Developmental outcome of very low birth weight infants in a developing country

BACKGROUND: Advances in neonatal care allow survival of extremely premature infants, who are at risk of handicap. Neurodevelopmental follow up of these infants is an essential part of ongoing evaluation of neonatal care. The neonatal care in resource limited developing countries is very different to that in first world settings. Follow up data from developing countries is essential; it is not appropriate to extrapolate data from units in developed countries. This study provides follow up data on a population of very low birth weight (VLBW) infants in Johannesburg, South Africa. METHODS: The study sample included all VLBW infants born between 01/06/2006 and 28/02/2007 and discharged from the neonatal unit at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Bayley Scales of Infant and Toddler Development Version 111 (BSID) 111 were done to assess development. Regression analysis was done to determine factors associated with poor outcome. RESULTS: 178 infants were discharged, 26 were not available for follow up, 9 of the remaining 152 (5.9%) died before an assessment was done; 106 of the remaining 143 (74.1%) had a BSID 111 assessment. These 106 patients form the study sample; mean birth weight and mean gestational age was 1182 grams (SD: 197.78) and 30.81 weeks (SD: 2.67) respectively. The BSID (111) was done at a median age of 16.48 months. The mean cognitive subscale was 88.6 (95% CI: 85.69 - 91.59), 9 (8.5%) were < 70, mean language subscale was 87.71 (95% CI: 84.85 - 90.56), 10 (9.4%) < 70, and mean motor subscale was 90.05 (95% CI: 87.0 - 93.11), 8 (7.6%) < 70. Approximately one third of infants were identified as being at risk (score between 70 and 85) on each subscale. Cerebral palsy was diagnosed in 4 (3.7%) of babies. Factors associated with poor outcome included cystic periventricular leukomalacia (PVL), resuscitation at birth, maternal parity, prolonged hospitalisation and duration of supplemental oxygen. PVL was associated with poor outcome on all three subscales. Birth weight and gestational age were not predictive of neurodevelopmental outcome. CONCLUSION: Although the neurodevelopmental outcome of this group of VLBW infants was within the normal range, with a low incidence of cerebral palsy, these results may reflect the low survival of babies with a birth weight below 900 grams. In addition, mean subscale scores were low and one third of the babies were identified as "at risk", indicating that this group of babies warrants long-term follow up into school going age

Developmental outcome of very low birth weight infants in a developing country

Background: Advances in neonatal care allow survival of extremely premature infants, who are at risk of handicap. Neurodevelopmental follow up of these infants is an essential part of ongoing evaluation of neonatal care. The neonatal care in resource limited developing countries is very different to that in first world settings. Follow up data from developing countries is essential; it is not appropriate to extrapolate data from units in developed countries. This study provides follow up data on a population of very low birth weight (VLBW) infants in Johannesburg, South Africa. Methods: The study sample included all VLBW infants born between 01/06/2006 and 28/02/2007 and discharged from the neonatal unit at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Bayley Scales of Infant and Toddler Development Version 111 (BSID) 111 were done to assess development. Regression analysis was done to determine factors associated with poor outcome. Results: 178 infants were discharged, 26 were not available for follow up, 9 of the remaining 152 (5.9%) died before an assessment was done; 106 of the remaining 143 (74.1%) had a BSID 111 assessment. These 106 patients form the study sample; mean birth weight and mean gestational age was 1182 grams (SD: 197.78) and 30.81 weeks (SD: 2.67) respectively. The BSID (111) was done at a median age of 16.48 months. The mean cognitive subscale was 88.6 (95% CI: 85.69-91.59), 9 (8.5%) were < 70, mean language subscale was 87.71 (95% CI: 84.85-90.56), 10 (9.4%) < 70, and mean motor subscale was 90.05 (95% CI: 87.0-93.11), 8 (7.6%) < 70. Approximately one third of infants were identified as being at risk (score between 70 and 85) on each subscale. Cerebral palsy was diagnosed in 4 (3.7%) of babies. Factors associated with poor outcome included cystic periventricular leukomalacia (PVL), resuscitation at birth, maternal parity, prolonged hospitalisation and duration of supplemental oxygen. PVL was associated with poor outcome on all three subscales. Birth weight and gestational age were not predictive of neurodevelopmental outcome. Conclusion: Although the neurodevelopmental outcome of this group of VLBW infants was within the normal range, with a low incidence of cerebral palsy, these results may reflect the low survival of babies with a birth weight below 900 grams. In addition, mean subscale scores were low and one third of the babies were identified as "at risk", indicating that this group of babies warrants long-term follow up into school going age

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi

Targeting Class A and C Serine \u3b2-Lactamases with a Broad-Spectrum Boronic Acid Derivative

Production of \u3b2-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight \u3b2-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-\u3b2-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies

Structure and functional characterization of pyruvate decarboxylase from Gluconacetobacter diazotrophicus

BACKGROUND: Bacterial pyruvate decarboxylases (PDC) are rare. Their role in ethanol production and in bacterially mediated ethanologenic processes has, however, ensured a continued and growing interest. PDCs from Zymomonas mobilis (ZmPDC), Zymobacter palmae (ZpPDC) and Sarcina ventriculi (SvPDC) have been characterized and ZmPDC has been produced successfully in a range of heterologous hosts. PDCs from the Acetobacteraceae and their role in metabolism have not been characterized to the same extent. Examples include Gluconobacter oxydans (GoPDC), G. diazotrophicus (GdPDC) and Acetobacter pasteutrianus (ApPDC). All of these organisms are of commercial importance. RESULTS: This study reports the kinetic characterization and the crystal structure of a PDC from Gluconacetobacter diazotrophicus (GdPDC). Enzyme kinetic analysis indicates a high affinity for pyruvate (KM 0.06 mM at pH 5), high catalytic efficiencies, pHopt of 5.5 and Topt at 45 degrees C. The enzyme is not thermostable (T of 18 minutes at 60 degrees C) and the calculated number of bonds between monomers and dimers do not give clear indications for the relatively lower thermostability compared to other PDCs. The structure is highly similar to those described for Z. mobilis (ZmPDC) and A. pasteurianus PDC (ApPDC) with a rmsd value of 0.57 A for C? when comparing GdPDC to that of ApPDC. Indole-3-pyruvate does not serve as a substrate for the enzyme. Structural differences occur in two loci, involving the regions Thr341 to Thr352 and Asn499 to Asp503. CONCLUSIONS: This is the first study of the PDC from G. diazotrophicus (PAL5) and lays the groundwork for future research into its role in this endosymbiont. The crystal structure of GdPDC indicates the enzyme to be evolutionarily closely related to homologues from Z. mobilis and A. pasteurianus and suggests strong selective pressure to keep the enzyme characteristics in a narrow range. The pH optimum together with reduced thermostability likely reflect the host organisms niche and conditions under which these properties have been naturally selected for. The lack of activity on indole-3-pyruvate excludes this decarboxylase as the enzyme responsible for indole acetic acid production in G. diazotrophicus.IS

Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar−/−) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans

Obesity and caries in four-to-six year old English children: a cross-sectional study.

BACKGROUND: Obesity and caries are common conditions in childhood and can have significant implications on children's wellbeing. Evidence into their association remains conflicting. Furthermore, studies examining the ssociation between obesity and caries commonly focus on individual-level determinants. The present study aimed to examine the association between obesity and caries in young English children and to determine the impact of deprivation and area-level characteristics on the distribution of the two conditions. METHODS: This was a cross-sectional study among children in Plymouth city aged four-to-six years. Anthropometric measurements included weight and height (converted to Body Mass Index centiles and z-scores), and waist circumference. Caries was assessed by using the sum of the number of teeth that were decayed, missing or filled. A questionnaire was used to obtain information on children's demographic characteristics, oral hygiene, and dietary habits. The impact of deprivation on anthropometric variables and caries was determined using Linear and Poisson regression models, respectively. Multiple logistic regression was used to assess the association between different anthropometric measures and caries. Logistic regression models were also used to examine the impact of several demographic characteristics and health behaviours on the presence of obesity and caries. RESULTS: The total sample included 347 children aged 5.10 ± 0.31 (mean ± SD). Deprivation had a significant impact on caries and BMI z-scores (p < 0.05). Neither BMI- nor waist circumference z-scores were shown to be significantly associated with dental caries. Among the neighbourhood characteristics examined, the percentage of people dependent on benefits was found to have a significant impact on caries rates (p < 0.05). Household's total annual income was inversely related to caries risk and parental educational level affected children's tooth brushing frequency. CONCLUSIONS: No associations between any measure of obesity and caries were found. However, deprivation affected both obesity and caries, thus highlighting the need to prioritise disadvantaged children in future prevention programmes

The d subunit plays a central role in human vacuolar H+-ATPases

The multi-subunit vacuolar-type H+-ATPase consists of a V1 domain (A–H subunits) catalyzing ATP hydrolysis and a V0 domain (a, c, c′, c″, d, e) responsible for H+ translocation. The mammalian V0 d subunit is one of the least-well characterized, and its function and position within the pump are still unclear. It has two different forms encoded by separate genes, d1 being ubiquitous while d2 is predominantly expressed at the cell surface in kidney and osteoclast. To determine whether it forms part of the pump’s central stalk as suggested by bacterial A-ATPase studies, or is peripheral as hypothesized from a yeast model, we investigated both human d subunit isoforms. In silico structural modelling demonstrated that human d1 and d2 are structural orthologues of bacterial subunit C, despite poor sequence identity. Expression studies of d1 and d2 showed that each can pull down the central stalk’s D and F subunits from human kidney membrane, and in vitro studies using D and F further showed that the interactions between these proteins and the d subunit is direct. These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism

The motor development of orphaned children with and without HIV: Pilot exploration of foster care and residential placement

<p>Abstract</p> <p>Background</p> <p>The AIDS epidemic has lead to an increase in orphaned children who need residential care. It is known that HIV leads to delayed motor development. However, the impact of place of residence on motor function has not been investigated in the South African context. The aim of the study was therefore to establish if children in institutionalised settings performed better or worse in terms of gross motor function than their counterparts in foster care. A secondary objective was to compare the performance of children with HIV in these two settings with those of children who were HIV negative.</p> <p>Methods</p> <p>Forty-four children both with and without HIV, were recruited from institutions and foster care families in Cape Town. The Peabody Development Motor Scale (PDMS II) was used to calculate the total motor quotient (TMQ) at baseline and six months later. Comparisons of TMQ were made between residential settings and between children with and without HIV.</p> <p>Results</p> <p>Twenty-one children were infected with HIV and were significantly delayed compared to their healthy counterparts. Antiretroviral therapy was well managed among the group but did not appear to result in restoration of TMQ to normal over the study period. HIV status and place of residence emerged as a predictor of TMQ with children in residential care performing better than their counterparts in foster care. All children showed improvement over the six months of study.</p> <p>Conclusions</p> <p>Foster parents were well supported administratively in the community by social welfare services but their children might have lacked stimulation in comparison to those in institutional settings. This could have been due to a lack of resources and knowledge regarding child development. The assumption that foster homes provide a better alternative to institutions may not be correct in a resource poor community and needs to be examined further.</p

Interaction of Rio1 Kinase with Toyocamycin Reveals a Conformational Switch That Controls Oligomeric State and Catalytic Activity

Rio1 kinase is an essential ribosome-processing factor required for proper maturation of 40 S ribosomal subunit. Although its structure is known, several questions regarding its functional remain to be addressed. We report that both Archaeoglobus fulgidus and human Rio1 bind more tightly to an adenosine analog, toyocamycin, than to ATP. Toyocamycin has antibiotic, antiviral and cytotoxic properties, and is known to inhibit ribosome biogenesis, specifically the maturation of 40 S. We determined the X-ray crystal structure of toyocamycin bound to Rio1 at 2.0 Å and demonstrated that toyocamycin binds in the ATP binding pocket of the protein. Despite this, measured steady state kinetics were inconsistent with strict competitive inhibition by toyocamycin. In analyzing this interaction, we discovered that Rio1 is capable of accessing multiple distinct oligomeric states and that toyocamycin may inhibit Rio1 by stabilizing a less catalytically active oligomer. We also present evidence of substrate inhibition by high concentrations of ATP for both archaeal and human Rio1. Oligomeric state studies show both proteins access a higher order oligomeric state in the presence of ATP. The study revealed that autophosphorylation by Rio1 reduces oligomer formation and promotes monomerization, resulting in the most active species. Taken together, these results suggest the activity of Rio1 may be modulated by regulating its oligomerization properties in a conserved mechanism, identifies the first ribosome processing target of toyocamycin and presents the first small molecule inhibitor of Rio1 kinase activity