PubMed Health⌕ Search

Biomedical subjects

Timothy Barrett

Publications and source records attributed to Timothy Barrett.

13 recordsLinked to original sources
PubMed2006

The characterisation of the human Wolfram syndrome gene promoter demonstrating regulation by Sp1 and Sp3 transcription factors.

Wolfram Syndrome (DIDMOAD) is an autosomal recessive disorder characterised by insulin deficient diabetes mellitus and neurodegeneration. Mutations in a novel gene, WFS1, were found in nearly all patients and segregated with the disease. The WFS1 gene is expressed in all tissue types studied and the 890aa protein product is localised to the endoplasmic reticulum (ER). In this study, we used a combination of reporter assays and in vitro and in vivo transcription factor binding assays to analyse the regulation of expression of the human WFS1 gene in neuronal derived cells. A single transcription start site was mapped and a minimal promoter identified within 25 bp upstream of this site. This minimal promoter contains two DNA binding motifs (GC boxes) for the transcription factors Sp1/3/4 and binding of both Sp1 and Sp3 was demonstrated at both motifs in vitro and in vivo. The presence of intact GC boxes is essential for minimal promoter action. Thus, transcription factors of the Sp family are important regulators of the WFS1 promoter. A further up-regulating control region was identified containing three CCAAT box binding motifs; all demonstrated a reduction in expression after mutation. One CCAAT box represented part of a predicted ER stress response element.

Base Sequence↗
PubMed2005

Ethnic differences in insulin resistance and body composition in United Kingdom adolescents.

CONTEXT: Type 2 diabetes is increasingly recognized in childhood, occurring more frequently in the United Kingdom in South Asians and in girls. South Asian children have been shown to be more insulin resistant than white European children, and girls more insulin resistant than boys. It is not clear how these sex and ethnic differences relate to body composition in childhood. OBJECTIVE: The goal was to evaluate sex and ethnic differences in insulin sensitivity and body composition in healthy adolescents. DESIGN: This was a cross-sectional cohort study. SETTING: This was a community-based study. PARTICIPANTS: One hundred twenty-nine healthy white European and South Asian 14- to 17-yr-old adolescents participated. INTERVENTIONS: Body composition was assessed by anthropometry and dual-energy x-ray absorptiometry, and insulin sensitivity by homeostasis model assessment. MAIN OUTCOME MEASURES: The main outcome measures were body fat percentage and insulin sensitivity. RESULTS: We confirmed that South Asian adolescents were less insulin sensitive than white European adolescents (homeostasis model assessment of insulin sensitivity, 52.4 vs. 58.9%, P < 0.05), with a trend toward lower insulin sensitivity in girls. South Asian adolescents had significantly more body fat than white European adolescents (girls, 30.6 vs. 26.0%, P < 0.005; boys, 20.8 vs. 14.8%, P < 0.001), with more central fat (waist-thigh ratio in girls, 1.36 vs. 1.25, P < 0.001; boys, 1.52 vs. 1.42, P < 0.001). The sex-ethnic differences in insulin sensitivity were no longer seen when body fat was included as a covariate. CONCLUSIONS: Ethnic differences in insulin sensitivity are associated with ethnic differences in body fat. South Asian adolescents are more insulin resistant, with more body fat than white European adolescents, which may contribute to their increased risk of developing type 2 diabetes.

Adolescent↗
PubMed2005

Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified.

Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.

Adolescent↗
PubMed2005

Establishment of a universal size standard strain for use with the PulseNet standardized pulsed-field gel electrophoresis protocols: converting the national databases to the new size standard.

The PulseNet National Database, established by the Centers for Disease Control and Prevention in 1996, consists of pulsed-field gel electrophoresis (PFGE) patterns obtained from isolates of food-borne pathogens (currently Escherichia coli O157:H7, Salmonella, Shigella, and Listeria) and textual information about the isolates. Electronic images and accompanying text are submitted from over 60 U.S. public health and food regulatory agency laboratories. The PFGE patterns are generated according to highly standardized PFGE protocols. Normalization and accurate comparison of gel images require the use of a well-characterized size standard in at least three lanes of each gel. Originally, a well-characterized strain of each organism was chosen as the reference standard for that particular database. The increasing number of databases, difficulty in identifying an organism-specific standard for each database, the increased range of band sizes generated by the use of additional restriction endonucleases, and the maintenance of many different organism-specific strains encouraged us to search for a more versatile and universal DNA size marker. A Salmonella serotype Braenderup strain (H9812) was chosen as the universal size standard. This strain was subjected to rigorous testing in our laboratories to ensure that it met the desired criteria, including coverage of a wide range of DNA fragment sizes, even distribution of bands, and stability of the PFGE pattern. The strategy used to convert and compare data generated by the new and old reference standards is described.

Databases as Topic↗
PubMed2004

Chicken consumption is a newly identified risk factor for sporadic Salmonella enterica serotype Enteritidis infections in the United States: a case-control study in FoodNet sites.

The sources of sporadic Salmonella enterica serotype Enteritidis (SE) infections in the United States are unclear. To determine risk factors for sporadic SE infection, we conducted a population-based case-control study in 5 Foodborne Disease Active Surveillance Network surveillance areas. During the 12-month study, 396 cases of SE infection were ascertained. Among the 182 case patients and 345 controls, SE infection was univariately associated with international travel (matched odds ratio [MOR], 61; 95% confidence interval [CI], 8-447), eating undercooked eggs (MOR, 2.2; 95%CI, 1-5), and eating chicken prepared outside of the home (MOR, 2.2; 95% CI, 1.3-3.4). Multivariate analysis revealed that eating chicken outside of the home remained the only significant risk factor for illness (MOR, 2.0; 95% CI, 1.1-3.6). Chicken consumption has not previously been identified in the United States as a risk factor for SE infection. Measures to prevent SE infections include educating consumers and food handlers about food safety and interventions to decrease contamination of eggs and poultry.

Animals↗
PubMed2002

Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations.

Mutations in the WFS1 gene cause beta-cell death, resulting in a monogenic form of diabetes known as Wolfram syndrome. The role of variation in WFS1 in type 2 diabetes susceptibility is not known. We sequenced the WFS1 gene in 29 type 2 diabetic probands and identified 12 coding variants. We used 152 parent-offspring trios to look for familial association; the R allele at residue 456 (P = 0.04) and the H allele at residue 611 (P = 0.05) as well as the R456-H611 haplotype (P = 0.032) were overtransmitted to affected offspring from heterozygous parents. In a further cohort of 327 type 2 diabetic subjects and 357 normoglycemic control subjects, the H611 allele and the R456-H611 haplotype were present in more type 2 diabetic subjects than control subjects (one-tailed P = 0.06 and P = 0.023, respectively). In a combined analysis, the H611 allele was present in 60% of all diabetes chromosomes and 55% of all control chromosomes (odds ratio [OR] 1.24 [95% CI 1.03-1.48], P = 0.02), and the R456-H611 haplotype was significantly more frequent in type 2 diabetic subjects than in control subjects (60 vs. 54%, OR 1.29 [95% CI 1.08-1.54], P = 0.0053). Our results provide the first evidence that variation in the WFS1 gene may influence susceptibility to type 2 diabetes.

Adult↗
PubMed1999

Antimicrobial susceptibility of bacteria causing urinary tract infections in Latin American hospitals: results from the SENTRY Antimicrobial Surveillance Program (1997).

OBJECTIVE: To evaluate the antimicrobial susceptibility patterns among 469 pathogens isolated as a significant cause of urinary tract infections in 10 Latin American medical centers. METHODS: Consecutively collected isolates were susceptibility tested by broth microdilution methods, and selected isolates were characterized by molecular typing methods. RESULTS: Escherichia coli and Klebsiella spp. isolates revealed high rates of resistance to broad-spectrum penicillins and to fluoroquinolones. Ceftazidime MICs of >/=2 mg/L, suggesting the production of extended-spectrum b-lactamases (ESBLs), were observed in 37.7% of K. pneumoniae and 8.3% of Escherichia coli isolates. Enterobacter spp. isolates were characterized by high resistance rates to ciprofloxacin (35%) and to ceftazidime (45%), but they generally remained susceptible to cefepime (95% susceptible). Pseudomonas aeruginosa and Acinetobacter spp. were highly resistant to ciprofloxacin and ceftazidime. Imipenem was active against 80% of P. aeruginosa and 93% of Acinetobacter spp. isolates. CONCLUSIONS: Our results demonstrate a high level of resistance to various classes of antimicrobial agents among isolates causing nosocomial urinary tract infections in Latin American hospitals. Clonal dissemination of ESBL-producing K. pneumoniae strains was infrequent.

Journal Article↗