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BACKGROUND: Both police shootings and violent crime remain high in the United States of America compared to other developed nations but debates continue about whether race, mental health or other social factors are related to them. AIMS: Our aim was to test relationships between community factors indicative of socio-economic status, racial demographics, police shootings, and violent crime. METHODS: Data on police shootings, violent crime and community sociodemographic factors were drawn from two publicly accessible datasets: health and police records of 100 US municipalities and relationships between them explored using regression analyses. RESULTS: Data were from the 100 largest US municipalities as designated by the mapping police violence database. The median per capital violent crime rate was 5.94 and median killings by police per 10 thousand arrests was 13.7. Violent crime was found to be related mainly to income inequality and lower academic achievement in the community. Race was unrelated to violent crime after controlling for other factors. Police shootings were found to be related to community level mental health concerns, food insecurity and the municipality's violent crime rate. CONCLUSION: The evidence suggests that socio-economic factors are the primary drivers of both violent crime perpetration and police shootings. Policy approaches aimed at improving education and reducing poverty are likely to mitigate both violent crime and police shootings. However, it is important to recognise that being Black is an indicator of particular disadvantage within this context. This underscores the need for comprehensive strategies that address the systemic issues of racial disparities and socio-economic inequality, while also acknowledging the complex interplay of race, poverty and policing in the context of violent crime and police shootings.
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Policia , Factores Socioeconómicos , Violencia , Humanos , Estados Unidos/epidemiología , Policia/estadística & datos numéricos , Violencia/estadística & datos numéricos , Ciudades/estadística & datos numéricos , Homicidio/estadística & datos numéricos , Crimen/estadística & datos numéricos , Grupos Raciales/estadística & datos numéricos , MasculinoRESUMEN
Firearm violence remains a public health crisis in marginalized, urban communities, with Black adolescents bearing the burden of firearm homicides and injuries. As such, the prevention of firearm violence among adolescents has moved to a high priority of the U.S. public health agenda. The current paper reviews recent literature to highlight the heterogeneity in firearm behavior among Black adolescents and underscore the need for additional research on decision-making and firearm behavior to better understand how adolescents make decisions to acquire, carry, and use firearms. Through a discussion of the disproportionate levels of trauma exposure and trauma symptoms experienced by Black adolescents, the current paper also proposes a trauma-informed approach to understanding decision-making for risky firearm behavior. We discuss the broader impacts of this approach, including the development of a more comprehensive and contextually relevant understanding of the variability in risky firearm behavior and improvements in risk screening capabilities and preventive intervention strategies.
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Armas de Fuego , Heridas por Arma de Fuego , Adolescente , Humanos , Homicidio/prevención & control , Violencia/prevención & control , Asunción de Riesgos , Población Negra , Heridas por Arma de Fuego/prevención & controlRESUMEN
BACKGROUND: Following several high-profile police shootings of Black Americans, renewed debate has focused on race as a predictor of police violence. Past research has been inconsistent on this score. Some scholars argue that socioeconomic issues are better predictors of police-related violence than are race and ethnicity. AIMS: To test relationships between complaints of excessive use of police violence and racial/ethnic population demographics, allowing for social and mental health variables. METHODS: We examined records from all 195 municipal police departments in California to identify complaints of excessive force by police and tested for associations between such complaints and health, socio-economic and demographic data from county records, using multivariate analyses. RESULTS: There was no difference in reporting between communities according to Black or White American residency proportions; communities with more Latino Americans were less likely to complain formally of excessive use of police force. The strongest associate of complaints to police departments that their employees had used excessive force was experiencing mental distress in the community. CONCLUSIONS: Our findings are limited by reliance on complaints to police authorities rather than actual incidence of police use of excessive force and by having to map municipal data on to county data, but the finding that factors other than or in addition to any inherent police problems may contribute to excessive use of force by the police offers new lines for remedying the problem. In particular, our findings suggest that more training for police in recognising and managing mental distress and more provision of mental health experts to work alongside police would be worth evaluating as a next step.
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Etnicidad , Policia , Negro o Afroamericano , Hispánicos o Latinos , Humanos , Estados Unidos , ViolenciaRESUMEN
In this article, we explore the responses of 357 African American men between 15- and 24-years old living in four high crime high violence cities to better understand their perception of their environment and its impact on community violence. We focus on study participants' perceptions of their cities, explanations of violence, and their perceived contribution to the level of violence. Respondents describe their cities in grim terms with few opportunities. And, from their perspective, the dangerous environment in which they live necessitates gun possession, potentially perpetuating community violence. Our findings affirm that as with any other public health issue, the perception of place matters in understanding community violence. Further, our findings underscore the importance of seeking and responding to the lived experience of those most likely to be victims and perpetrators of community violence in crafting and implementing interventions.
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Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a 'best practice' for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches.
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Galactosemias/dietoterapia , Galactosemias/diagnóstico , Adolescente , Adulto , Niño , Trastornos del Conocimiento/etiología , Carbohidratos de la Dieta/administración & dosificación , Femenino , Galactosa/administración & dosificación , Galactosemias/complicaciones , Humanos , Lactante , Recién Nacido , Internacionalidad , Masculino , Tamizaje Neonatal , Enfermedades del Ovario/etiología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Glutaric Aciduria type 1 (GA 1) is an inherited disorder of lysine and tryptophan catabolism that typically manifests in infants with acute cerebral injury associated with intercurrent illness. We investigated the clinical, biochemical and molecular features in 14 known GA 1 patients in South Africa, most of whom were recently confirmed following the implementation of sensitive urine organic acid screening at our laboratory. Age at diagnosis ranged from 3days to 5years and poor clinical outcome reflected the delay in diagnosis in all but one patient. Twelve patients were unrelated black South Africans of whom all those tested (n=11) were found homozygous for the same A293T mutation in the glutaryl-CoA dehydrogenase (GCDH) gene. Excretion of 3-hydroxyglutarate (3-OHGA) was >30.1µmol/mmol creatinine (reference range <2.5) in all cases but glutarate excretion varied with 5 patients considered low excretors (glutarate <50µmol/mmol creatinine). Fibroblast GCDH activity was very low or absent in all of five cases tested. Heterozygosity for the A293T mutation was found 1 in 36 (95% CI; 1/54 - 1/24) unrelated black South African newborns (n=750) giving a predicted prevalence rate for GA 1 of 1 in 5184 (95% CI; 1/11664 - 1/2304) in this population. GA 1 is a treatable but often missed inherited disorder with a previously unrecognised high carrier frequency of a single mutation in the South African black population.
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Glutaril-CoA Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/epidemiología , Errores Innatos del Metabolismo de los Aminoácidos/genética , Población Negra/genética , Encefalopatías Metabólicas/epidemiología , Encefalopatías Metabólicas/genética , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/genética , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Sudáfrica/epidemiologíaRESUMEN
Complement component C6 is one of five terminal complement components incorporated into the membrane attack complex. Complete deficiency of C6 (C6Q0) leads to an increased susceptibility to Neisseria meningitidis infections, and affected individuals typically present with recurrent meningococcal disease. There is a relatively high prevalence of C6Q0 in the Western Cape, South Africa and three frameshift mutations have previously been described to be responsible for C6Q0 in this area-879delG, 1195delC, and 1936delG (current nomenclature). We have now genotyped a further nine genetically independent individuals with C6Q0, confirming previous reports that the most common defect in the Western Cape is 879delG. Moreover, we report the first identification of the 878delA mutation within the Western Cape, which has previously only been reported in individuals of African descent living in the United States or Europe. We also investigated the genotype of an Irish C6Q0 individual and her sibling, and report two previously undescribed mutations. One mutation alters a tyrosine codon to a stop codon within exon 10. The second mutation is within the 5' donor splice site of intron 3, and would, in all probability, disrupt splicing. These two mutations were shown to segregate independently. We also discuss the nomenclature for reporting C6 and C7 gene mutations, as the current nomenclature does not follow the recognised guidelines.
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Complemento C6/genética , Predisposición Genética a la Enfermedad , Infecciones Meningocócicas/genética , Neisseria meningitidis , Complemento C6/química , Complemento C6/deficiencia , Humanos , Mutación , Linaje , Sudáfrica , Tirosina/química , Tirosina/genéticaRESUMEN
BACKGROUND: Phenocopies of homozygous familial hypercholesterolemia (hoFH) having autosomal recessive inheritance, were recently found to arise from defects in the LDL receptor (LDLR) adapter protein, called ARH, which facilitates the clearance of circulating LDL. Discrimination between the two causes of the phenotype at a clinical level may not be possible when parents display moderate hypercholesterolaemia. An effective strategy is thus required to identify the appropriate mechanism for the disorder. METHODS: Fibroblast LDL uptake studies were coupled with Western blotting for ARH protein in cell extracts, to identify the defective gene before DNA studies were initiated. Two subjects with the hoFH phenotype, but with indeterminate dyslipidaemia in their parents, were fully worked up. RESULTS: Defective LDL metabolism was established in both patients by functional and protein studies and further confirmed by detecting deleterious mutations, in the LDLR and ARH genes. The ARH patient is the first subject of Negroid identity to be described and records a specific mutation in this racial grouping. CONCLUSION: This study highlights the occasional complexity and uncertainty of a clinical diagnosis of hoFH and presents Western blotting of leucocyte extracts for ARH protein, as a rapid strategy for the detection of ARH before sequencing the gene for mutation(s). This strategy may be particularly useful in populations where founder mutations for ARH and LDLR defects are rare or co-exist.
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Proteínas Adaptadoras Transductoras de Señales/genética , Hipercolesterolemia/genética , Receptores de LDL/fisiología , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/fisiología , Adulto , Western Blotting , Femenino , Haplotipos , Humanos , Masculino , Mutación , Fenotipo , Polimorfismo de Nucleótido Simple , Receptores de LDL/genéticaRESUMEN
BACKGROUND: The objective of this study was to document the clinical, laboratory and genetic features of galactosemia in patients from the Cape Town metropolitan region. METHODS: Diagnoses were based on thin layer chromatography for galactosuria/galactosemia and assays of erythrocyte galactose-1-phosphate uridyltransferase (GALT) and galactokinase activities. Patients were screened for the common S135L and Q188R transferase gene mutations, using PCR-based assays. Screening for the S135L mutation in black newborns was used to estimate the carrier rate for galactosemia in black South Africans. RESULTS: A positive diagnosis of galactosemia was made in 17 patients between the years 1980 to 2001. All had very low or absent galactose-1-phosphate uridyltransferase (GALT) activity, and normal galactokinase levels. The mean age at diagnosis was 5.1 months (range 4 days to 6.5 months). A review of 9 patients showed that hepatomegaly (9/9), and splenomegaly, failure to thrive, developmental delay, bilateral cataracts (6/9) were the most frequent features at diagnosis. Six had conjugated hyperbilirubinemia. Four experienced invasive E. coli infection before diagnosis. Ten patients were submitted to DNA analysis. All 4 black patients and 2 of mixed extraction were homozygous for the S135L allele, while all 3 white patients were homozygous for the Q188R allele. The remaining patient of mixed extraction was heterozygous for the Q188R allele. The estimated carrier frequency of the S135L mutation in 725 healthy black newborns was 1/60. CONCLUSIONS: In the absence of newborn screening the delay in diagnosis is most often unacceptably long. Also, carrier frequency data predict a galactosemia incidence of approximately 1/14 400 for black newborns in the Cape Metropole, which is much higher than the current detection rate. It is thus likely that many patients go undetected.
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Galactosemias/diagnóstico , Galactosemias/genética , Portador Sano , Femenino , Galactoquinasa/sangre , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Reacción en Cadena de la Polimerasa , Sudáfrica , UTP-Hexosa-1-Fosfato Uridililtransferasa/sangre , UTP-Hexosa-1-Fosfato Uridililtransferasa/genéticaRESUMEN
BACKGROUND: The objective of this study was to describe the clinical and molecular features of the first South African family with X-linked hyper-IgM syndrome (HIGM1). METHODS: Diagnoses were based on immunoglobulin results and the absence of CD40 ligand (CD40L) expression on activated T-cells. Complete molecular characterisation involved CD40L cDNA sequencing, and genomic DNA analysis by polymerase chain reaction amplification, restriction enzyme digestion and sequencing. A PCR-based diagnostic assay was established for carrier detection and prenatal diagnosis in this family. RESULTS: There were originally six children, three males and three females. The eldest boy died after being diagnosed with hypogammaglobulinaemia, before HIGM1 was considered. This disorder was diagnosed in the second eldest boy at the age of 5 years, after failing to detect CD40L expression on his activated T-cells. A deficiency of CD40L was also confirmed in the youngest male at the age of 5 years. Both younger brothers have since died of infections relating to HIGM1. Molecular investigation showed that exon 3 was deleted from the CD40L mRNA of the affected males. Genomic DNA analysis identified a 1.5 kilobase deletion, spanning exon 3 and including extended flanking intronic sequence. Carrier status in the mother was confirmed by RT-PCR of her CD40L mRNA. Genetic analysis of the three female children was deferred because they were below the legal consenting age of 18 years. A PCR-based assay for genomic DNA was established for easy identification of female carriers and affected males in the future. CONCLUSIONS: This study confirmed the diagnosis of HIGM1 in the first South African family to be investigated and identified a novel mutation in the CD40L gene.
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Ligando de CD40/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipergammaglobulinemia/genética , Inmunoglobulina M , Mutación , Niño , Análisis Mutacional de ADN , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Hipergammaglobulinemia/inmunología , Masculino , Linaje , SudáfricaRESUMEN
L-2 hydroxyglutaric aciduria is an autosomal recessive error of metabolism that manifests as an encephalopathy. The most common presenting signs are seizures, tremors, ataxia and/ or dementia. Some affected dogs show only subtle behavioural changes. Amongst canines, the condition has been best described in Staffordshire Bull Terriers. Although this is the first reported case in South Africa, at least three other affected dogs have been indentified by polmerase chain reaction (PCR) in this country. Affected dogs have normal haematology, serum biochemistry and routine urine analysis. This report discusses the advantages and limitations of the three main diagnostic modalities, namely: magnetic resonance imaging, urine gas chromatography-mass spectrometry and genetic testing. The aim of this report is to increase awareness of the condition, assist diagnosis in encephalopathic dogs and improve detection of carriers amongst breeding stock.
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Encefalopatías Metabólicas Innatas/veterinaria , Enfermedades de los Perros/diagnóstico , Animales , Anticonvulsivantes/uso terapéutico , Encefalopatías Metabólicas Innatas/diagnóstico , Encefalopatías Metabólicas Innatas/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/orina , Perros , Femenino , Fenobarbital/uso terapéutico , Riboflavina/uso terapéutico , Sudáfrica , Complejo Vitamínico B/uso terapéuticoAsunto(s)
Computadoras de Mano , Criminales , Castigo , Medición de Riesgo/métodos , Trastorno de la Conducta Social/rehabilitación , Justicia Social , Programas Informáticos , Agresión , Carácter , Crimen , Criminales/legislación & jurisprudencia , Criminales/psicología , Criminales/estadística & datos numéricos , Empatía , Humanos , Conducta Impulsiva , Legislación como Asunto/ética , Legislación como Asunto/normas , Legislación como Asunto/tendencias , Pruebas Neuropsicológicas , Factores de Riesgo , Justicia Social/ética , Justicia Social/normas , Justicia Social/tendencias , TemperamentoRESUMEN
Host recognition of mycobacterial surface molecules occurs through toll like receptors (TLR) 2 and 6. The adaptor protein TIRAP mediates down stream signalling of TLR2 and 4, and polymorphisms in the TIRAP gene (TIRAP) have been associated with susceptibility and resistance to tuberculosis (TB) in adults. In order to investigate the role of polymorphic variation in TIRAP in childhood TB in South Africa, which has one of the highest TB incidence rates in the world, we screened the entire open reading frame of TIRAP for sequence variation in two cohorts of childhood TB from different ethnic groups (Xhosa and mixed ancestry). We identified 13 SNPs, including seven previously unreported, in the two cohorts, and found significant differences in frequency of the variants between the two ethnic groups. No differences in frequency between individual SNPs or combinations were found between TB cases and controls in either cohort. However the 558C-->T SNP previously associated with TB meningitis (TBM) in a Vietnamese population was found to be associated with TBM in the mixed ancestry group. Polymorphisms in TIRAP do not appear to be involved in childhood TB susceptibility in South Africa, but may play a role in determining occurrence of TBM.
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Etnicidad , Predisposición Genética a la Enfermedad , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-1/genética , Tuberculosis/genética , Secuencia de Bases , Estudios de Casos y Controles , Estudios de Cohortes , Cartilla de ADN , Haplotipos , Humanos , Incidencia , Reacción en Cadena de la Polimerasa , Sudáfrica/epidemiología , Tuberculosis/epidemiología , Tuberculosis/etnologíaRESUMEN
OBJECTIVE: To determine haplotype background of common mutations in the genes encoding surfactant proteins B and C (SFTPB and SFTPC) and to assess recombination in SFTPC. STUDY DESIGN: Using comprehensive resequencing of SFTPC and SFTPB, we assessed linkage disequilibrium (LD) (D'), and computationally inferred haplotypes. We computed average recombination rates and Bayes factors (BFs) within SFTPC in a population cohort and near SFTPC (+/-50 kb) in HapMap cohorts. We then biochemically confirmed haplotypes in families with sporadic SFTPC mutations (n = 11) and in individuals with the common SFTPB mutation (121ins2, n = 30). RESULTS: We detected strong evidence (weak LD and BFs > 1,400) for an intragenic recombination hot spot in both genes. The 121ins2 SFTPB mutation occurred predominantly (89%) on 2 common haplotypes. In contrast, no consistent haplotypes were associated with mutated SFTPC alleles. Sporadic SFTPC mutations arose on the paternal allele in four of five families; the remaining child had evidence for somatic recombination on the mutated allele. CONCLUSIONS: In contrast to SFTPB, disease alleles at SFTPC do not share a common haplotype background. Most sporadic mutations in SFTPC occurred on the paternal allele, but somatic recombination may be an important mechanism of mutation in SFTPC.
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Enfermedades Pulmonares Intersticiales/genética , Mutación/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Recombinación Genética/genética , Negro o Afroamericano/genética , Alelos , Teorema de Bayes , Estudios de Cohortes , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Haplotipos/genética , Humanos , Lactante , Datos de Secuencia Molecular , Mutagénesis Insercional/genética , Proteína B Asociada a Surfactante Pulmonar/genética , Factores Sexuales , Población Blanca/genéticaRESUMEN
The prevalence of the common mutations in the surfactant protein-B (121ins2), surfactant protein-C (I73T), and ATP-binding cassette member A3 (E292V) genes in population-based or case-control cohorts of newborn respiratory distress syndrome (RDS) is unknown. We determined the frequencies of these mutations in ethnically diverse population and disease-based cohorts using restriction enzyme analysis (121ins2 and E292V) and a 5' nuclease assay (I73T) in DNA samples from population-based cohorts in Missouri, Norway, South Korea, and South Africa, and from a case-control cohort of newborns with and without RDS (n = 420). We resequenced the ATP-binding cassette member A3 gene (ABCA3) in E292V carriers and computationally inferred ABCA3 haplotypes. The population-based frequencies of 121ins2, E292V, and I73T were rare (<0.4%). E292V was present in 3.8% of newborns with RDS, a 10-fold greater prevalence than in the Missouri cohort (p < 0.001). We did not identify other loss of function mutations in ABCA3 among patients with E292V that would account for their RDS. E292V occurred on a unique haplotype that was derived from a recombination of two common ABCA3 haplotypes. E292V was over-represented in newborns with RDS suggesting that E292V or its unique haplotype impart increased genetic risk for RDS.
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Transportadoras de Casetes de Unión a ATP/genética , Mutación , Proteína B Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Lactante , Recién Nacido , Corea (Geográfico) , Masculino , Missouri , Noruega , Vigilancia de la Población , Proteína B Asociada a Surfactante Pulmonar/deficiencia , Proteína C Asociada a Surfactante Pulmonar/deficiencia , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Factores de Riesgo , SudáfricaRESUMEN
We describe 7 novel mutations occurring on the major allele of the human AGT gene in patients with primary hyperoxaluria type 1, an autosomal recessive disease resulting from a deficiency of the liver peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44). These mutations include 3 small deletions, 570delG, 744delC, and 983_988del, two splice junction mutations, IVS7-1G-->C and IVS8+1G-->T, and two nonsense mutations, R111X and W251X. We have also identified recurrences of previously identified reported mutations, 679-(IVS6+2)delAAgt, IVS8-3C-->G and 33insC. Deletion mutation 679-(IVS6+2)delAAgt has now been identified in a second Chinese patient and may be specific to that population. In contrast, 33insC has been found in patients of varying ethnic and racial backgrounds; a single vs multiple origin for this mutation is thus an intriguing question. It also appears to occur at a high frequency on the major allele. Five of the novel mutations were detected in patients who were compound heterozygotes for one of the common mis-targeting mutation, G170R or F152I, while the other two mutations occurred in the same patient.
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Alelos , Hiperoxaluria Primaria/genética , Mutación/genética , Transaminasas/genética , Adulto , Niño , Preescolar , Humanos , Lactante , Hígado/enzimología , Persona de Mediana Edad , Análisis de Secuencia de ADN , SíndromeRESUMEN
We describe a novel missense mutation (A112D) and polymorphism (V326I) in the human AGT gene in two black African patients with primary hyperoxaluria type 1, an autosomal recessive disease resulting from a deficiency of the liver peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44). V326I was found in DNA from normal control Blacks with an allele frequency of 3%. Expression studies confirmed that A112D reduced AGT enzyme activity by 95% while V326I had no effect. Both A112D and V326I were homozygous in both patients and lie on a variant of the minor allele of the AGT gene. This variant haplotype, Mi(A), includes an intron 1 duplication and intron 4 VNTR (38 repeat) but lacks the P11L and I340M normally associated with the minor allele in Caucasians. Among the South African Blacks tested, the Mi(A) haplotype had an allele frequency of 12% compared to 3 % for the Caucasian-type minor allele haplotype.
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Población Negra/genética , Hiperoxaluria Primaria/enzimología , Transaminasas/genética , Alelos , Secuencia de Bases , ADN/química , ADN/genética , Análisis Mutacional de ADN , Electroforesis en Gel de Poliacrilamida , Escherichia coli/genética , Regulación Enzimológica de la Expresión Génica , Frecuencia de los Genes , Pruebas Genéticas , Haplotipos , Humanos , Hiperoxaluria Primaria/diagnóstico , Hiperoxaluria Primaria/genética , Datos de Secuencia Molecular , Mutación Missense , Polimorfismo Genético , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sudáfrica , Transaminasas/deficiencia , Transaminasas/metabolismoRESUMEN
The mechanisms of protective immunity to tuberculosis remain poorly understood in humans. A whole-blood infection model that employs a luminescent readout was used to analyze the role of T cells in control of mycobacterial infection. Control of mycobacterial growth in blood from healthy tuberculin-positive individuals was shown to be mediated predominantly by CD4(+) T cells. Comparison of age-matched cohorts of human immunodeficiency virus (HIV)-infected and -uninfected children from South Africa demonstrated an association between low CD4 cell counts, low interferon (IFN)-gamma production, and impaired ability to regulate growth of Mycobacterium bovis bacille Calmette-Guérin in blood from HIV-infected children. Impaired control of infection was not reconstituted by the addition of exogenous IFN-gamma. The whole-blood assay provides an important tool for monitoring and dissecting of human immune responses to mycobacterial infection.
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Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/microbiología , VIH/fisiología , Mycobacterium tuberculosis/fisiología , Tuberculosis/complicaciones , Tuberculosis/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/sangre , Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Niño , Preescolar , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Humanos , Lactante , Masculino , Mycobacterium tuberculosis/inmunología , Tuberculosis/sangre , Tuberculosis/microbiologíaRESUMEN
Missense mutations in exon 5 of the LPL gene are the most common reported cause of LPL deficiency. Exon 5 is also the region with the strongest homology to pancreatic and hepatic lipase, and is conserved in LPL from different species. Mutant LPL proteins from post-heparin plasma from patients homozygous for missense mutations at amino acid positions 176, 188, 194, 205, and 207, and from COS cells transiently transfected with the corresponding cDNAs were quantified and characterized, in an attempt to determine which aspect of enzyme function was affected by each specific mutation. All but one of the mutant proteins were present, mainly as partially denatured LPL monomer, rendering further detailed assessment of their catalytic activity, affinity to heparin, and binding to lipoprotein particles difficult. However, the fresh unstable Gly(188)-->Glu LPL and the stable Ile(194)-->Thr LPL, although in native conformation, did not express lipase activity. It is proposed that many of the exon 5 mutant proteins are unable to achieve or maintain native dimer conformation, and that the Ile(194)-->Thr substitution interferes with access of lipid substrate to the catalytic pocket. These results stress the importance of conformational evaluation of mutant LPL. Absence of catalytic activity does not necessarily imply that the substituted amino acid plays a specific direct role in catalysis.