Mutations in the carboxyl terminus of the agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors

Several mutations that cause ectopic expression of the agouti gene result in obesity, hyperinsulinemia, and yellow coat color. A candidate pathway for agouti induced obesity and hyperinsulinemia is through altered signaling by melanocortin receptors, as agouti normally regulates coat coloration through antagonism of melanocortin receptor 1. Furthermore, melanocortin peptides mediate functions including steroidogenesis, lipolysis, and thermoregulation. We report apparent inhibition dissociation constants for mouse and human agouti protein inhibition of ligand binding to the melanocortin receptors, to determine which of these receptors might be involved in agouti induced diabetes. The similarity in the apparent K(I) values for agouti inhibition of ligand binding to the brain melanocortin receptors 3 and 4 (mouse: K(I) app = 190 +/- 74 and 54 +/- 18 nM; human: K(I) app = 140 +/- 56 and 70 +/- 18 nM, respectively) suggests that the MC3-R is a potential candidate for a receptor mediating the effects of agouti protein overexpression. Agouti residues important for melanocortin receptor inhibition were identified through the analysis of deletion constructs and site-specific variants. Val83 is important for inhibition of binding to MC1-R (K(I) app for Val83Ala agouti increased 13-fold relative to wild-type protein). Arg85, Pro86, and Pro89 are important for selective inhibition of binding between MC1-R and MC3-R and MC4-R as their apparent K(I) values are essentially unchanged at MC1-R, while they have increased 6-10-fold relative to wild-type protein at MC3-R and MC4-R.     

Epidemiological studies in children of a low-endemic region, a high-endemic region, and dwellers of a leprosy colony: evaluation of anti-ND-BSA antibodies and lepromin response

Children residing in a low-endemic region (LER), a high-endemic region (HER), and a leprosy colony contact population (CP) were evaluated for lepromin response as well as reactivity to the Mycobacterium leprae-specific synthetic antigen, ND-BSA. The mean reactivity to ND-BSA in the LER group (OD 0.03 +/- 0.03, N = 71) was significantly lower (p < 0.001) than that in the contact population (OD 0.14 +/- 0.09, N = 140) as well as the population residing in the HER (OD 0.09 +/- 0.08, N = 1340). ELISA-positive results were the highest (21.4%) with the CP group and lowest (0.0%) in the LER group, suggesting that it was a measure of the extent of exposure of M. leprae. In the contact population, females showed a preponderance for ELISA positivity over males (p < 0.005), a finding not observed with the HER population. The Mitsuda responses showed a Gaussian-type distribution in all of the three populations examined with the mean response being highest in the LER (6.0 mm +/- 2.9) and lowest in the HER (4.5 mm +/- 2.0) groups. The percent positivity for the Mitsuda reaction was found to be highest in the LER (93.0%) and lowest in the HER (88.3%) groups. The Mitsuda response thus appears to be independent of M. leprae exposure, and its interpretation in a given population needs consideration of several factors, such as nutritional, environmental, etc.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reproducibility of peak expiratory flow measurements

The ease of PEF measurement and the availability of inexpensive, portable instruments have led to its increasing use. However, relatively little literature exists addressing the testing procedure, optimal frequency, instrument precision, and virtually no epidemiologic literature exists describing the variability of repeated PEF tests within a single test session (reproducibility). A summary of data from one of the authors' own worker population studies is presented which addresses precision of PEF measurement.     

Burst fractures of the second through fifth lumbar vertebrae. Clinical and radiographic results

Fifty-five patients who had sustained a burst fracture of the lumbar spine were followed for a mean of seventy-nine months (range, twenty-four to 192 months) after the injury. Thirty patients had been managed non-operatively with a short period of bed rest followed by protected mobilization. The remaining twenty-five patients had been managed operatively: eight, with posterior arthrodesis with long-segment hook-and-rod fixation; eight, with posterior arthrodesis with short-segment transpedicular fixation; six, with posterior arthrodesis and instrumentation followed by anterior decompression and arthrodesis; and three, with anterior decompression and arthrodesis. Thirty-six patients had been neurologically intact at the time of presentation and had remained so throughout the follow-up period. No neurological deterioration or symptoms of late spinal stenosis were seen. Isolated partial single-nerve-root deficits resolved regardless of the method of treatment. Patients who had had a complete single or a multiple-nerve-root paralysis seemed to have benefited from anterior decompression. Although the anatomical results as seen on the most recent radiographs were superior for the group that had been managed operatively with long posterior fixation or anterior and posterior arthrodesis, the most recent pain scores and the functional outcomes were similar for all treatment groups. At the latest follow-up evaluation, some loss of spinal alignment was noted in the patients who had been managed with short transpedicular fixation; the alignment at the most recent follow-up examination was comparable with that in the patients who had been managed non-operatively. For the patients who had had non-operative treatment, we were unable to predict the deformity at the time of follow-up on the basis of the initial diagnostic radiographs. The clinical outcome was not related to the deformity at the latest follow-up evaluation. On the basis of the results of our study, we recommend non-operative treatment for patients who do not have neurological dysfunction or who have an isolated partial nerve-root deficit at the time of presentation. For patients who have a multiple-nerve-root paralysis, anterior decompression is indicated.