Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder resulting from mutations in the autoimmune regulator ( AIRE ) gene. There is no information on AIRE mutations in Indians. In a cross-sectional study, nine patients (eight families), from four referral hospitals in India, were studied for AIRE mutations by direct sequencing. We screened for new mutations in 150 controls by allele-specific PCR. The patients had 1–7 known components of APECED. Three patients had unusual manifestations: presentation with type 1 diabetes; chronic sinusitis and otitis media; and facial dysmorphism. All patients carried homozygous, probably recessive, AIRE mutations. Two unrelated patients from a small in-bred community (Vanika Vaisya) in south India carried an unreported missense mutation, p.V80G, in the N-terminal caspase recruitment domain. Another unique mutation, p.C302X, resulting in a truncated protein with deletion of both zinc-finger domains, was detected in a patient from Gujarat. Neither mutation was detected in controls. Other mutations, previously described in Caucasians, were: 13 base pair deletion (p.C322fsX372) in 4 (38%), and Finn-major (p.R257X) and p.R139X (Sardinian) mutation in one subject each. In conclusion, in this first series of APECED in Indians, we detected AIRE mutations previously reported in Caucasians, as well as unique mutations. Of these, p.V80G is possibly an ancestral mutation in an in-bred community.     

Prostate Cancer Cognitive-Behavioral Factors in a West African Population

Background Similar to African American men, several published studies indicate high incidence of prostate cancer among Nigerian men. However, there is no published study on personal factors that influence prostate cancer detection in this population. We explored prostate cognitive-behavioral factors among indigenous Nigerian men and Nigerian immigrants residing in the US. Methods A cross-sectional survey methodology was employed to collect data from Nigerian men residing in Abeokuta (Nigeria) and Houston (US). Study participants were men between 35 and 79 years. Results The demographic characteristics of both study groups were similar. Based on two-sample comparison results, indigenous Nigerian men demonstrated significant differences from US Nigerian men on several prostate cancer personal cognitive-behavioral factors, including perceived susceptibility to prostate cancer, attitude towards prostate cancer screening and prostate cancer knowledge. Conclusion Emigration of Nigerian men from Nigeria to the US has a significant impact on prostate cancer knowledge and beliefs.     

Giant cell tumour of the proximal end of the ulna

Summary An extremely rare case of giant cell tumour of the proximal end of the ulna, which was clinically aggressive but histologically benign, is reported in a 28-year-old man. The tumor was excised in en bloc but patient died 8 months after surgery. To the best of our knowledge, this is the first reported case from South East Asia and the second available in the English-language literature. It therefore warrants report.     

Development of a therapeutic adenoviral vector for cholangiocarcinoma combining tumor-restricted gene expression and infectivity enhancement

Cholangiocarcinoma is an invasive malignancy that is most often unresectable upon diagnosis and unresponsive to chemotherapy and radiation. While adenoviral gene therapy has shown promise in treating many tumors, systemic toxicity and low tumor transduction efficiency have hampered its application in many gastrointestinal cancers. To overcome these difficulties, we have constructed an adenoviral vector utilizing a tumor-specific promoter (TSP) for selective transgene expression and a vector with an RGD-motif in the fiber-knob region for infectivity enhancement. In seeking a TSP for cholangiocarcinoma, Secretory Leukoprotease Inhibitor, Midkine, Gastrin Releasing Peptide, VEGF, Cox-2M, and Cox-2L promoters were configures in adenoviral vectors, and evaluated in cholangiocarcinoma cells lines (Oz and SkChA-1). Luciferase assays demonstrated that Cox-2 promoters (M and L) showed the highest promoter activity, with Cox-2M appearing slightly stronger than Cox-2L. Infectivity enhanced vectors with RGD-motif in the fiber-knob region were also constructed with the luciferase transgene driven by a CMV control and the Cox-2M and Cox-2L promoters. Subsequent luciferase assays comparing the unmodified vectors to the RGD-modified versions demonstrated higher levels of luciferase activity than the RGD-infected cells. This paradigm was then applied to a therapeutic HSV-TK/GCV model by constructing RGD-enhanced HSV-TK vectors driven by Cox-2M and Cox-2L promoters. In vitro cytocidal effect analysis confirmed that the RGD-modified, cox-2 (M and L) driven vectors showed a stronger cytocidal effect upon gancyclovir administration than the vectors with wild-type fiber. The Cox-2 promoter demonstrates a favorable selectivity profile for cholangiocarcinoma, and RGD-modification further enhances transduction efficiency. This combination has potential to overcome the obstacles to clinical application of adenoviral gene therapy in cholangiocarcinoma. Presented at the Forty-Third Annual Meeting of The Society for Surgery of The Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation).     

Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism

Biochemical data implicate an underlying disorder of androgen biosynthesis and/or metabolism in the aetiology of polycystic ovary syndrome (PCOS). We have examined the segregation of the genes coding for two key enzymes in the synthesis and metabolism of androgens, cholesterol side chain cleavage (CYP11a) and aromatase (CYP19), with PCOS in 20 multiply-affected families. All analyses excluded CYP19 cosegregation with PCOS, demonstrating that this locus is not a major determinant of risk for the syndrome. However, our results provide evidence for linkage to the CYP11a locus (NPL score = 3.03, p = 0.003). Parametric analysis using a dominant model suggests genetic heterogeneity, generating a maximum HLOD score of 2.7 (alpha = 0.63). An association study of 97 consecutively identified Europids with PCOS and matched controls demonstrates significant allelic association of a CYP11a 5' UTR pentanucleotide repeat polymorphism with hirsute PCOS subjects (p = 0.03). A strong association was also found between alleles of this polymorphism and total serum testosterone levels in both affected and unaffected individuals (p = 0.002). Our data demonstrate that variation in CYP11a may play an important role in the aetiology of hyperandrogenaemia which is a common characteristic of polycystic ovary syndrome.      

Insulin Therapy in Type 2 Diabetic Subjects Suppresses Plasminogen Activator Inhibitor (PAI-1) Activity and Proinsulin-like Molecules Independently of Glycaemic Control

Eleven Type 2 diabetic subjects (10 male 1 female: age 56.2 ± 9.7 (SD) yr) were treated in random order either with insulin or with sulphonylureas for 8 weeks each, without attempting to alter glycaemic control between the two treatment periods. Insulin treatment was associated with suppression of endogenous insulin secretion (fasting C-peptide levels -35.0 ± 24.2%; p = 0.006), and of intact proinsulin (-43.1 ± 36.8%; p = 0.03) and 32,33 split proinsulin -20.1 ± 27.0%; p = 0.03). Activity of plasminogen activator inhibitor (PAI-1), a fast acting inhibitor of fibrinolysis, decreased significantly (-14.3% ± 27.5 %; p = 0.02) but no changes occurred in concentration of lipoproteins or apoproteins between therapies. Changes in concentrations of 32,33 split and intact proinsulin were closely and significantly related (r_s = 0.83; p < 0.001) to each other but not with changes in concentrations of C-peptide (intact proinsulin r_s = -0.41; p = 0.11) and 32,33 split proinsulin r_s = -0.27; (p = 0.21). Percentage changes in intact proinsulin concentrations were positively correlated with those in PAI-1 (r_s = 0.51; p = 0.05). There was, however a paradoxical negative relationship between changes in C-peptide concentrations and those of PAI-1 (r_s = -0.73; p = 0.006). These preliminary observations suggest that insulin treatment in Type 2 diabetic subjects without any changes in glycaemic control is associated with a reduced activity of PAI-1, but is without effect on any other cardiovascular risk factors. Concentrations of insulin precursor molecules may play a role in determining fibrinolytic activity.     

Fibular osteosynthesis for delayed type II and type III femoral neck fractures in children.

Seventeen transcervical/basal femoral neck fractures in children were treated by free fibular graft and cancellous lag screw. Two cases were failures of a previous surgery, and 15 had been untreated for 3 weeks or more. Four cases had radiological evidence of avascular necrosis of the head and one of the neck preoperatively; five cases had neck resorption. At an average of 48.1 months postsurgery all fractures had united and there was only one new case of avascular necrosis. Four cases had coxa vara, and four cases had premature epiphyseal closure. There were 13 good, three fair, and one poor result(s) using Ratliff's criteria. We recommend this procedure in cases with delayed initial appearance or failed previous surgery. Complications of the procedure such as long screw/graft and fibular fracture are preventable. The incidence of coxa vara in cases with neck resorption may be reduced by adding subtrochanteric osteotomy to the procedure.