Increased Collagen-Linked Pentosidine Levels and Advanced Glycosylation End Products in Early Diabetic Nephropathy

RATIONALE: Advanced glycosylation end products (AGEs) may play an important role in the development of diabetic vascular sequelae. An AGE cross-link, pentosidine, is a sensitive and specific marker for tissue levels of AGEs. OBJECTIVES: To evaluate the role of AGEs in the development of diabetic nephropathy and retinopathy, we studied pentosidine levels and the clinical characteristics of 48 subjects with insulin-dependent diabetes mellitus. Diabetic nephropathy was classified as normal, microalbuminuria, or gross proteinuria, and retinopathy was graded as none, background, or proliferative. NEWLY OBSERVED FINDINGS: Significant elevation of pentosidine (P = 0.025) was found in subjects with microalbuminuria or gross proteinuria (73.03 +/- 9.47 vs 76.46 +/- 6.37 pmol/mg col) when compared with normal (56.96 +/- 3.26 pmol/mg col). Multivariate analysis to correct for age, duration of diabetes, and gender did not modify the results. Elevated pentosidine levels were also found in those with proliferative when compared with those with background retinopathy (75.86 +/- 5.66 vs 60.42 +/- 5.98 pmol/mg col) (P \u3c 0.05). CONCLUSIONS: Microalbuminuria is associated with elevated levels of pentosidine similar to those found in overt diabetic nephropathy suggesting that elevated AGE levels are already present during the earliest detectable phase of diabetic nephropathy

Long-term yogurt consumption and risk of incident hypertension in adults

The Nurses' Health Study and Health Professionals Follow-up Study cohorts are supported by grants UM1 CA186107, UM1 CA176726, and UM1 CA167552 from the National Institutes of Health. The current analyses were supported by small grants from the National Dairy Council, the General Mills Bell Institute for Health and Nutrition, and the Boston Nutrition and Obesity Research Center. The Boston Nutrition Obesity Research Center is administratively based at Boston Medical Center and is funded by the National Institutes of Health (NIH/NIDDK) grant P30DK046200. (UM1 CA186107 - National Institutes of Health; UM1 CA176726 - National Institutes of Health; UM1 CA167552 - National Institutes of Health; small grants from the National Dairy Council; General Mills Bell Institute for Health and Nutrition; Boston Nutrition and Obesity Research Center; P30DK046200 - National Institutes of Health (NIH/NIDDK))Accepted manuscrip

Virological features associated with the development of broadly neutralizing antibodies to HIV-1.

CAPRISA, 2015.Abstract available in pdf

HIV-1 Subtype C-Infected Children with Exceptional Neutralization Breadth Exhibit Polyclonal Responses Targeting Known Epitopes

We have previously shown that HIV-1-infected children develop broader and more potent neutralizing antibody responses than adults. This study aimed to determine the antibody specificities in 16 HIV-1 subtype C-infected children who displayed exceptional neutralization breadth on a 22-multisubtype virus panel. All children were antiretroviral treatment (ART) naive with normal CD4 counts despite being infected for a median of 10.1 years with high viral loads. The specificity of broadly neutralizing antibodies (bNAbs) was determined using epitope-ablating mutants, chimeric constructs, and depletion or inhibition of activity with peptides and glycoproteins. We found that bNAbs in children largely targeted previously defined epitopes, including the V2-glycan, V3-glycan, CD4bs, and gp120-gp41 interface. Remarkably, 63% of children had antibodies targeting 2 or 3 and, in one case, 4 of these bNAb epitopes. Longitudinal analysis of plasma from a mother-child pair over 9 years showed that while they both had similar neutralization profiles, the antibody specificities differed. The mother developed antibodies targeting the V2-glycan and CD4bs, whereas bNAb specificities in the child could not be mapped until 6 years, when a minor V2-glycan response appeared. The child also developed high-titer membrane-proximal external region (MPER) binding antibodies not seen in the mother, although these were not a major bNAb specificity. Overall, exceptional neutralization breadth in this group of children may be the result of extended exposure to high antigenic load in the context of an intact immune system, which allowed for the activation of multiple B cell lineages and the generation of polyclonal responses targeting several bNAb epitopes. IMPORTANCE An HIV vaccine is likely to require bNAbs, which have been shown to prevent HIV acquisition in nonhuman primates. Recent evidence suggests that HIV-infected children are inherently better at generating bNAbs than adults. Here, we show that exceptional neutralization breadth in a group of viremic HIV-1 subtype C-infected children was due to the presence of polyclonal bNAb responses. These bNAbs targeted multiple epitopes on the HIV envelope glycoprotein previously defined in adult infection, suggesting that the immature immune system recognizes HIV antigens similarly. Since elicitation of a polyclonal bNAb response is the basis of next-generation HIV envelope vaccines, further studies of how bNAb lineages are stimulated in children is warranted. Furthermore, our findings suggest that children may respond particularly well to vaccines designed to elicit antibodies to multiple bNAb epitopes

Theoretical Evaluations of the Fission Cross Section of the 77 eV Isomer of 235-U

We have developed models of the fission barrier (barrier heights and transition state spectra) that reproduce reasonably well the measured fission cross section of $^{235}$U from neutron energy of 1 keV to 2 MeV. From these models we have calculated the fission cross section of the 77 eV isomer of $^{235}$U over the same energy range. We find that the ratio of the isomer cross section to that of the ground state lies between about 0.45 and 0.55 at low neutron energies. The cross sections become approximately equal above 1 MeV. The ratio of the neutron capture cross section to the fission cross section for the isomer is predicted to be about a factor of 3 larger for the isomer than for the ground state of $^{235}$U at keV neutron energies. We have also calculated the cross section for the population of the isomer by inelastic neutron scattering form the $^{235}$U ground state. We find that the isomer is strongly populated, and for $E_n = 1 MeV$ the $(n,n'\gamma)$ cross section leading to the population of the isomer is of the order of 0.5 barn. Thus, neutron reaction network calculations involving the uranium isotopes in a high neutron fluence are likely to be affected by the 77 eV isomer of $^{235}$U. With these same models the fission cross sections of $^{233}$U and $^{237}$U can be reproduced approximately using only minor adjustments to the barrier heights. With the significant lowering of the outer barrier that is expected for the outer barrier the general behavior of the fission cross section of $^{239}$Pu can also be reproduced.Comment: 17 pages including 8 figure

HIV broadly neutralizing antibody targets.

CAPRISA, 2015.Abstract available in pdf

Gendered nationalism : the gender gap in support for the Scottish National Party

Recent major surveys of the Scottish electorate and of Scottish National Party (SNP) members have revealed a distinct gender gap in support for the party. Men are markedly more likely than women to vote for the SNP and they comprise more than two-thirds of its membership. In this article, we use data from those surveys to test various possible explanations for the disproportionately male support for the SNP. While popular accounts have focused on the gendered appeal of recent leaders and on the party’s fluctuating efforts at achieving gender equality in its parliamentary representation, we find much stronger support for a different explanation. Women are less inclined to support and to join the SNP because they are markedly less supportive of its central objective of independence for Scotland. Since men and women barely differ in their reported national identities, the origins of this gender gap in support for independence presents a puzzle for further research

Indices of Mediterranean diet adherence and breast cancer risk in a community-based cohort

IntroductionA Mediterranean-style dietary pattern is believed to have cancer-protective effects. We compared the prospective associations between adherence to four established Mediterranean diet indices and breast cancer risk (including total, postmenopausal, and hormone receptor positive cases) in women in the Framingham Offspring Study.MethodsThe four indices used two different approaches to measuring adherence to a Mediterranean diet: (a) scores based on the population-specific median intakes of Mediterranean diet-related foods in a given population (i.e., alternate Mediterranean Diet (aMED) index and Mediterranean Diet Score (MDS) index), and (b) scores based on compliance with recommended intakes of relevant foods from the Mediterranean diet pyramid [i.e., Mediterranean Diet (MeDiet) index and Mediterranean Style Dietary Pattern (MSDP) index]. Dietary data were derived from semiquantitative food frequency questionnaires collected in 1991-95. Participants included 1579 women aged ≤ 30 years who were free of prevalent cancer. Women were followed through 2014, and Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for various confounders.ResultsDuring a median follow-up of approximately 18 years, 87 breast cancer cases were documented. Women in the highest (vs. lowest) score category of the pyramid-based scores (i.e., MeDiet or MSDP) had approximately 45% statistically significantly lower breast cancer risks. These effects were even stronger for any hormone receptor positive cases using the MeDiet index (highest vs. lowest score categories: HR = 0.45, 95% CI: 0.22–0.90). Neither of the median intake-based scores (i.e., aMED, MDS) was associated with breast cancer risk.DiscussionOur results suggest that the methodology and the composition of Mediterranean diet indices influence their ability to assess conformity to this specific diet pattern and predict breast cancer risk

Associations between metabolic disorders and risk of cancer in Danish men and women:a nationwide cohort study

BACKGROUND: The prevalence of metabolic disorders is increasing and has been suggested to increase cancer risk, but the relation between metabolic disorders and risk of cancer is unclear, especially in young adults. We investigated the associations between diabetes, hypertension, and hypercholesterolemia on risk of all-site as well as site-specific cancers. METHODS: We consecutively included men and women from nationwide Danish registries 1996–2011, if age 20–89 and without cancer prior to date of entry. We followed them throughout 2012. Metabolic disorders were defined using discharge diagnosis codes and claimed prescriptions. We used time-dependent sex-stratified Poisson regression models adjusted for age and calendar year to assess associations between metabolic disorders, and risk of all-site and site-specific cancer (no metabolic disorders as reference). RESULTS: Over a mean follow-up of 12.6 (±5.7 standard deviations [SD]) years, 4,826,142 individuals (50.2 % women) with a mean age of 41.4 (±18.9 SD) years had 423,942 incident cancers. Incidence rate ratios (IRRs) of all-site cancer in patients with diabetes or hypertension were highest immediately following diagnosis of metabolic disorder. In women, cancer risk associated with diabetes continued to decline albeit remained significant (IRRs of 1.18–1.22 in years 1–8 following diagnosis). For diabetes in men, and hypertension, IRRs stabilized and remained significantly increased after about one year with IRRs of 1.10-1.13 in men for diabetes, and 1.07–1.14 for hypertension in both sexes. Conversely, no association was observed between hypercholesterolemia (treatment with statins) and cancer risk. The association between hypertension and cancer risk was strongest in young adults aged 20–34 and decreased with advancing age. CONCLUSIONS: Diabetes and hypertension were associated with increased risk of all-site cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2122-7) contains supplementary material, which is available to authorized users

Ontogeny-based immunogens for the induction of V2-directed HIV broadly neutralizing antibodies.

CAPRISA, 2017.Abstract available in pdf