Objective. Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome.Methods. Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells.Results. In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with

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To examine the interrelationships of cigarette smoking, relative weight, and the occurrence of natural menopause, the authors prospectively evaluated the experience of 66,663 female US registered nurses who were premenopausal in 1976. Over a two-year period, 5004 women became post-menopausal. Current smokers were more likely than past or never smokers to develop menopause, although the effects of smoking diminished with age. The rate ratios of menopause for current smokers vs. never smokers (with 95% confidence limits) for women aged 30-39, 40-44, 45-49, and 50-55 years were 1.90 (1.10-3.28), 2.16 (1.73-2.69), 1.53 (1.41-1.67), and 1.20 (1.12-1.28). These rate ratios were not appreciably affected by adjustment for relative weight. Median ages at menopause were 52.4 for never smokers and 51.9, 51.0, 50.7, and 50.4 years for women who currently smoked 1-14, 15-24, 25-34, and 35 or more cigarettes per day. A crude linear relationship between relative weight and occurrence of menopause was observed. Comparing the leanest and heaviest quintiles, rate ratios for menopause among women aged 30-39, 40-44, 45-49, and 50-55 years were 1.42 (0.74-2.75), 1.26 (0.95-1.69), 1.25 (1.13-1.41) and 1.08 (0.99-1.19). The effect of relative weight was in part explained by the tendency of current smokers to weigh less than nonsmokers. After adjustment for current cigarette consumption a weak linear relationship between relative weight and menopause remained among women who smoked, although no such association was seen among nonsmokers.

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