Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND)

The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes.     

A case of oncogenic osteomalacia with preoperative secondary hyperparathyroidism: description of the biochemical response of FGF23 to octreotide therapy and surgery

Oncogenic osteomalacia is a rare condition characterized by a low serum phosphate, reduced tubular reabsorption of phosphate and a low or inappropriately normal 1,25 dihydroxyvitamin D and is usually secondary to a phosphaturic mesenchymal tumor. Complete tumor resection results in resolution of all features. We report a patient with oncogenic osteomalacia and concurrent secondary hyperparathyroidism. Serum phosphate failed to normalize preoperatively with octreotide therapy, although this treatment did suppress serum FGF23. The postoperative course was distinguished by marked hyperphosphatemia that was associated with elevated serum 1,25 dihydroxyvitamin D concentrations.     

Segregation analyses of asthma and respiratory allergy: the Humboldt family study.

We performed segregation analyses of asthma and respiratory allergy based on data from 309 nuclear families comprising 1,053 individuals living in the town of Humboldt, Saskatchewan, in 1993, using the REGD program of the S.A.G.E. program package. For adults, information on asthma and history of respiratory allergy was provided by the subjects themselves, and for children by their parents. When asthma was considered as the trait in segregation analysis, models of no major effect, with or without familial effects, were rejected, but they were not rejected after adjusting for history of respiratory allergy. The major gene hypothesis was not rejected before adjusting for history of respiratory allergy. When respiratory allergy was analyzed as the trait, both major gene and multifactorial models fitted the data well, regardless of whether there was adjustment for asthma or not. Other covariates adjusted for in the segregation analyses were age, sex, number of household smokers, current smoking, number of household members, generation, and house type. The data suggest that a major gene related to respiratory allergy may explain the familial aggregation of asthma.     

Confidence limits based on the first occurrence of an event

Confidence limits for population prevalence based on the first occurrence of an item in a medical database, or for incidence based on time to first occurrence, should be based on the geometric or exponential distributions, respectively. These intervals are presented and compared with the corresponding intervals based on the binomial and Poisson distributions. The lower confidence limits are shown to be the same, but the upper limits are smaller, hence leading to shorter intervals. Applications of these intervals are also presented.     

Reversible optic neuropathy associated with low-dose methotrexate therapy.

A 66-year-old woman had progressive bilateral optic neuropathy with dense central scotomas and dyschromatopsia. She had been taking oral methotrexate 2.5 mg three times per week for rheumatoid arthritis for the previous 10 months (total intake 322.5 mg) without folic acid supplementation. She had never smoked or abused alcohol and her diet was healthy. Serum folate was reduced at 1.6 ng/mL (normal >4 ng/mL) and vitamin B12 levels were normal. After stopping methotrexate and after administration of oral folic acid, she experienced complete recovery of vision. Serum folate levels returned to normal during folic acid treatment but decreased to below normal once folic treatment was stopped. The persistently low folate level remains unexplained and may reflect a genetic defect in folate metabolism. Methotrexate can cause toxic side effects resulting from folate inhibition but has not been shown definitively to cause a reversible optic neuropathy associated with low serum folate.     

Safety of research bronchoscopy, biopsy and bronchoalveolar lavage in asthma.

Bronchoscopy with endobronchial biopsy (EBB) and/or bronchoalveolar lavage (BAL) has become an important research tool in asthma. A recent report has suggested audit and reporting of the safety of these procedures. A total of 159 asthmatic patients (84 males, 75 females), aged 18-52 (median 27) yrs, forced expiratory volume in one second 53-120 (median 88) % predicted, underwent 273 bronchoscopies in six clinical research studies. On 228 occasions, EBB and BAL were performed and, on 45 occasions, EBB was performed alone. On 48 occasions, bronchoscopy was performed 24 h post-allergen challenge. Adverse events occurred on 34 out of 273 occasions, none of which were following allergen challenge. Post-EBB and BAL, four patients developed pleuritic chest pain, shortness of breath and fever. A further two patients experienced pleuritic chest pain alone post-EBB/BAL. Bronchospasm or worsening of asthma symptoms occurred on 14 occasions, 13 post-EBB/BAL and on one occasion post-EBB alone. Fever/flu-like symptoms were reported on nine occasions following EBB and BAL. One subject had haemoptysis post-EBB/BAL, but required no intervention. In conclusion, bronchoscopy, endobronchial biopsy and bronchoalveolar lavage can be performed safely in asthmatic patients. Most of the complications were seen where bronchoalveolar lavage and endobronchial biopsy were both performed, suggesting that bronchoalveolar lavage accounts for most of the adverse events.