Latest developments in the treatment of severe malnutrition in children.
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Child, Preschool↗
Biomedical subjects
A Ashworth
Publications and source records attributed to A Ashworth.
Functions of the BRCA1 and BRCA2 genes.
Mutations in the BRCA1 and BRCA2 genes confer a high risk of breast cancer development. Both genes encode very large proteins of unknown function but recent results suggest that they may have roles in transcriptional regulation and DNA repair. These advances offer the prospect of understanding not only the normal cellular function of these genes but also how their loss leads to tumour formation.
Animals↗
A missense mutation in the BRCA2 gene in three siblings with ovarian cancer.
Inherited susceptibility to ovarian cancer has been associated with germline defects at several loci. The major known ovarian cancer susceptibility gene is BRCA1 on chromosome 17q, which confers a risk of approximately 60% by the age of 70 years. Truncating mutations in BRCA2 on chromosome 13q also predispose to ovarian cancer, although they confer a lower risk than mutations in BRCA1. We have studied the molecular basis of ovarian cancer predisposition in a Finnish family with three affected sisters. Analysis of polymorphic markers provided evidence against linkage to BRCA1, but the sibship was consistent with linkage to BRCA2. Conformation-sensitive gel electrophoresis was used to screen the entire coding sequence of BRCA2. A G to A transition at nucleotide 8702 was observed, which is predicted to convert glycine 2901 to aspartate in the encoded protein. This sequence variant was not detected in 220 cancer-free Finnish control individuals, or in several hundred cancer families of many nationalities previously screened for BRCA2 mutations. Taken together with the fact that this amino acid residue and the surrounding region of BRCA2 is identical in mouse and chicken, the data suggest that this alteration is a disease-causing BRCA2 missense mutation. Previously published data indicate that the risks of breast and ovarian cancer conferred by BRCA2-truncating mutations varies with the position of the mutation in the gene. The missense mutation reported here suggests that the BRCA2 domain including and surrounding glycine 2901 may be more important in preventing neoplastic transformation in ovarian epithelium than in breast epithelium.
Adult↗
Zinc supplementation, mental development and behaviour in low birth weight term infants in northeast Brazil.
OBJECTIVE: To test whether zinc supplementation reduces the deficits in mental development and behaviour that are found in term infants of low birth weight in the study population. DESIGN: A prospective double-blind, part-randomised efficacy trial. SETTING: A low-income population in Pernambuco, northeast Brazil, where the economy is largely dependent on sugar-cane production, and where over 90% of deliveries occur in health facilities. SUBJECTS: During a 20-month period, all singleton, term infants weighing 1500-2499 g born to families of low income ( < US $280/month) were enrolled at birth (n = 205). At 6 and 12-months, the numbers tested were 163 and 138 respectively. INTERVENTION: Infants born from January 1993-January 1994 were randomly assigned to receive daily, except Sundays, a placebo (n = 66) or 1 mg zinc (n = 68). Those born February-August 1994 were given 5 mg zinc (n = 71). Supplementation was for eight weeks, starting at birth. Field workers visited each infant at home to administer the supplement. RESULTS: At 6 and 12-months, mental and psychomotor development was assessed with the Bayley Scales of Infant Development and no significant differences in the scores of the three groups were found. At 12-months, behaviour was also assessed on 5 ratings. Ratings were highest in infants given 5 mg zinc (P = 0.042). CONCLUSIONS: Zinc supplementation (5 mg/d) for eight weeks may reverse some of the poor behaviours, particularly responsiveness, exhibited by low birth weight infants. No amelioration of their mental and psychomotor deficits was found.
Behavior↗
Nutrition interventions to reduce diarrhoea morbidity and mortality.
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Breast Feeding↗
Growth, morbidity, and mortality of children in Dhaka after treatment for severe malnutrition: a prospective study.
Over 1300 severely malnourished children (< 60% of US National Center for Health Statistics weight-for-height, with edema, or both) are admitted each year to the Children's Nutrition Unit in Dhaka. Fatality during treatment is low and recovery is rapid. Our aim was to determine whether this initial success is sustained when children return home. A previous attempt to address this question was frustrated by the difficulty in tracing children after discharge because most are from slum settlements and families move frequently. This prospective study with fortnightly monitoring was therefore undertaken. The main outcomes of interest were anthropometric status, relapse, morbidity, and mortality. Children (n = 437) who had been treated for severe malnutrition when aged 12-59 mo and had reached the discharge criterion of 80% of weight-for-height, were followed for the next 12 mo. During follow-up, 7.5% were lost without trace, 0.6% relapsed, and 2.3% died. Morbidity was high, with a mean of seven episodes of diarrhea during the year. Outpatient visits for diarrhea occurred for 67% of children, and 58% had pneumonia (10% had pneumonia three times). After 12 mo, mean weight-for-height was 91% (-0.92 z score) but mean height-for-age remained at 84% (-4.14 z score). Weight gain, but not height gain, tended to be lower in children who experienced more diarrhea. Fever and cough were not associated with either weight or height gain. The high prevalence of illness highlights the need for continued accessible health care and for interventions to reduce disease acquisition.
Bangladesh↗
Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full-term infants in northeast Brazil.
In Brazil, the highest incidence of low birth weight (LBW) occurs in the northeast, and diarrhea and respiratory infections are the main causes of infant mortality and morbidity. We hypothesized that LBW infants may be zinc deficient, and that this might be adversely affecting their immune function, morbidity, and postnatal growth. We therefore examined the effect of zinc supplementation on these outcomes during the first 6 mo of life. LBW full-term infants (mean birth weight 2337 g) were given daily for 8 wk either 5 mg Zn (n = 71), 1 mg Zn (n = 68), or a placebo (n = 66). Morbidity was determined prospectively through daily home visits (except on Sunday) during weeks 0-8, then twice weekly in weeks 9-26. Anthropometric measurements were made at 0, 4, 8, 17, and 26 wk. Immune function was assessed at 8 wk by the phytohemagglutinin skin test. Supplementation (5 mg Zn) was associated with a 28% reduction in diarrhea prevalence over the 6-mo period [after adjustment for confounders (P = 0.043)], and a 33% reduction in the prevalence of cough (NS, adjusted prevalence P = 0.073). All infants had a positive immune response at 8 wk. Although supplementation had no significant effect on weight and length gains from 0 to 26 wk, infants given 5 mg Zn gained more weight than infants given placebo during weeks 17-26 (P = 0.024, analysis of variance). There was no effect on any outcome with 1 mg Zn. We conclude that 5 mg Zn/d is of benefit to LBW, full-term infants who only have a modest weight deficit.
Cough↗
The human FXY gene is located within Xp22.3: implications for evolution of the mammalian X chromosome.
It has been proposed that the pseudoautosomal region of mammals has evolved by sequential addition of autosomal material onto the X and Y chromosomes followed by movement of the pseudoautosomal boundary to create X-unique regions. We have previously described a gene, Fxy , that spans the pseudoautosomal boundary in mice such that the first three exons of the gene are located on the X chromosome, but the remainder of the gene is located on both X and Y chromosomes. Therefore, this gene might be in a state of transition between pseudoautosomal and X-unique locations. In support of this theory we show here that the human FXY gene is located in Xp22.3 in humans, proximal to the pseudoautosomal boundary.
Amino Acid Sequence↗
The Y* rearrangement in mice: new insights into a perplexing PAR.
In essence, the Y* rearrangement in the mouse is a Y chromosome that has been hijacked by a non-Y centromere attached distal to the pseudoautosomal region (PAR). All the Y-unique material is thought to be unaltered, but the recombinatory behaviour of the Y* with the X during male meioisis led to the conclusion that part of the PAR is inverted. In the course of a cross set up to introduce the X-linked mutation Patchy fur (Paf) into XY* males, the Y* chromosome was found to carry the wild type allele of Paf. Paf maps close to the X PAR boundary, so we hypothesised that the inverted region of the Y* PAR originated from an X chromosome that provided not only an inverted copy of proximal PAR, but also an X PAR boundary together with some adjacent X-unique material that included the Paf locus. This hypothesis was validated by Southern analysis using an X PAR boundary probe to show that Y* has an X PAR boundary. Thus the Y* PAR has resulted from an end to end fusion of an X and a Y PAR. Furthermore, it was shown that in conjunction with this PAR-PAR fusion, there has been deletion of both copies of the distally located pseudoautosomal gene Steroid sulfatase (Sts).
Animals↗
Treatment of malnutrition in Brazil: simple solutions to common problems.
At the largest rehabilitation centre in Ceará, Brazil, the World Health Organization (WHO) guidelines for improved dietary management of severe malnutrition were implemented. Rates of weight gain increased fourfold, daily food costs were reduced, and staff time was saved. Implementation was achieved within 1 week, including training. Other centres are encouraged to adopt similar measures.
Brazil↗
Effectiveness of nutrition centers in Ceará state, northeastern Brazil.
Childhood malnutrition has been a major, long-standing health concern in northeastern Brazil. In response, during 1992-1994, the state government of Ceará, with financial support from the World Bank, established 34 new nutrition centers. During 1996 an evaluation of the centers was conducted to determine their effectiveness in treating children with malnutrition and to identify weaknesses in the system and possible solutions. Also evaluated were the adequacy of resources, admission and discharge criteria, staff training, and community satisfaction. Effectiveness was found to be low. Treatment procedures did not conform with World Health Organization recommendations. Rates of weight gain were inadequate, and the mean duration of rehabilitation--8.7 months--was too long. Case fatality in two centers was unacceptably high, 40% and more. Entry and exit criteria for rehabilitation were ill defined, resulting in some nonmalnourished children being enrolled. Few staff were adequately trained; knowledge was weak, especially about case management; and mothers were not effectively instructed. Recommendations include setting objectives for the centers, improving referral systems, standardizing entry criteria, improving case management, and establishing performance indicators.
Brazil↗
Effects of intrauterine growth retardation on mortality and morbidity in infants and young children.
This review aims to quantify the risks of mortality and morbidity associated with intrauterine growth retardation (IUGR). Twenty-nine data sets with birth-weight-specific mortalities are examined to determine whether consistent patterns of risk emerge when data from different populations are compared. Measures of mortality risk are also made with birth weight as a dichotomous variable. Twelve data sets are presented. From the data available, it is estimated that for term infants weighing 2000-2499 g at birth, the risk of neonatal death is 4 times higher than for infants weighing 2500-2999 g, and 10 times higher than for infants weighing 3000-3499 g. The risk of postneonatal death in term infants weighing 2000-2499 g is estimated to be 2 times higher than for infants 2500-2999 g, and 4 times that of infants weighing 3000-3499 g. Estimates of risk for IUGR infants are less consistent than for preterm infants. This could be due to methodological differences, particularly smaller sample sizes in the studies in developing countries, or may reflect real variation in risk. The latter may be associated with the heterogeneity of IUGR across populations, or to varying risks depending, for example, on which infections predominate or infant age at peak prevalence. IUGR is most prevalent in developing countries and the review therefore focuses on morbidity from diarrhoeal and respiratory infections. Data from nine studies are presented. There is an increased risk of diarrhoea in term infants < 2500 g and an increased risk of pneumonia. The risks of morbidity and mortality appear to differ depending on whether infants are wasted or stunted at birth. Stunted infants of low birth weight have higher neonatal mortality than wasted newborns, but this could be due to inclusion of infants with congenital anomalies who are often stunted. Wasted infants are more prone than stunted infants to neonatal morbidity. No comparative postneonatal data were located.
Birth Weight↗
Report of the IDECG Working Group on effects of IUGR on infants, children and adolescents: immunocompetence, mortality, morbidity, body size, body composition, and physical performance.
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Adolescent↗
Nuclear location and cell cycle regulation of the BRCA2 protein.
Women carrying a germ-line mutation in the BRCA1 or BRCA2 genes have a high risk of developing breast cancer, and loss of the wild-type allele in tumors suggests that these genes function as tumor suppressor genes. The BRCA2 gene encodes a 3418-amino acid protein with no significant sequence similarity to any known protein. To begin to elucidate the cellular role of BRCA2, we have raised antibodies to the BRCA2 protein and used these to study its subcellular localization and expression. We show that BRCA2 is a nuclear protein expressed in response to cell proliferation and that BRCA2 expression is initiated before DNA synthesis.
Animals↗
A role for JNK/SAPK in proliferation, but not apoptosis, of IL-3-dependent cells.
Activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) has been implicated in the induction of apoptosis in a variety of systems [1] [2] [3] [4] [5] [6] [7] [8]. BAF3 cells are pre-B cells that undergo apoptosis following IL-3 withdrawal or ceramide treatment [9] [10]. JNK/SAPK in BAF3 cells is stimulated by ceramide and also during cell proliferation in response to IL-3 [11], but its role in the apoptotic response is not clear. We have devised a method of selectively inhibiting JNK/SAPK activity using a dual-specificity threonine/tyrosine phosphatase, M3/6. Expression of this phosphatase in BAF3 cells prevented ceramide stimulation of JNK/SAPK activity but did not affect apoptosis following IL-3 withdrawal or ceramide treatment. IL-3-stimulated proliferation of BAF3 cells expressing the phosphatase was, however, inhibited. Hence JNK/SAPK activation is likely to be involved in the proliferative response of these cells but is not required for apoptosis. Selective ablation by dual-specificity phosphatases should be a general method for determining the functions of specific mitogen-activated kinase pathways.
Animals↗
A gene spans the pseudoautosomal boundary in mice.
The X and Y chromosomes of the mouse, like those of other mammals, are heteromorphic over most of their length, but at the distal ends of the chromosomes is a region of sequence identity, the pseudoautosomal region (PAR), where the chromosomes pair and recombine during male meiosis. The point at which the PAR diverges into X- and Y-specific sequences is called the pseudoautosomal boundary. We have completed a genomic walk from the X-specific Amelogenin gene to the PAR. Analysis of this region revealed that the pseudoautosomal boundary of mice is located within an intron of a transcribed gene that encodes a novel RING finger protein. The first three of the exons of the gene are located on the X chromosome whereas the 3' exons of the gene are located on both X and Y chromosomes. This unusual arrangement may indicate that the gene is in a state of transition from pseudoautosomal to X-unique and provides evidence for a process of attrition of the pseudoautosomal region on the Y chromosome.
Amelogenin↗
3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase.
BACKGROUND: The activation of protein kinase B (PKB, also known as c-Akt) is stimulated by insulin or growth factors and results from its phosphorylation at Thr308 and Ser473. We recently identified a protein kinase, termed PDK1, that phosphorylates PKB at Thr308 only in the presence of lipid vesicles containing phosphatidylinositol 3,4,5-trisphosphate (Ptdlns(3,4,5)P3) or phosphatidylinositol 3,4-bisphosphate (Ptdlns(3,4)P2). RESULTS: We have cloned and sequenced human PDK1. The 556-residue monomeric enzyme comprises a catalytic domain that is most similar to the PKA, PKB and PKC subfamily of protein kinases and a carboxy-terminal pleckstrin homology (PH) domain. The PDK1 gene is located on human chromosome 16p13.3 and is expressed ubiquitously in human tissues. Human PDK1 is homologous to the Drosophila protein kinase DSTPK61, which has been implicated in the regulation of sex differentiation, oogenesis and spermatogenesis. Expressed PDK1 and DSTPK61 phosphorylated Thr308 of PKB alpha only in the presence of Ptdlns(3,4,5)P3 or Ptdlns(3,4)P2. Overexpression of PDK1 in 293 cells activated PKB alpha and potentiated the IGF1-induced phosphorylation of PKB alpha at Thr308. Experiments in which the PH domains of either PDK1 or PKB alpha were deleted indicated that the binding of Ptdlns(3,4,5)P3 or Ptdlns(3,4)P2 to PKB alpha is required for phosphorylation and activation by PDK1. IGF1 stimulation of 293 cells did not affect the activity or phosphorylation of PDK1. CONCLUSIONS: PDK1 is likely to mediate the activation of PKB by insulin or growth factors. DSTPK61 is a Drosophila homologue of PDK1. The effect of Ptdlns(3,4,5)P3/Ptdlns(3,4)P2 in the activation of PKB alpha is at least partly substrate directed.
3-Phosphoinositide-Dependent Protein Kinases↗
Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7).
Mitogen-activated protein (MAP) kinase phosphatases constitute a growing family of dual specificity phosphatases thought to play a role in the dephosphorylation and inactivation of MAP kinases and are therefore likely to be important in the regulation of diverse cellular processes such as proliferation, differentiation, and apoptosis. For this reason it has been suggested that MAP kinase phosphatases may be tumor suppressors. We have determined the chromosomal locations of three human dual specificity phosphatase genes by fluorescence in situ hybridization and radiation hybrid mapping. The genes were localized to three different chromosomes, MKP2 (DUSP4) to 8p11-p12, MKP3 (DUSP6) to 12q22-q23, and MKPX (DUSP7) to 3p21. This will allow the potential roles of these genes in disease processes to be evaluated.
Base Sequence↗