Biomedical subjects

T Ahmad

Publications and source records attributed to T Ahmad.

At least 19 recordsLinked to original sources

PubMed2006

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility.

Killer immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and some T-cell subsets and produce either activation or inhibitory signals upon binding with the appropriate human leucocyte antigen (HLA) ligand on target cells. Recent genetic association studies have implicated KIR genotype in the development of several inflammatory conditions. Ulcerative colitis (UC) is an inflammatory disorder of the colonic mucosa that results from an inappropriate activation of the immune system driven by host bacterial flora. We developed a polymerase chain reaction-sequence specific primer (SSP)-based assay to genotype 194 UC patients and 216 control individuals for 14 KIR genes, the HLA-Cw ligand epitopes of the KIR2D receptors and a polymorphism of the lectin-like-activating receptor NKG2D. Initial analysis found the phenotype frequency of KIR2DL2 and -2DS2 to be significantly increased in the UC cohort (P=0.030 and 0.038, respectively). Logistic regression analysis revealed a protective effect conferred by KIR2DL3 in the presence of its ligand HLA-Cw group 1 (P=0.019). These results suggest that KIR genotype and HLA ligand interaction may contribute to the genetic susceptibility of UC.

Base Sequence↗

PubMed2006

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.

The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

Adult↗

PubMed2006

Comparison of cartilage scoring and cartilage sparing otoplasty--A study of 203 cases.

UNLABELLED: The Edinburgh experience of different methods of otoplasty techniques in 203 patients (406 ears) over a five-year period is reviewed. MATERIALS AND METHODS: The patients were divided into three groups - Group A (anterior cartilage scoring), Group B (cartilage sparing in the fashion of posterior suturing) and Group C (posterior suturing refined with posterior fascial flap). Demographic details, operation technique, operation time, grade of the surgeon, suture materials, early and late complications, recurrence and revision rates, patients' and physicians' comments at the follow-up clinic were retrieved from the case notes. The pre- and the post-operative photographs were assessed by a blinded lay observer and a physician and scored on a visual analogue scale. Median follow-up was 11 months. RESULTS: The recurrence rate was 11.0%, 8.0% and 4.8% in Groups A, B and C, respectively (p = 0.0214). Complications were more common in Group A (8.8%) and Group B (7.9%) compared to Group C (1.2%) (p = 0.0208). The cosmetic result was judged best in Group C. In our experience, cartilage-sparing otoplasty refined with the post-auricular fascial flap results in significantly reduced complication rate and improved aesthetic outcome.

Adolescent↗

PubMed2006

A novel point mutation in P450c17 (CYP17) causing combined 17alpha-hydroxylase/17,20-lyase deficiency.

CONTEXT: Combined 17alpha-hydroxylase/17,20-lyase deficiency is a rare cause of congenital adrenal hyperplasia and hypogonadism. Novel single amino acid changes in P450c17 provide potentially important insights into key structural domains for enzyme function. OBJECTIVE, DESIGN, AND SETTING: We report a novel missense mutation in P450c17 in a 17-yr-old female presenting with a malignant mixed germ cell tumor with yolk sac elements who demonstrated clinical and biochemical features of combined 17alpha-hydroxylase/17,20-lyase deficiency. METHODS: Quantitative urinary steroid analysis was performed by high resolution gas chromatography. All eight coding exons of CYP17 were PCR amplified and sequenced. The position of arginine at codon 96 was modeled using the CYP17 structure 2c17 (www.rcsb.org). The CYP17 genes were subcloned into pcDNA3, expressed in HEK-293 cells, and chromatographed. PATIENT AND RESULTS: 17alpha-Hydroxylase deficiency was confirmed by marked reductions in urinary and serum cortisol, androgens, and estradiol. Mutational analysis revealed a novel homozygous R96Q missense mutation in P450c17, affecting an amino acid in a key substrate-binding region of the enzyme, leading to complete inactivity. CONCLUSION: The description of a second missense mutation at codon 96 (R96W and R96Q) in the substrate-binding region of P450c17 provides strong evidence for the key role of this amino acid in 17alpha-hydroxylase/17,20-lyase function. An association between a malignant germ cell tumor and 17alpha-hydroxylase deficiency has not been reported previously, although the presence of gonadoblastoma in the ovary of a patient with this condition has recently been described.

Adolescent↗

PubMed2006

Combination chemotherapy with carboplatin, capecitabine and epirubicin (ECarboX) as second- or third-line treatment in patients with relapsed ovarian cancer: a phase I/II trial.

Platinum-based combination chemotherapy has been proven to be superior to single-agent platinum in the treatment of relapsed ovarian cancer after a treatment-free interval of more than 6 months. A response rate of 41% was previously reported by our group using a combination of epirubicin, cisplatin and 5-FU in patients who relapsed within 12 months, we therefore assessed a similar, but more convenient combination of epirubicin, carboplatin and capecitabine in this phase-I/II trial. In total, 18 patients with recurrent epithelial ovarian carcinoma, who had not received more than two lines of chemotherapy and the treatment-free interval exceeded 6 months were treated with carboplatin AUC5, epirubicin 50 mg m(-2) and capecitabine at several dose levels on continuous 21 day cycles and 14 of 21 day cycles. Patients were assessed for toxicity and by CT and CA-125 for response. The overall response rate was 61.1%, with three complete and eight partial responses. Grade 3/4 haematological toxicity was seen in 10 out of 18 patients and caused dose reductions and treatment delays. The combination of epirubicin, carboplatin and capecitabine showed good activity but caused excessive toxicity. A phase-II trial using carboplatin and capecitabine is underway.

Administration, Oral↗

PubMed2006

Effect of different non-chloride sodium sources on the performance of heat-stressed broiler chickens.

1. One hundred and eighty 1-d-old broiler chicks were used to evaluate the effect upon broiler performance during severely hot summer months of three different sodium salts: sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3) and sodium sulphate (Na2SO4), in starter and finisher diets having an identical electrolyte balance (DEB) of 250 mEq/kg. 2. The non-chloride sodium salts were added to contribute the same amount of sodium and were substituted at the expense of builder's sand in the basal diets containing common salt (NaCl) as Na and Cl source. 3. Each diet was fed to three experimental units having 15 chicks each until 42 d of age. Severe heat-stress conditions, maintained in the rearing room, were indicated by high average weekly room temperature (minimum 29.3 degrees C; maximum 38.0 degrees C). 4. Diets containing sodium salts gave better body weight gain, feed intake and feed to gain ratio than the control diet. Sodium salts also enhanced water intake as well as water to feed intake ratio. This effect was more pronounced in broilers fed NaHCO3 supplement (with NaCl in the basal diets). 5. The increased water intake resulted in lower body temperature in heat-stressed birds fed NaHCO3 supplemented diet than in birds fed other sodium salts. A lower mortality rate was noted with NaHCO3 (15.15%), Na2CO3 (13.64%) and Na2SO4 (15.15%) supplements than with the control (33.33%) treatment. 6. Better carcase and parts yield were observed in sodium supplemented broilers. Sodium salts reduced the alkalotic pH and enhanced the blood sodium content, which ultimately improved the blood electrolyte balance and overall performance of heat-stressed broilers. 7. Supplementing broiler diets with sodium salts improved the live performance of heat-stressed broilers and better productive performance was noted with NaHCO3 than other sodium supplements.

Animals↗

PubMed2006

The identification of three novel MICA alleles by sequence-based typing.

During a study of MICA frequency in a healthy population and a cohort of patients suffering with inflammatory bowel disease, three DNA samples produced unusual reactivity patterns using polymerase chain reaction sequence-specific primers (PCR-SSP). These samples were subsequently characterized by sequence-based typing (SBT). Here, we report the sequence of these three novel MICA alleles.

Alleles↗

PubMed2006

IFN gamma and CXCR-1 gene polymorphisms in idiopathic bronchiectasis.

Idiopathic bronchiectasis is a disease of chronic, bacterial lung infection, unresolving inflammation and progressive lung damage. Bronchiectasis can be associated with autoimmune diseases including ulcerative colitis. Defects of both innate and adaptive immunity have been proposed. The airway inflammation is characterized by interleukin-8 (IL-8) expression and infiltration by neutrophils and T cells. Here we investigated two candidate gene polymorphisms that may contribute to disease susceptibility: a CXCR-1 (+2607 G/C) gene polymorphism that is implicated in IL-8 binding and neutrophil trafficking as well as the interferon-gamma (IFNgamma) (+874 T/A) polymorphism which is linked to levels of IFNgamma production. These polymorphisms were distributed similarly in the idiopathic bronchiectasis group and controls, suggesting that these two candidate gene polymorphisms are not associated with disease susceptibility.

Alleles↗

PubMed2005

Effect and interactions of dietary sodium and chloride on broiler starter performance (hatching to twenty-eight days of age) under subtropical summer conditions.

One-day-old Starbro male broiler chicks (n = 360) were used to determine the effect of increasing levels of Na+ and Cl- above the NRC (1994) recommendations for growing broilers diets (hatching to 28 d) in extremely hot weather. The average maximum and minimum temperatures recorded were 39 and 32 degrees C, respectively. An average relative humidity was 58.2% during the experimental period. Three levels of dietary Na+ (0.20, 0.25, and 0.30%) and Cl- (0.30, 0.40, and 0.50%) were used in 3 x 3 factorial arrangement while maintaining a dietary electrolyte balance (DEB) of 250 mEq/kg. Higher weight gain (P < 0.002) and maximum water consumption (P < 0.05) were observed for birds fed diets containing 0.25 and 0.30% Na+, respectively. Litter moisture was significantly higher (P < 0.05) for birds fed diets containing 0.25% Na+ and 0.40 and 0.50% Cl-. High dietary Na+ (0.30%) tended to increase breast yield (P < 0.003) and decreased abdominal fat (P < 0.001). There was no effect of Na+ on blood pH or serum HCO3-. Diets containing 0.40% Cl- increased the dressing percentage (P < 0.001) and leg yield (P < 0.001) and decreased serum HCO3- (P < 0.001). There was no effect of dietary Cl- on blood pH, feed intake, weight gain, feed:gain, water intake, water:feed intake, or mortality. Significant dietary effect of Na+ x Cl- was noted only for litter moisture (P < 0.001), dressing percentage (P < 0.05), breast (P < 0.05) and leg (P < 0.001) yields, abdominal fat (P < 0.002), and serum HCO3- (P < 0.001). Birds fed diet containing 0.25% Na+ and 0.30% Cl- performed as well as those fed other diets when the cyclic temperature ranged from 32 to 39 degrees C.

Aging↗

PubMed2005

New IBD genes?

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Chromosomes, Human↗

PubMed2004

Phenotype-determining genes in inflammatory bowel disease.

Inflammatory bowel disease (IBD) has traditionally been categorized as either ulcerative colitis or Crohn's disease on the basis of clinical, radiological and histological criteria. Within these diseases however, significant heterogeneity is observed, suggesting the existence of phenotypic subtypes, based on features such as location and behaviour of disease. Evidence for a possible genetic basis for these subgroups emerged in the 1990s from epidemiological studies in multiply affected families. Recent advances in our understanding of the relationship between genotype and phenotype in IBD now challenge traditional clinical classifications, promising a taxonomy of disease based on precise molecular, rather than ambiguous clinical definitions. While many of the genes remain unidentified, the emerging data suggest that IBD comprises a heterogeneous family of oligogenic inflammatory disorders in which the specific clinical manifestations of disease in any individual are determined by the interaction of genetic and environmental factors. These data have highlighted both the importance and difficulties of classifying patients into accurately defined clinical subgroups, and suggest that a genetic basis for the observed disease heterogeneity may account for the discrepant findings from earlier genetic studies. Despite the considerable insights offered to investigators these advances have yet to impact on the clinical management of patients.

Genetic Predisposition to Disease↗

PubMed2004

Differential bone turnover in an angulated fracture model in the rat.

We have developed a simple rat model of angulated tibial fracture which elicits substantial differences in bone formation and resorption within the same bone. In 35 rats the right mid-tibia was manually fractured and fixed with an intramedullary 17-gauge cannula needle. Twenty tibias were fixed in anterior angulation (27 +/- 5 degrees) and 15 in posterior angulation (31 +/- 5 degrees). Serial X-rays were taken over a 12-week period. All fractures healed completely within five weeks. In both groups, bone thickness was already significantly greater on the concave side than on the convex side at week 3 and remained so until the end of the experiment. The thickness on the convex side decreased dramatically within 3 to 5 weeks and gradually thereafter. For morphological analysis of bone mineralization, 3 rats from each group were given calcein and alizarin red injected at different time points up to 14 weeks. Maximum new bone formation was noted within the first 3 weeks. Over the ensuing weeks, new bone formation remained intense on the concave side, but it was virtually absent on the convex side. These results show that angulated fracture deformity reproducibly exhibits differential bone turnover, which can be exploited in research on local regulatory factors. To exemplify the utility of the model, an immunohistochemical study on two local markers was done. Callus tissue of five rats in the anterior angulation group at week 3 post-fracture was stained for the cytokine IL- 1beta, a stimulator of bone resorption, and the neuropeptide CGRP, an inhibitor of resorption, showing clear differences in positive staining between the concave and convex sides. Our in-vivo model offers a means of analyzing morphologically and quantitatively the differential expression and action of factors involved in local bone turnover.

Animals↗

PubMed2004

Analysis of the CC chemokine receptor 5 (CCR5) Delta32 polymorphism in Behçet's disease.

Chemokines are important determinants of the early inflammatory response. The CC chemokine receptor 5 (CCR5) Delta32 variant results in a non-functional form of the chemokine receptor, and has been implicated in a variety of immune-mediated diseases. To investigate its role in the pathogenesis of Behçet's disease, we studied 350 patients and 519 healthy controls from three ethnic groups. While significant inter-ethnic variation in allele frequency was observed, no association was identified with disease, even when data were stratified by the known susceptibility gene HLA-B*51.

Alleles↗

PubMed2003

NOD2/CARD15 gene polymorphisms and Crohn's disease in the Chinese population.

BACKGROUND: Crohn's disease affects people world-wide, but the incidence in Asia is lower than in Western countries. This difference may be due to genetic and/or environmental factors. Three single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene have been identified to be independently associated with the development of Crohn's disease in Caucasians. Whether these SNPs are involved in the pathogenesis of Crohn's disease in the Chinese population is unknown. AIM: To determine if NOD2/CARD15 gene polymorphisms are found in Chinese patients with Crohn's disease. METHODS: Sixty-five consecutive Chinese Crohn's disease patients had genotyping performed using sequence-specific PCR directed against the wild-type and the Arg702Trp, Gly908Arg and 3020insC variants of the NOD2/CARD15 gene. Controls consisted of 63 patients with ulcerative colitis and 70 patients with dyspepsia. RESULTS: None of the patients with Crohn's disease had heterozygous or homozygous SNP variants. Similarly none of the ulcerative colitis or dyspeptic controls had these SNPs. CONCLUSION: The three previously described SNPs associated with the development of Crohn's disease in Caucasians are not found in Chinese patients with Crohn's disease.

Adolescent↗

PubMed2003

The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis.

Linkage and association studies implicate the human leucocyte antigen (HLA) region in genetic susceptibility to ulcerative colitis (UC). However, associations with specific variants have been inconsistent, even within defined ethnic groups. A genetic basis for the disease heterogeneity of UC may account for these discrepant findings from studies in unselected populations. Here, we examine the contribution of the HLA region to the clinical phenotype of UC. We studied 321 accurately phenotyped patients recruited from a single UK centre, with a median follow-up time of 15 years. Individuals were genotyped for 340 polymorphisms constructed into 25 gene-specific allelic haplotypes between HLA-A and Tapasin. Data were analysed with respect to age of onset, disease extent and severity. Strongest association with overall susceptibility was identified with HLA-DRB1 alleles replicating previous studies (DRB1*0103, DRB1*1502 and DRB1*0401). We report a novel association with homozygosity of a tumour necrosis factor (TNF) promoter haplotype (TNF-1031T, -863C, -857C, -380G, -308G and -238G) and distal disease extent that does not extend with time (distal vs total 40.9 vs 25.7%; RR = 2.0; 95% CI 1.23-3.24). We confirm the association of DRB1*0103 with total disease and/or disease requiring colectomy and further demonstrate that DRB1*0103 is associated with shorter time to surgery. Genes in the HLA play a role in modifying disease phenotype. Further studies are required to dissect how these genes functionally interact with each other and with environmental factors to determine clinical patterns of disease

Adolescent↗

PubMed2003

Can findings from postal questionnaires be combined with interview results to improve the response rate among ethnic minority populations?

STUDY OBJECTIVE: To maximise the response rate in a community survey among ethnic minorities by combining postal questionnaires and interviews and to evaluate the validity of combining results from these different methods. DESIGN: A cross-sectional community survey of a local population using postal questionnaires with interview questionnaires for non-respondents. Postal questionnaires were in English and interview questionnaires were prepared in South Asian languages. A sub-sample completed both postal and interview questionnaires. SETTING: Two general practices in Tameside, Greater Manchester, UK. PARTICIPANTS: Questionnaires were mailed to 1,267 people. People were included if they defined their ethnicity as Indian, Pakistani, Bangladeshi or a combination of these. Fifty-five people who returned postal questionnaires were also interviewed. MAIN RESULTS: Overall response rate was 75%. Comparison of questionnaire and interview responses produced values of kappa ranging from marginally below zero to one. Equivalence was greater with a shorter time between postal completion and interview and where questions were more objective. CONCLUSIONS: It is possible to achieve a good response rate for an epidemiological study among ethnic minorities by using both postal questionnaires and interviews. Care should be taken when results from these two methods are combined, since equivalence is uncertain.

Adolescent↗

PubMed2003

Genotype-based phenotyping heralds a new taxonomy for inflammatory bowel disease.

Inflammatory bowel disease (IBD) has traditionally been categorized as either ulcerative colitis or Crohn disease on the basis of clinical, radiologic, and histologic criteria. Within these diseases, however, significant heterogeneity is observed, suggesting the existence of phenotypic subtypes, based on features such as location and behavior of disease. Evidence for a possible genetic basis of these subgroups first emerged in the 1990s from epidemiologic studies in multiply affected families. Recent advances in our understanding of the genetics of IBD, in particular the identification of NOD2/CARD15, have provided the opportunity to explore the genetic basis for this heterogeneity. This article reviews recent studies investigating the contribution of genetics to IBD phenotype. Although many of the genes remain unidentified, the emerging data suggests that IBD comprises a heterogeneous family of oligogenic inflammatory disorders in which the specific clinical manifestations of disease in any individual are determined by the interaction of genetic and environmental factors. These data have validated the approach of classifying patients into accurately defined clinical subgroups, and they raise the possibility that a genetic basis for the observed disease heterogeneity may account for the discrepant findings from earlier genetic studies. A future molecular classification will provide the framework to understanding the different biologic mechanisms that underlie the clinical subgroups of IBD and, by patient stratification, permit the unraveling of the complex interaction between the genetic and environmental causes of disease.

Journal Article↗

PubMed2003

Fulminant Crohn's colitis after allogeneic stem cell transplantation.

We report a case of fulminant Crohn's colitis that occurred following non-myeloablative allogeneic stem cell transplantation for Hodgkin's lymphoma. Adoptive transfer of inflammatory bowel disease by haematopoietic cells is recognised in several animal models of inflammatory bowel disease and remission of Crohn's disease has been reported in patients who have received a bone marrow transplant. However, adoptive transfer of Crohn's disease susceptibility leading to phenotypic manifestation of the disease after transplantation has not been previously reported. Having ruled out an infective cause of a colitis in this case, we speculated that adoptive transfer of Crohn's disease may have occurred and performed a genetic analysis of known susceptibility loci for significant donor-recipient mismatches. The donor and recipient had several haplotype mismatches in HLA class III genes at the IBD3 locus. In addition, the donor (but not the recipient) had a polymorphism of the 5' UTR of NOD2/CARD15 that may be associated with Crohn's disease. This case highlights the question of whether adoptive transfer of Crohn's disease can occur between allogeneic stem cell transplant donor and recipient, in a similar fashion to that reported for other autoimmune diseases. This report should also stimulate debate regarding the need for stem cell transplant donor screening for inflammatory bowel disease.

5' Untranslated Regions↗