting mammary carcinogenesis. A major objective of this study was to evaluate how changes in the concentration of CLA in mammary tissue as a function of CLA exposure/withdrawal were correlated with the rate of occurrence of mammary carcinomas. Rats treated with a single dose of dimethylbenz[a]anthracene (DMBA) at 50 days of age were given 1% CLA in the diet for either 4 weeks, 8 weeks or continuously following carcinogen administration. No cancer protection was evident in the 4 or 8 week-CLA treatment groups. Significant tumor inhibition was observed only in rats that were given CLA for the entire duration of the experiment (20 weeks). Analysis of CLA in the mammary gland showed that the incorporation of CLA was much higher in neutral lipids than in phospholipids. When CLA was removed from the diet, neutral lipid- and phospholipid-CLA returned to basal values in about 4 and 8 weeks, respectively. The rate of disappearance of neutral lipid-CLA (rather than phospholipid-CLA) subsequent to CLA withdrawal paralleled more closely the rate of occurrence of new tumors in the target tissue. It appears that neutral lipid-CLA may be a more sensitive marker of tumor protection than phospholipid-CLA. However, the physiological relevance of CLA accumulation in mammary lipids is unclear and remains to be determined. A secondary goal of this study was to investigate whether CLA might selectively inhibit clonal expansion of DMBA- initiated mammary epithelial cells with wild-type versus codon 61 mutated Ha-ras genes. Approximately 16% of carcinomas in the control group (without CLA) were found to express codon 61 ras mutation. Although continuous treatment with CLA reduced the total number of carcinomas by 70%, it did not alter the proportion of ras mutant versus wild-type carcinomas, suggesting that CLA inhibits mammary carcinogenesis irrespective of the presence or absence of the ras mutation.      

Detection of 1,N6-ethenoadenine in rat urine after chloroethylene oxide exposure

The four etheno adducts of vinyl chloride formed in DNA, 1,N6- ethenoadenine (epsilonA), 3,N4-ethenocytosine, 1,N2-ethenoguanine and N2,3-ethenoguanine were previously reported to be released from DNA by a family of enzymes in the base-excision repair pathway (Dosanjh et al., Proc. Natl Acad. Sci. USA, 91, 1024-1028, 1994; Hang et al., Carcinogenesis, 17, 155-157, 1996; Hang et al., Proc. Natl Acad. Sci. USA, 94, 12869-12874, 1997). Adducts excised from DNA by glycosylases are usually excreted in urine and have been reported to be potential biomarkers of DNA damage in exposed individuals. In this study, we report the detection of epsilonA in the urine of rats exposed to chloroethylene oxide (CEO) using immunoaffinity columns made with specific monoclonal antibodies for enrichment, followed by quantitation by HPLC with fluorescence detection. Chemical analysis of urine samples revealed the presence of a compound chromatographically identical to authentic epsilonA standard. This compound was confirmed by mass spectral analysis. EpsilonA was present in urine of control and CEO- treated rats, with the latter having up to 50-fold greater amounts. The cumulative excretion of epsilonA reached a plateau between 24 and 48 h post-exposure. While it is clear that CEO treatment results in increased excretion of epsilonA, the exact source of the adduct is unknown. When rats were administered epsilonA i.v., approximately 10% of the administered dose was excreted in urine. This research demonstrates that urinary excretion of epsilonA may be a potential biomarker for in vivo alkylation of DNA and nucleotide pools.      

Interindividual variation in the metabolic activation of heterocyclic amines and their N-hydroxy derivatives in primary cultures of human mammary epithelial cells

The heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine (PhIP) are pyrolysis products formed when meat is cooked and are rodent mammary carcinogens. They are thought to be metabolically activated by N-hydroxylation, catalysed by cytochrome P450 (CYP), followed by O-acetylation catalysed by N- acetyltransferases. Primary cultures of human mammary epithelial cells (HMECs) prepared from up to 26 individuals for each compound, were treated with IQ, MeIQ, or PhIP (500 microM) or with N-hydroxy-2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) or N-hydroxy-2-amino- 3-methylimidazo[4,5-f]quinoline (N-OH-IQ) (20 microM) and the levels of adduct formation in their DNA analysed by 32P-post-labelling. In order to investigate whether pharmacogenetic polymorphisms influence DNA adduct formation, the NAT2 genotype of each individual was determined by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method that distinguishes between the wild-type and four variant alleles. Presence of two variant alleles designates a slow NAT2 acetylator, whereas individuals with one or two wild-type alleles are designated fast NAT2 acetylators. Interindividual variations in total DNA adduct levels ranged for IQ from 0.64-63.1 DNA adducts per 10(8) nucleotides (mean 7.80), for MeIQ from 1.99-17.8 (mean 6.63), for PhIP from 0.13-4.0 (mean 0.96), for N-OH-PhIP from 6.32-497 (mean 176) and for N-OH-IQ from 0.92-30.6 (mean 9.24). The higher adduct levels observed in cells treated with the N-OH metabolites suggests that N- hydroxylation is the rate-limiting step in HMECs and this may be due to low CYP levels. In contrast, the Phase II reaction catalysed by N- acetyltransferases is probably the major step in the metabolic activation of heterocyclic amines that occurs in the breast. Higher mean levels of heterocyclic amine-DNA adduct formation were detected in the cells of NAT2 fast acetylators compared with slow acetylators, with mean adduct levels per 10(8) nucleotides following IQ treatment, of 12.74 and 3.57 respectively, following PhIP treatment, of 1.20 and 0.74, respectively, following MeIQ treatment, of 7.90 and 5.08, respectively and following N-OH-PhIP-treatment, of 243.1 and 130.0, respectively. However, due to the large variations in adduct levels, these differences in mean values were not statistically significant with the limited number of individuals studied. This appears to be the first pilot study to demonstrate interindividual variations in the metabolic activation of heterocyclic amines and their metabolic intermediates in primary cultures of HMECs in vitro.      

Induction of cell cycle arrest by the endogenous product of lipid peroxidation, malondialdehyde

We have investigated the effect of the endogenous genotoxin malondialdehyde (MDA) on cell cycle kinetics and the expression and biochemical activity of several cell cycle regulatory proteins. MDA treatment of two human cell lines (RKO and H1299) resulted in a 3- to 6- fold elevation in the levels of the major detectable MDA-DNA adduct, M1G-dR. The increase in M1G-dR was accompanied by irreversible cell cycle arrest, elevation in p53 and p21 protein levels, and inhibition of cyclin E- and cyclin B-associated kinase activities. The decrease in cyclin E- and cyclin B-dependent kinase activities was caused by increased p21 and decreased cdc2 levels, respectively. Comparable levels of p21 induction were observed in RKO (wild-type p53) and H1299 (p53-null) cells. Thus, MDA was able to engage cell cycle checkpoint function in human cell lines when used at concentrations that produce M1G-dR levels of the same magnitude found in human tissues.      

Effects of long-term growth hormone releasing hormone 1 -29 in significantly short children

Seven children with significant idiopathic short stature (SISS) whose heights were significantly below the third percentile (SD score for height —2.5 to —3.5) and who had normal levels of growth hormone (GH) were treated with growth hormone releasing hormone (GH-RH) in a dose of 30 /μg/kg/day. Therapy was discontinued if patients failed to increase their rates of growth by more than 2.0 cm/year over their pre-therapy growth rate. Treatment was discontinued in two of the patients after 12 months but was continued in the other five for 24 months. These data demonstrate that some patients with SISS grow well during the first 2 years of treatment with GH-RH.