Biomedical subjects

J L Holder

Publications and source records attributed to J L Holder.

3 recordsLinked to original sources

PubMed2000

Profound obesity associated with a balanced translocation that disrupts the SIM1 gene.

Studies of mice and humans have revealed a number of genes that when mutated result in severe obesity. We have studied a unique girl with early-onset obesity and a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2. Her weight gain is most likely due to excessive food intake, since measured energy expenditure was normal. We cloned and sequenced both translocation breakpoints. The translocation does not appear to affect any transcription unit on 1p, but it disrupts the SIM1 gene on 6q. SIM1 encodes a human homolog of Drosophila Sim (Single-minded), a transcription factor involved in midline neurogenesis, and is a prototypical member of the bHLH-PAS (basic helix-loop-helix + period, aryl hydrocarbon receptor, Single-minded) gene family. Our subject's trans- location separates the 5' promoter region and bHLH domain from the 3' PAS and putative transcriptional regulation domains. The transcriptional targets of SIM1 are not known. Mouse Sim1 is expressed in the developing kidney and central nervous system, and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. Previous neuroanatomical and pharmacological studies have implicated the PVN in the regulation of body weight: PVN neurons express the melanocortin 4 receptor and appear to be physiological targets of alpha-melanocyte-stimulating hormone, which inhibits food intake. We hypothesize that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.

Age of Onset↗

PubMed1996

Reduced survival of apolipoprotein E4 homozygotes in Down's syndrome?

An increased frequency of apolipoprotein E (ApoE) allele epsilon 4 has been established in Alzheimer's disease (AD) subjects. Based on the observation that all individuals with Down's syndrome (DS) develop the neuropathology of AD by the age of 40 years we sought to determine whether ApoE genotype affected the clinical symptoms of AD. Unexpectedly, we failed to find any epsilon 4 homozygotes, as have other published studies: this is highly significant statistically. We suggest this is due to decreased survival or, less likely, embryonic lethality of epsilon 4 homozygotes in DS.

Adult↗

PubMed1989

Low dose dextran 40 in reconstructive hip surgery patients.

Preoperative and postoperative bilateral lower extremity venography was used to evaluate the efficacy of low dose dextran 40 in prophylaxis of deep venous thrombosis in reconstructive hip surgery patients. Patients were given dextran 40 at 50 cc/hr, with 250 cc given perioperatively and 500 cc given on postoperative days two and four. Five of 227 patients had positive venograms preoperatively. Of these 227 patients, 179 met protocol requirements and had venography postoperatively. Venous thrombosis occurred in 33 (18%) of those studied postoperatively. Of these, 11 were calf clots without extension to the popliteal region. Therefore, there were 22 patients (12%) with femoral or popliteal involvement overall. There were two deaths, neither of which was secondary to pulmonary embolus or a complication of dextran. There were two wound complications. These results suggest that low dose dextran 40 administered as indicated is a safe and efficacious means of deep venous thrombosis prophylaxis in reconstructive hip surgery patients.

Arthroplasty↗