Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea

OBJECTIVE: To evaluate the impact of zinc supplementation on the clinical course, stool weight, duration of diarrhoea, changes in serum zinc, and body weight gain of children with acute diarrhoea. DESIGN: Randomised double blind controlled trial. Children were assigned to receive zinc (20 mg elemental zinc per day) containing multivitamins or control group (zinc-free multivitamins) daily in three divided doses for two weeks. SETTING: A diarrhoeal disease hospital in Dhaka, Bangladesh. PATIENTS: 111 children, 3 to 24 months old, below 76% median weight for age of the National Center for Health Statistics standard with acute diarrhoea. Children with severe infection and/or oedema were excluded. MAIN OUTCOME MEASURES: Total diarrhoeal stool output, duration of diarrhoea, rate of weight gain, and changes in serum zinc levels after supplementation. RESULTS: Stool output was 28% less and duration 14% shorter in the zinc supplemented group than placebo (p = 0.06). There were reductions in median total diarrhoeal stool output among zinc supplemented subjects who were shorter (less than 95% height for age), 239 v 326 g/kg (p < 0.04), and who had a lower initial serum zinc (< 14 mmol/l), 279 v 329 g/kg (p < 0.05); a shortening of mean time to recovery occurred (4.7 v 6.2 days, p < 0.04) in those with lower serum zinc. There was an increase in mean serum zinc in the zinc supplemented group (+2.4 v -0.3 mumol/l, p < 0.001) during two weeks of supplementation, and better mean weight gain (120 v 30 g, p < 0.03) at the time of discharge from hospital. CONCLUSIONS: Zinc supplementation is a simple, acceptable, and affordable strategy which should be considered in the management of acute diarrhoea and in prevention of growth faltering in children specially those who are malnourished.     

Longitudinal neurological follow-up of a group of HIV-seropositive and HIV-seronegative hemophiliacs: results from the hemophilia growth and development study

BACKGROUND: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up. METHODS: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models. RESULTS: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change. CONCLUSIONS: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.     

Spectrum of point mutations in the coding region of the hypoxanthine- guanine phosphoribosyltransferase (hprt) gene in human T-lymphocytes in vivo

The hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in 6- thioguanine (TG) resistant T-lymphocytes is a useful target for the study of somatic in vivo mutagenesis, since it provides information about a broad spectrum of mutation. Mutations in the hprt coding region were studied in 124 TG-resistant T-cell clones from 38 healthy, non- smoking male donors from a previously studied population of bus maintenance workers, fine-mechanics and laboratory personnel. Their mean age was 43 years (range 23-64) and their hprt mutant frequency was 9.3 +/- 5.2 x 10(-6) (mean +/- SD, range 1.4-22.6 x 10(-6)). Sequence analysis of hprt cDNA identified 115 unique mutations; 76% were simple base substitutions, 10% were +/-1 bp frameshifts, and 10% were small deletions within exons (3-52 bp). In addition, two tandem base substitutions and one complex mutation were observed. Simple base substitutions were observed at 55 (20%) of 281 sites known to be mutable in the hprt coding sequence. The distribution of these mutations was significantly different than would be expected based upon a Poisson distribution (P < 0.0001), suggesting the existence of 'hotspots'. All of the 87 simple base substitutions occurred at known mutable sites, but eight were substitutions of a kind that have not previously been reported at these sites. The most frequently mutated sites were cDNA positions 197 and 146, with six and five independent mutations respectively. Four mutations were observed at position 131, and three each at positions 143, 208, 508 and 617. Transitions (52%) were slightly more frequent than tranversions (48%), and mutations at GC base pairs (56%) more common than mutations at AT base pairs (44%). GC > AT was the most common type of base pair substitution (37%). The majority of the mutations at GC base pairs (78%) occurred at sites with G in the non-transcribed strand. All but one of eight mutations at CpG- sites were of the kind expected from deamination of methylated cytosine. Deletion of a single base pair (-1 frameshift) was three times more frequent than insertion of a single bp (+1 frameshift). Almost half (6/13) of the small (3-52 bp) deletions within the coding sequence clustered in the 5' end of exon 2. Short repeats and other sequence motifs that have been associated with replication error were found in the flanking regions of most of the frameshifts and small deletions. However, several differences in the local sequence context between +/-1 frameshift and deletion mutations were also noticed. The present results identify positions 197, 146 and possibly 131 as hotspots for base substitution mutations, and confirm previously reported hotspots at positions 197, 508 and 617. In addition, the earlier notion of a deletion hotspot in the 5'end of exon 2 was confirmed. The observations of these mutational cluster regions in different human populations suggest that they are due to endogeneous mechanisms of mutagenesis, or to ubiquitous environmental influences. The emerging background spectrum of somatic in vivo mutation in the human hprt gene provides a useful basis for comparisons with radiation or chemically induced mutational spectra, as well as with gene mutations in human tumors.      

Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene

Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are presumed to be specific biomarkers of exposure to benzene. We analyzed BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a subsample consisting of 19 workers and 19 controls from Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers. The adducts were analyzed by gas chromatography-mass spectrometry following reaction of the protein with trifluoroacetic anhydride and methanesulfonic acid. When subjects were divided into controls (n = 42) and workers exposed to < or =31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were 32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure: Spearman r = 0.67, P < 0.0001). To our knowledge, these results represent the first observation in humans that BO-Hb levels are significantly correlated with benzene exposure. Median BO-Alb levels in these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb, respectively, also reflecting a significant correlation with exposure (Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from both Hb and Alb adducts was very similar. These results clearly affirm the use of both Hb and Alb adducts of BO as biomarkers of exposure to high levels of benzene. As part of our investigation of the background levels of BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g) and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the observed background adducts reflect an artifact of the assay, while other portions are indicative of either unknown exposures or endogenous production of adducts.      

Eosinophilic granuloma revealed by torticollis: a case report]

Langerhans cell histiocytose is a rare condition in childhood. It presents in different ways ranging from a single bony disease to a multisystemic disease involving vital organs. CASE REPORT: We report a case of single bone involvement revealed by torticollis in an eight-year-old boy. The diagnosis was evocated on radiological findings and confirmed by histologic aspects. After a period of 2,5 years, this child is in total spontaneous remission. CONCLUSION: Torticollis must be explored and watched. Eosinophilic granuloma can be a rare aetiology in children. The outcome is often favorable.     

Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs. PATIENTS AND METHODS: Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed. RESULTS: Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC). CONCLUSION: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.     

Large Electrocaloric Responsivity and Energy Storage Response in the Lead-Free Ba(GexTi1−x)O3 Ceramics

Ferroelectric property that induces electrocaloric effect was investigated in Ba(Ge_xTi_1−x)O₃ ceramics, known as BTGx. X-ray diffraction analysis shows pure perovskite phases in tetragonal symmetry compatible with the P4mm (No. 99) space group. Dielectric permittivity exhibits first-order ferroelectric-paraelectric phase transition, confirmed by specific heat measurements, similar to that observed in BaTiO₃ (BTO) crystal. Curie temperature varies weakly as a function of Ge-content. Using the direct and indirect method, we confirmed that the adiabatic temperature change ΔT reached its higher value of 0.9 K under 8 kV/cm for the composition BTG6, corresponding to an electrocaloric responsivity ΔT/ΔE of 1.13 × 10⁻⁶ K.m/V. Such electrocaloric responsivity significantly exceeds those obtained so far in other barium titanate-based lead-free electrocaloric ceramic materials. Energy storage investigations show promising results: stored energy density of ~17 mJ/cm³ and an energy efficiency of ~88% in the composition BTG5. These results classify the studied materials as candidates for cooling devices and energy storage applications.