Improved Homology Model of the Human all-trans Retinoic Acid Metabolizing Enzyme CYP26A1.

A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data. The distances between the ligands and the heme group iron of the enzyme are in agreement with corresponding distances obtained for substrates and azole inhibitors for other cytochrome systems. The calculated theoretical binding energies agree with recently reported experimental data and show that the model is capable of discriminating between natural substrate, strong inhibitors (R116010 and R115866), and weak inhibitors (liarozole, fluconazole, tetralone derivatives).

Pellagra-like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit.

An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.

Gamma-ray induced degradation of diazinon and atrazine in natural groundwaters.

Degradation of diazinon and atrazine pesticides present in natural groundwaters was investigated on a laboratory scale upon gamma-irradiation from a (60)Co source. The effects of pesticide type, initial concentration, characteristics of natural groundwater, potential radical scavengers and absorbed dose on efficiency of pesticide degradation were investigated using GC-MS. gamma-Irradiation experiments were carried out for three concentrations (i.e. 0.329, 1.643 and 3.286 microM/diazinon and 0.464, 2.318 and 4.636 microM/atrazine) with irradiation doses over the range 0.5-5.6 kGy for diazinon and 0.2-21 kGy for atrazine. gamma-Radiolysis showed that diazinon was much easier to degrade by ionizing radiation compared to atrazine in all natural groundwater samples. This was observed at the three initial concentrations over the range irradiation doses. The irradiation doses required for degradation of 50 and 90% diazinon (distilled water) and atrazine (humic aqueous solution) at the three concentrations were not sufficient to degrade the same concentrations in different natural groundwater samples. Moreover, the presence of naturally occurring inorganic scavengers in solutions of diazinon and atrazine decreased significantly the efficiency of radiolytic degradation of pesticides, especially at higher concentrations.

Radiolytic degradation of atrazine aqueous solution containing humic substances.

Degradation of atrazine herbicide in humic substances (HS) aqueous solutions and distilled water solutions was investigated on a laboratory scale upon gamma-irradiation from a (60)Co source. In addition, the effect of ionizing radiation on the atrazine residues removal efficiency was investigated in relation to degradation of by-products. gamma-Irradiation experiments were carried out for three targeted concentrations (i.e. 0.464, 2.318 and 4.636 microM) with doses over the range 0.1-60 kGy. The initial concentration of herbicide, scavengers and irradiation doses play a significant role in the degradation efficiency as shown by decay constants of atrazine residues. gamma-Radiolysis showed that atrazine exhibited high degradation percentages at low absorbed doses in HS aqueous solutions compared to distilled water solutions. Absorbed doses from 0.6 to 21 kGy and from 6 to 72 kGy at a dose rate of 14.52 kGyh(-1) achieved 90% degradation for atrazine with initial concentrations over the range 0.464-4.636 microM in humic and distilled water solutions, respectively. The radiolytic degradation by-products and their mass balances were qualitatively determined with good confidence using gas chromatography/quadruple mass spectrometry (GC/MS) with electron impact ionization (EI(+)) mode.

Q branch features in the hot parallel bands of (13)C(2)H(2) in the three micron region.

A systematic study of the high-resolution spectrum of (13)C(2)H(2) in the 3microm spectral region shows Q branch features in five hot parallel bands. These bands are due to the nu(3)+nu(4) (Pi(u))<--nu(4) (Pi(g)), nu(3)+nu(5) (Pi(g))<--nu(5)(Pi(u)), nu(3)+2nu(4) (Delta(u))<--2nu(4)(Delta(g)), nu(3)+2nu(5) (Delta(u))<--2nu(5)(Delta(g)) and nu(3)+nu(4)+nu(5)(Delta(g))<--nu(4)+nu(5)(Delta(u)) transitions. Sub-Q-branches (Q(e<--f) and Q(f<--e))are found to be resolved in the first three hot bands. More than 70 Q branch lines have been assigned, spread over the five hot bands. We have applied separate linear least squares fit to the transition wavenumbers of each Q branch/sub-Q-branches, which have yielded values of band origins and rotational constants, in agreement with those derived from the analysis of the P and R branches in earlier work. The analysis of the sub-Q-branches have also provided values of the l-doubling constants. This is the first report on the observation of Q branch lines in Delta-Delta hot bands, in the FTIR spectrum of (13)C(2)H(2).

The effect of cider vinegar on some nutritional and physiological parameters in mice.

The present work was designed to investigate health effects of cider vinegar using mice as experimental model. Groups of female ICR (CD-1) mice were treated with daily oral doses of 0.17, 0.51 and 1.02 ml of the vinegar/kg body weight for 4 weeks. Cider vinegar induced a significant reduction in weight gain in animals treated with 0.51 ml/kg while others showed no significant differences in weight gain. The mean dry matter intake increased in animals treated with the smallest dose and significantly decreased in others. Hemoglobin (Hb), total erythrocyte counts (TEC) and total leukocyte counts (TLC) were raised in all treated groups. The activity of liver aspartate amino transferase (AST) decreased in the group treated with the smallest dose while no significant variations were recorded in the other groups. No significant differences were recorded neither in the activity of hepatic alanin amino transferase (ALT) nor in hepatic acid phosphatase (ACP). Liver alkaline phosphatase (ALP) noticeably elevated only in animals treated with 0.51 ml of vinegar/kg body weight per day. Treated groups also showed statistically significant increases in both mean liver and spleen weight. Kidney weight did not show significant differences. High doses of cider vinegar induced histopathological alterations in liver, stomach and duodenum. Vacuolated hepatocytes, erosion of gastric mucosa, dilatation in gastric glands and duodenum villus blunting are the common observed lesions noticed in organs of high dose-treated animals.

A longitudinal study of prolonged breastfeeding in relation to child undernutrition.

BACKGROUND: In a number of studies prolonged breastfeeding was associated with a higher risk of undernutrition, although most of these studies are limited by their cross-sectional design which does not allow examination of temporal relationships between full weaning and undernutrition. METHODS: The relationship between prolonged breastfeeding and child growth was examined prospectively among children under 36 months old who participated in a large cohort study. At baseline and at each of three 6-monthly follow-up visits breastfeeding status was assessed and all subjects were weighed and measured. RESULTS: Undernourished children were more likely to be breastfed for a longer period of time compared with normal children. We found a small difference between breastfed and fully weaned children in the gain in height over the following 6-month period; however, breastfed children were likely to gain significantly less weight, particularly among children who were aged 6-12 months. Similar findings were noted when these associations were examined among children who were normally nourished at the time of breastfeeding assessment. The inverse association between breastfeeding status and weight gain was significantly larger among children of poor or illiterate mothers compared with children of relatively more affluent or literate mothers, respectively. CONCLUSIONS: Our findings suggest that the inverse association is not causal, and may be explained by poorer complementary feeding among breastfed compared with weaned children. Children from poorer households and whose parents are illiterate are more likely to have less than adequate complementary feeding. The importance of adequate complementary feeding in the second half of infancy needs to be stressed in nutrition education programmes.

PIP: The relationship between prolonged breast feeding and growth was investigated in a prospective study of 28,753 Sudanese children under 36 months of age enrolled in a broader cohort study of child health and nutrition. 81% of children were breast-fed at 12 months, but this prevalence declined to 62% at 18 months and 27% at 24 months. Stunted or wasted children were more likely to be breast-fed for a longer period of time than their well-nourished counterparts. There was only a small difference between breast-fed and fully weaned children in 6-month height gains; however, breast-fed children gained significantly less weight, especially in the 6-12-month age group. The inverse association between breast feeding status and weight gain was significantly larger among children of poor or illiterate mothers than those of literate, more affluent mothers. It is postulated that this inverse association is a result of poorer complementary feeding among breast-fed compared with weaned children, especially in low-income households. These findings suggest a need for nutrition education programs to emphasize the need for adequate complementary feeding in the second half of infancy.

The effect of vitamin A supplementation on the growth of preschool children in the Sudan.

OBJECTIVES: This study assessed the effect of vitamin A supplementation at 6-month intervals on child growth. METHODS: Sudanese children (n = 28,740) 6 to 72 months of age were weighed and measured at baseline and at each of three follow-up visits. RESULTS: Periodic vitamin A supplementation had no effect on the rate of weight or height gain in the total population or on the incidence of wasting, stunting, or wasting and stunting among children who were normally nourished at baseline. CONCLUSIONS: Reducing poverty and improving access to adequate diets should remain the goals of programs designed to improve the nutritional status of malnourished populations.

Dietary vitamin A intake in relation to child growth.

Severe deficits in ponderal and linear growth are problems of major public health significance among children in developing countries. We prospectively examined the association of dietary vitamin A intake with child growth among 28,740 Sudanese children ages 6-72 months. At baseline and at each 6-month visit, all subjects were weighed and measured. Dietary vitamin A intake during the prior 24 hours was assessed using recall of vitamin A-containing foods. Dietary vitamin A intake was associated with attained height and weight after controlling for age, sex, morbidity, and socioeconomic variables. Compared with children in the bottom quintile of intake, those in the top quintile were 11 mm taller [95% confidence interval (CI) = 8-13] and 237 gm heavier (95% CI = 153-320). Higher dietary vitamin A intake was also associated with reduced risk of stunting [relative risk (RR) for 5th vs 1st quintile = 0.7; 95% CI = 0.5-0.9] and wasting (RR = 0.7; 95% CI = 0.5-0.9). Adequate intake of foods containing vitamin A may improve child growth where vitamin A deficiency prevails, but this relation may not be due to vitamin A per se.

A prospective study of malnutrition in relation to child mortality in the Sudan.

We examined prospectively the relation between malnutrition and mortality among Sudanese children. A cohort of 28753 children between the ages of 6 mo and 6 y was examined every 6 mo for 18 mo. Two hundred thirty-two children died during 18 mo of follow-up (480624 child-months). Low weight-for-height was associated with an increased risk of mortality (P < 0.0001). Even children with Z scores between -1 and -2 were 50% more likely to die in the following 6 mo than were children with Z scores > -1 (multivariate relative mortality: 1.5; 95% CI: 1.1, 2.2). There was also an inverse relation between height-for-age and mortality (P < 0.0001). Among breast-fed children, the relative mortality associated with a Z score for weight-for-height of < -3 compared with > -2 was 7.3 (95% CI: 3.3, 15.9); among children not breast-fed, it was 26.0 (95% CI: 12.8, 53.0; P for interaction = 0.001). A strong and significant synergy was also found between infection and wasting or stunting as predictors of child mortality (P for interaction = 0.001 and 0.02. respectively). In developing countries, children who are below the customary cutoff point of -2 Z for weight-for-height may be at higher risk of death. Breast-feeding and reduction of morbidity should be advocated in programs designed to reduce malnutrition and mortality among children.

PIP: The authors prospectively examined the relation between malnutrition and mortality in a cohort of 28,753 Sudanese children aged 6 months to 6 years. Children in the cohort were examined every 6 months for 18 months, during which 232 children died. Low weight-for-height was significantly associated with an increased risk of mortality. Even children with Z scores between -1 and -2 were 50% more likely to die in the following 6 months than were children with Z scores greater than -1. A significant inverse relation was identified between height-for-age and mortality. Among breast-fed children, the relative mortality associated with a Z score for weight-for-height of less than -3 compared with greater than -2 was 7.3, 26.0 among non-breast-fed children. A strong and significant synergy was also found between infection and wasting or stunting as predictors of child mortality. These findings indicate that children in developing countries who are below the customary cutoff point of -2 Z for weight-for-height may be at greater risk of death. Breast feeding and the reduction of morbidity should be advocated in programs designed to reduce malnutrition and mortality among children.

Dietary vitamin A intake and the incidence of diarrhea and respiratory infection among Sudanese children.

The relationship of vitamin A deficiency and child survival has been documented in a number of studies but not in others, yet the relationship of vitamin A with child morbidity remains controversial. We prospectively examined the relationship of dietary vitamin A intake and the incidences of diarrhea and respiratory infection among 28,753 Sudanese children between the ages of 6 mo and 6 y. Total dietary vitamin A intake was strongly and inversely associated with the risk of diarrhea (multivariate risk in top relative to bottom quintile = 0.58, 95% confidence interval = 0.47-0.72); we also observed a strong inverse association with the risk of having cough and fever (0.60, 0.45-0.81). On the other hand, we noted a significantly positive association of dietary vitamin A intake and incidence of cough alone (1.69, 1.52-1.88), a sign that may be assocsated with a healthy respiratory epithelium. Vitamin A intake was also negatively associated with the risk of measles. These prospective data emphasize the importance of adequate dietary vitamin A intake to protect the health of children in developing countries.

Dietary vitamin A intake and the risk of mortality among children.

Increased consumption of dietary vitamin A is advocated as a long-term solution to vitamin A deficiency. We prospectively examined the relationship of dietary vitamin A intake and child mortality among 28,753 Sudanese children aged 6 mo to 6 y, who participated in a trial of vitamin A supplementation. After 18 mo of follow-up, 232 children died. Total dietary vitamin A intake was strongly and inversely associated with risk of mortality. The age- and sex-adjusted relative risk (RR) of mortality for a comparison of children in extreme quintiles was 0.35 (95% CIs 0.21-0.60; P for trend over quintiles < 0.0001). Even after possible confounding by socioeconomic variables was adjusted for, vitamin A intake was significantly protective (multi-variate relative risk 0.53). Dietary vitamin A intake was especially protective among children who were wasted and stunted or who had diarrhea or cough. These prospective data support an important role of dietary vitamin A in reducing childhood mortality in developing countries.

Vitamin A supplementation and dietary vitamin A in relation to the risk of xerophthalmia.

We examined the effect of 60-mg (200,000-IU) supplements of vitamin A administered every 6 mo on the incidence of xerophthalmia among preschool children who were free of eye symptoms and signs of vitamin A deficiency. We also prospectively studied the relationship of dietary vitamin A intake with the same endpoint. After 18 mo of follow-up, 400 children developed xerophthalmia during 80,104 child-periods of follow-up. Vitamin A supplementation only modestly reduced the risk of xerophthalmia (relative risk 0.88, 95% confidence interval 0.72-1.07, P = 0.19). On the other hand, total dietary vitamin A intake was strongly associated with reduced risk of xerophthalmia; the multivariate relative risk when children in extreme quintiles were compared was 0.38 (95% confidence interval 0.19-0.74; P for trend over quintiles = 0.002). These results emphasize the need for further data on factors that modify the bioavailability of large-dose vitamin A supplements. Increased consumption of inexpensive vegetables and fruits is highly likely to reduce significantly the risks of vitamin A deficiency, including nutritional blindness in developing countries.

Vitamin A supplementation and child survival.

Previous studies of the effect of 6-monthly vitamin A supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebo-controlled trial of vitamin A supplementation in the Sudan among 28,753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200,000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 IU vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8.4/1000) in the vitamin A group and 112 (7.9/1000) in the placebo group (relative risk 1.06, 95% confidence interval 0.82-1.37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. The lack of an effect of large-dose vitamin A supplementation on mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Reducing poverty, improvements in sanitation, and access to adequate diets should remain the main goals to improve child survival.

Goat pox in the Sudan.

Out outbreak of goat pox occurred among 60 adult and young goats in the Sudan. Among the findings of special interest was the extensive and wide distribution of pox lesions on the bodies of the animals. The severe involvement of the mucous membranes of the muzzle, eyes and nostrils gave rise to acute respiratory distress and systemic reaction. The suppression of secondary bacterial infection with local and systemic terramycin in addition to supportive therapy of affected animals alleviated the condition and none of the animals died. Typical pox lesions were produced experimentally on goats and sheep using infected material from goats. Human infections were not encountered.