Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT).

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy of type 1 diabetes mellitus reduces the risk of development and progression of microvascular complications. The Epidemiology of Diabetes Interventions and Complications (EDIC) study assessed whether these benefits persisted after the end of DCCT. Results for the adolescent DCCT cohort are reported here. STUDY DESIGN: Of the DCCT adolescent cohort (n = 195), 175 participated in EDIC, 151 had fundus photography, and 156 had albumin excretion rate measured at year 3 or 4. The odds of progression of retinopathy and albuminuria from closeout of the DCCT until EDIC year 4 were assessed. RESULTS: In contrast to the 7.4 years of the DCCT, during which mean hemoglobin A(1c) levels were significantly lower with intensive therapy than conventional therapy (8.06% vs 9.76%; P <.0001), the subsequent first 4 years of EDIC had mean hemoglobin A(1c) levels that were similar between the former intensive and the former conventional groups (8.38% vs 8.45%). However, the prevalence of worsening of 3 steps or more in retinopathy and of progression to proliferative or severe nonproliferative retinopathy were reduced by 74% (P <.001) and 78% (P <.007), respectively, in the former intensive therapy group compared with the former conventional group. CONCLUSIONS: These findings provide further support for the DCCT recommendation that most adolescents with type 1 diabetes receive intensive therapy aimed at achieving glycemic control as close to normal as possible to reduce the risk of microvascular complications.

Inverse complementary homologues of short cysteine signatures.

Inversions of short genomic sequences may play a central role in the generation of protein complexity. We report here the existence of an heterogeneous group of proteins (the trefoil precursors MUC-1 and MUA-1, six preproendothelins, and five classes of zinc finger knot proteins) having both cysteine signatures (Cs) and their inverse complementary sequences (Cs) in the same polypeptide chain. We have also found cases in which the (Cs) of a given signature is not present in the same protein, but elsewhere. TGEKPYK, a cysteine-free motif of the human transcription factor, Krab, coexists with its inverse complementary sequence in 31 proteins; the inverse complementary alone is present in a great number of proteins. Our findings suggest that short DNA inversions are a widespread feature of the genome.

Microsatellites provide evidence for Y chromosome diversity among the founders of the New World.

Recently, Y chromosome markers have begun to be used to study Native American origins. Available data have been interpreted as indicating that the colonizers of the New World carried a single founder haplotype. However, these early studies have been based on a few, mostly complex polymorphisms of insufficient resolution to determine whether observed diversity stems from admixture or diversity among the colonizers. Because the interpretation of Y chromosomal variation in the New World depends on founding diversity, it is important to develop marker systems with finer resolution. Here we evaluate the hypothesis of a single-founder Y haplotype for Amerinds by using 11 Y-specific markers in five Colombian Amerind populations. Two of these markers (DYS271, DYS287) are reliable indicators of admixture and detected three non-Amerind chromosomes in our sample. Two other markers (DYS199, M19) are single-nucleotide polymorphisms mostly restricted to Native Americans. The relatedness of chromosomes defined by these two markers was evaluated by constructing haplotypes with seven microsatellite loci (DYS388 to 394). The microsatellite backgrounds found on the two haplogroups defined by marker DYS199 demonstrate the existence of at least two Amerind founder haplotypes, one of them (carrying allele DYS199 T) largely restricted to Native Americans. The estimated age and distribution of these haplogroups places them among the founders of the New World.

Tumor necrosis factor alpha interferes with the cell cycle of normal and papillomavirus-immortalized human keratinocytes.

We have shown that normal and human papillomavirus (HPV) type 16 immortalized human foreskin keratinocytes are growth inhibited by tumor necrosis factor alpha (TNF-alpha), whereas HPV-18- and SV40-immortalized keratinocytes are resistant to this cytokine (1). In this report, we investigated the expression of mitotic regulatory proteins, such as cyclin A, cyclin B, and p34cdc2. After exposure to TNF-alpha, normal and HPV-16-immortalized cells exhibited a dramatic decrease in the expression of these proteins. In contrast, no alteration in the levels of these proteins was observed after treatment of the resistant cell lines, as well as two HPV-positive cervical carcinoma cell lines. Expression of cyclin E does not seem to be modulated by TNF-alpha in any of the cells tested. On the other hand, cyclin D1, expression is slightly increased in normal keratinocytes and in the HPV-16-immortalized cells, whereas no alteration was observed in the HPV-18-transfected cells. The phosphorylation state of pRb correlated with cell growth; sensitive cells, which accumulate in G0-G1, after exposure to TNF-alpha, exhibited an accumulation of hypophosphorylated pRb, whereas no effect on pRb phosphorylation was observed for HPV-18-immortalized cells. These results clearly correlate with TNF-alpha-induced growth arrest in G0-G1.

AIDS and women in Brazil: the emerging problem.

This paper compares and problematizes the public discourse on AIDS and sexuality with the actual private discourse of low-income urban women in Brazil. Women's perspectives on sexuality are explored by examining what they say about anal sex, virginity, and fidelity and are seen as approximating culturally scripted ideals for sexual behavior. AIDS discourses that are being proposed by the Brazilian government, Brazilian AIDS activist groups and the women's movement are examined in light of these perspectives. Condom literacy, a central component to the Brazilian AIDS activist campaign, is problematized within the context of low-income women's lives.

Interaction of angiotensin II with the cholinergic and noradrenergic systems in the rat pineal gland: regulation of indole metabolism.

The pineal gland, angiotensin, and noradrenergic and cholinergic systems are involved in the regulation of tissue indole metabolism. Angiotensin II increased noradrenaline release and the production of hydroxy- and methoxyindoles by pineal slices. Electrical field stimulation (EFS) of pineal slices released angiotensin II and reproduced many of the actions of exogenous angiotensin II on serotonin and melatonin biosynthesis and release. Both sarcosine-isoleucine-angiotensin II ([Sar, Ile]-ANG II) and atropine blocked, and nadolol increased, the effect of EFS and exogenous angiotensin II on serotonin production. Nadolol blocked both the EFS-induced and the angiotensin II-induced production of melatonin. Atropine and [Sar, Ile]-ANG II did not modify melatonin biosynthesis in electrically stimulated slices, but the muscarinic receptor antagonist increased the stimulatory effect of angiotensin II. These data showed that EFS released angiotensin II and noradrenaline from pineal slices and that a close functional connection exists between the peptide and acetylcholine. The stimulation of serotonin biosynthesis and release by these two neurotransmitters was negatively regulated by noradrenaline acting through beta-adrenergic receptors.

Effect of sustained pharmacologic vitamin E levels on incidence and severity of retinopathy of prematurity: a controlled clinical trial.

The incidence and severity of retinopathy of prematurity (ROP) as affected by vitamin E prophylaxis at pharmacologic serum levels (5 mg/dl) were evaluated in a double-masked clinical trial of infants with a birth weight less than or equal to 2000 gm or a gestational age less than or equal to 36 weeks. The infants were enrolled by age 5 days and randomly assigned to receive parenterally administered, and later orally administered, free alpha-tocopherol (vitamin E) or its placebo. Study medication was continued until retinal vascularization was complete or active ROP had subsided, except in infants with a diagnosis of severe disease, in whom vitamin E was substituted for study medication. Acute ROP data were collected on 755 infants. Logistic regression analysis, with control for immaturity, oxygen exposure, and other illness risk factors, showed a decrease in incidence of ROP in vitamin E-treated infants (p = 0.003, all infants; p = 0.035, infants weighing less than or equal to 1500 gm at birth). Among the 424 infants weighing less than or equal to 1500 gm at birth, the age at enrollment influenced treatment effect (age day 0 to 1, p = 0.006 (n = 288) vs age day 2 to 5, p greater than 0.1 (n = 136]. Overall, 77.6% of infants with ROP had mild disease. Moderate to severe ROP was confined to infants weighing greater than or equal to 1500 gm at birth (25 given placebo, 25 given vitamin E), with progression to severe disease in nine placebo-treated versus three vitamin E-treated infants (p = 0.048). The incidence of severe ROP per se was not significantly decreased (all birth weights, p = 0.086; less than or equal to 1500 gm birth weight, p = 0.080); the sample size was too small, however, to assess this end point adequately. An increased incidence of sepsis and late-onset necrotizing enterocolitis was found among vitamin E-treated infants weighing less than or equal to 1500 gm at birth who received study medication for greater than or equal to 8 days (p = 0.006). Because most ROP is mild in degree and regresses completely, the risk/benefit ratio of pharmacologic prophylaxis for ROP is unfavorable. Treatment of moderate and severe ROP with vitamin E above physiologic serum levels (greater than 3 mg/dl) appears promising and should be further investigated. The interpretation of cicatricial outcome was confounded by the small number of patients involved and by subsequent treatment of severe ROP in placebo-treated infants with vitamin E.

Pharmacokinetics of inhaled salbutamol in patients with cystic fibrosis versus healthy young adults.

We studied the disposition of inhaled salbutamol in adolescents with cystic fibrosis (CF) and compared it with the pharmacokinetics of the drug given by the intravenous and inhaled routes in healthy adults. After inhalation of salbutamol, CF patients had a significantly larger area under the concentration-time curve derived from amounts of drug in the systemic circulation. The differences in serum concentration of salbutamol were not reflected in differences in change of heart rate. We conclude that the rate and extent of pulmonary absorption of inhaled salbutamol in patients with CF differ from those in healthy adults.

Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal insufficiency associated with Xp21 interstitial deletion.

We report an interstitial deletion in the short arm of the X chromosome in a 6-year-old boy with Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal insufficiency, intermittent hypoglycemia, spasticity, psychomotor retardation, and growth delay. His mother also has this deletion in an X chromosome. From our findings, we propose that the human glycerol kinase locus and the human X-linked adrenal hypoplasia locus are in the Xp21 band.

Oligomenorrhea in adolescent girls.

Forty-two patients ages 15 to 20 years (average 17.3 years) were evaluated for oligomenorrhea. Group I consisted of 19 patients with evidence of androgen excess (hirsutism, clitoromegaly, acne); and Group II included 23 patients without evidence of androgen excess. Sixteen of the 19 patients in Group I had elevated serum LH and normal FSH values. Serum total testosterone concentration was elevated in 12 patients and free T was elevated in one additional patient. In nine patients urinary 17KS excretion was elevated and dexamethasone suppressible. For the purpose of treatment, patients in Group I were divided into three subgroups: IA, polycystic ovary syndrome--12 patients; IB, adrenal block--two patients; IC, combined adrenal and ovarian hyperandrogenism--five patients. Among the 23 Group II patients, four had persistently elevated serum LH and normal FSH values, suggesting PCO; three had menopausal levels of LA and FSH; one had hyperprolactinemia and a depressed floor of the pituitary sella; and the remaining 15 patients had low to normal serum levels of LH and FSH, consistent with hypothalamic suppression. Guidelines for the diagnosis and treatment of adolescents with oligomenorrhea are discussed on the basis of these findings.