No abstract

Gnas is an imprinted gene with multiple gene products resulting from alternative splicing of different first exons onto a common exon 2. These products include stimulatory G protein ␣-subunit (Gs␣), the G protein required for receptor-stimulated cAMP production; extralarge Gs␣ (XL␣s), a paternally expressed Gs␣ isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. G s␣ undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2 m؊/؉ ) or paternal (E2 ؉/p؊ ) allele results in opposite effects on energy metabolism. E2 m؊/؉ mice are obese and hypometabolic, whereas E2 ؉/p؊ mice are lean and hypermetabolic. We now studied the effects of Gs␣ deficiency without disrupting other Gnas gene products by deleting G s␣ exon 1 (E1). E1 ؉/p؊ mice lacked the E2 ؉/p؊ phenotype and developed obesity and insulin resistance. The lean, hypermetabolic, and insulin-sensitive E2 ؉/p؊ phenotype appears to result from XL␣s deficiency, whereas loss of paternalspecific Gs␣ expression in E1 ؉/p؊ mice leads to an opposite metabolic phenotype. Thus, alternative Gnas gene products have opposing effects on glucose and lipid metabolism. Like E2 m؊/؉ mice, E1 m؊/؉ mice had s.c. edema at birth, presumably due to loss of maternal Gs␣ expression. However, E1 m؊/؉ mice differed from E2 m؊/؉ mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1 m؊/؉ mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1 ؉/p؊ mice. Differences between E1 m؊/؉ and E1 ؉/p؊ mice presumably result from differential effects on Gs␣ expression in tissues where Gs␣ is normally imprinted.G protein ͉ genomic imprinting ͉ pseudohypoparathyroidism

Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15-90 mg), nortriptyline (25 -100 mg), their combination, and a benztropine "active placebo" (0.25-1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0-10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was 14% for nortriptyline (95% CI= [−2%, 30%]), 7% for morphine (95% CI= [−8%, 22%]), and 7% for the combination treatment (95% CI= [−4%, 18%]). Mean doses were: nortriptyline alone, 84 +/− 24.44 (SD)mg/day; morphine alone, 62 +/−29mg/day; and combination, morphine, 49 +/−27 mg/day plus nortriptyline, 55 mg+/− 33.18 mg/ day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.

Background Controversy exists regarding the optimal rate of weight loss for long-term weight management success. Purpose This study examined whether gradual initial weight loss was associated with greater long-term weight reduction than rapid initial loss. Methods Groups were drawn from participants in the TOURS trial, which included a sample of middle-aged (mean =59.3 years) obese women (mean BMI =36.8) who received a 6-month lifestyle intervention followed by a 1-year extended care program. Participants were encouraged to reduce caloric intake to achieve weight losses of 0.45 kg/ week. Groups were categorized as “FAST” (≥0.68 kg/week, n=69), “MODERATE” (≥0.23 and <0.68 kg/week, n= 104), and “SLOW” (<0.23 kg/week, n=89) based on rate of weight loss during first month of treatment. Results The FAST, MODERATE, and SLOW groups differed significantly in mean weight changes at 6 months (−13.5, −8.9, and −5.1 kg, respectively, ps <0.001), and the FAST and SLOW groups differed significantly at 18 months (−10.9, −7.1, and −3.7 kg, respectively, ps <0.001). No significant group differences were found in weight regain between 6 and 18 months (2.6, 1.8, and 1.3 kg, respectively, ps < 0.9). The FAST and MODERATE groups were 5.1 and 2.7 times more likely to achieve 10% weight losses at 18 months than the SLOW group. Conclusion Collectively, findings indicate both short- and long-term advantages to fast initial weight loss. Fast weight losers obtained greater weight reduction and long-term maintenance, and were not more susceptible to weight regain than gradual weight losers.