Developmental trajectories of adolescents' depressive symptoms: predictors of change

In a sample of 240 adolescents assessed annually in Grades 6 through 11, the developmental trajectories of their depressive symptoms were examined using latent factor growth modeling. Growth in mother-reported adolescent depressive symptoms was quadratic; growth in adolescent-reported symptoms was linear. In the model with gender and maternal depression, girls reported a greater increase in depressive symptoms over time than boys, and adolescents of mothers with histories of mood disorders had higher initial levels of depressive symptoms than offspring of never-depressed mothers. After gender and maternal depression were controlled, initial levels of negative attributions and stressors significantly predicted initial levels of adolescent- and mother-reported depressive symptoms. Attributional styles that were increasingly negative across time were associated with significantly higher initial levels (mother reported) and increasing growth (adolescent reported) of depressive symptoms. Reciprocal models in which development of depressive symptoms predicted the development of attributions and stress also were examined.     

AIDS vaccine development: the long and winding road

Development of a vaccine that provides sterilizing immunity against HIV infection remains an elusive goal, due primarily to the difficulty in generating neutralizing antibodies to primary HIV isolates. In lieu of a present solution to this problem, recent approaches to develop vaccines against HIV/AIDS have focused not on preventing infection outright, but on eliciting potent antiviral CD8+ T-cell responses to limit HIV replication in individuals who become infected after vaccination. Successful control of HIV replication in vivo, enabled by vaccine-elicited immune responses should, in turn, attenuate an individual's rate of progression to AIDS while reducing their likelihood of subsequently transmitting HIV. Recent pre-clinical evaluation of CTL-based vaccines in non-human primate models of AIDS has shown several different vaccine modalities (e.g. heterologous 'prime/boost' strategies such as DNA + recombinant viral vectors) to be capable of eliciting high-level cellular immune responses that are associated with limitation of virus replication and protection against disease following challenge with select pathogenic virus isolates. However, it is not currently known to what extent these protective effects, observed under optimal experimental conditions in select animal models, can be translated into relevant protection of humans against AIDS. In this article we discuss the promise, potential limitations, and scientific challenges that currently provide the context for efforts to develop and successfully employ a safe and effective AIDS vaccine.     

HLA-B alleles of the Navajo: no evidence for rapid evolution in the Nadene

New HLA-B locus alleles have been found in South American Amerindian populations but were largely absent in North American Amerindian tribes also descended from this first Paleo-Indian migration. We have now extended these studies to the Navajo, descendants of the second Nadene migration. No new functional alleles were found at the B locus of this tribe. This limited study supports the notion that while new B locus variants are common in South American Amerindians, it is more difficult to find new B locus alleles in North American native peoples. Whether this dichotomy is due to differences in pathogen environment and/or population structures between North and South America remains a subject of speculation.     

Efficacy and safety of recombinant human activated protein C for severe sepsis

BACKGROUND: Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS: A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.     

Hoechst staining and exposure to UV laser during flow cytometric sorting does not affect the frequency of detected endogenous DNA nicks in abnormal and normal human spermatozoa

Controlling the sex of offspring by the separation of X and Y chromosome-bearing spermatozoa using flow cytometry has been reported as a clinical technique aiding prevention of X-linked diseases. Although this technique has resulted in several hundred normal births in animals and at least one human birth, there is still concern over its genetic safety due to the involvement of two potentially mutagenic agents: UV light and the fluorochrome dye, Hoechst 33342 (H33342). Human spermatozoa, particularly those considered abnormal, may be more likely to suffer DNA damage following exposure to mutagenic agents, compared with other mammalian species. The stability of normal fresh and decondensed human spermatozoa were examined after exposure to a range of levels of UV and H33342 staining, using an assay that detects endogenous nicks in the DNA of spermatozoa. The stability of abnormal and normal, fresh and frozen-thawed human spermatozoa was examined following UV laser, H33342 staining and flow cytometry treatments utilizing the same assay. There was an increase in the presence of endogenous nicks when spermatozoa were decondensed compared with fresh spermatozoa. There was no increase in the incidence of nicks in any group of spermatozoa after UV and fluorochrome exposure compared with controls without exposure.      

Modulation of disease severity of dystrophic epidermolysis bullosa by a splice site mutation in combination with a missense mutation in the COL7A1 gene

Dystrophic epidermolysis bullosa (EBD) is a clinically heterogeneous skin disorder, characterized by abnormal anchoring fibrils (AF) and loss of dermal-epidermal adherence. EBD has been linked to the COL7A1 gene at chromosome 3p21 which encodes collagen VII, the major component of the AF. Here we investigated two unrelated EBD families with different clinical phenotypes and novel combinations of recessive and dominant COL7A1 mutations. Both families shared the same recessive heterozygous 14 bp deletion at the exon-intron 115 boundary of the COL7A1 gene. The deletion caused in-frame skipping of exon 115 and the elimination of 29 amino acid residues from the pro-alpha1(VII) polypeptide chain. As a result, procollagen VII was not converted to collagen VII and the C-terminal NC-2 propeptide which is normally removed from the procollagen VII prior to formation of the anchoring fibrils was retained in the skin. All affected individuals also carried missense mutations in exon 73 of COL7A1 which lead to different glycine- to-arginine substitutions in the triple-helical domain of collagen VII. Combination of the deletion mutation with a G2009R substitution resulted in a mild phenotype. In contrast, combination of the deletion with a G2043R substitution led to a severe phenotype. The G2043R substitution was a de novo mutation which alone caused a mild phenotype. Thus, different combinations of dominant and recessive COL7A1 mutations can modulate disease activity of EBD and alter the clinical presentation of the patients.      

Children's perceptions of peers with somatic symptoms: the impact of gender, stress, and illness

OBJECTIVE: To investigate how illness characteristics influence children's responses to ill peers. METHODS: A sample of 363 4th and 5th graders responded to a vignette describing a peer with abdominal pain. In a 2 x 2 x 2 x 2 design, conditions varied by (a) evidence for organic disease, (b) presence of stress, (c) sex of vignette character, and (d) sex of respondent. Children rated symptom severity, liking for the peer, and whether the peer should be excused from normal responsibilities. RESULTS: Same sex preferences significantly influenced children's liking for a peer. Children viewed symptoms with an organic etiology as more severe than those without one. Under certain conditions, symptom severity judgments mediated the relation between the presence of organic disease and (a) liking and (b) granting relief from responsibility. The presence of stress had little effect on ratings of symptom severity, liking, or relief from responsibility. CONCLUSIONS: Gender and evidence of organic disease influence children's perceptions of and responses to symptomatic peers.     

Association of aortic atherosclerosis with cerebral beta-amyloidosis and learning deficits in a mouse model of Alzheimer's disease

High fat/high cholesterol diets exacerbate beta-amyloidosis in mouse models of Alzheimer's disease (AD). It has been impossible, however, to study the relationship between atherosclerosis and beta-amyloidosis in those models because such mice were on atherosclerosis-resistant genetic backgrounds. Here we report the establishment of AD model mice, B6Tg2576, that are prone to atherosclerosis. B6Tg2576 mice were produced by back-crossing Tg2576 mice, an AD mouse model overexpressing human amyloid beta-protein precursor with the Swedish double mutation, to C57BL/6 mice, a strain susceptible to diet-induced atherosclerosis. An atherogenic diet induced aortic atherosclerosis and exacerbated cerebral beta-amyloidosis in B6Tg2576 mice. Compared with age-matched non-transgenic littermates, B6Tg2576 mice developed significantly more diet-induced aortic atherosclerosis. Unexpectedly, normal diet-fed B6Tg2576 mice also developed fatty streak lesions (early atherosclerosis) in the aorta. The aortic atherosclerotic lesion area positively correlated with cerebral beta-amyloid deposits in B6Tg2576 mice on both atherogenic and normal diets. Furthermore, behavioral assessments demonstrated that B6Tg2576 mice fed an atherogenic diet had more spatial learning impairment than those fed a normal diet. Our results suggest that synergistic mechanisms may be involved in the pathogenesis of atherosclerosis and AD. These findings may have important implications in the prevention and treatment of cardiovascular diseases as well as AD.