Impact of Periodic Follow-Up Testing Among Urban American Indian Women With Impaired Fasting Glucose

of periodic follow-up testing among urban American Indian women with impaired fasting glucose. Prev Chronic Di

Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease

AbstractUnlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD

ABCC Multidrug Transporters in Childhood Neuroblastoma: Clinical and Biological Effects Independent of Cytotoxic Drug Efflux

Background Although the prognostic value of the ATP-binding cassette, subfamily C (ABCC) transporters in childhood neuroblastoma is usually attributed to their role in cytotoxic drug efflux, certain observations have suggested that these multidrug transporters might contribute to the malignant phenotype independent of cytotoxic drug efflux. Methods A v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN)-driven transgenic mouse neuroblastoma model was crossed with an Abcc1-deficient mouse strain (658 hMYCN1/−, 205 hMYCN+/1 mice) or, alternatively, treated with the ABCC1 inhibitor, Reversan (n = 20). ABCC genes were suppressed using short interfering RNA or overexpressed by stable transfection in neuroblastoma cell lines BE(2)-C, SH-EP, and SH-SY5Y, which were then assessed for wound closure ability, clonogenic capacity, morphological differentiation, and cell growth. Real-time quantitative polymerase chain reaction was used to examine the clinical significance of ABCC family gene expression in a large prospectively accrued cohort of patients (n = 209) with primary neuroblastomas. Kaplan-Meier survival analysis and Cox regression were used to test for associations with event-free and overall survival. Except where noted, all statistical tests were two-sided. Results Inhibition of ABCC1 statistically significantly inhibited neuroblastoma development in hMYCN transgenic mice (mean age for palpable tumor: treated mice, 47.2 days; control mice, 41.9 days; hazard ratio [HR] = 9.3, 95% confidence interval [CI] = 2.65 to 32; P < .001). Suppression of ABCC1 in vitro inhibited wound closure (P < .001) and clonogenicity (P = .006); suppression of ABCC4 enhanced morphological differentiation (P < .001) and inhibited cell growth (P < .001). Analysis of 209 neuroblastoma patient tumors revealed that, in contrast with ABCC1 and ABCC4, low rather than high ABCC3 expression was associated with reduced event-free survival (HR of recurrence or death = 2.4, 95% CI = 1.4 to 4.2; P = .001), with 23 of 53 patients with low ABCC3 expression experiencing recurrence or death compared with 31 of 155 patients with high ABCC3. Moreover, overexpression of ABCC3 in vitro inhibited neuroblastoma cell migration (P < .001) and clonogenicity (P = .03). The combined expression of ABCC1, ABCC3, and ABCC4 was associated with patients having an adverse event, such that of the 12 patients with the "poor prognosis” expression pattern, 10 experienced recurrence or death (HR of recurrence or death = 12.3, 95% CI = 6 to 27; P < .001). Conclusion ABCC transporters can affect neuroblastoma biology independently of their role in chemotherapeutic drug efflux, enhancing their potential as targets for therapeutic interventio

First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade \u3e 1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (\u3e 9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks

Uganda's HIV Prevention Success: The Role of Sexual Behavior Change and the National Response

There has been considerable interest in understanding what may have led to Uganda's dramatic decline in HIV prevalence, one of the world's earliest and most compelling AIDS prevention successes. Survey and other data suggest that a decline in multi-partner sexual behavior is the behavioral change most likely associated with HIV decline. It appears that behavior change programs, particularly involving extensive promotion of “zero grazing” (faithfulness and partner reduction), largely developed by the Ugandan government and local NGOs including faith-based, women’s, people-living-with-AIDS and other community-based groups, contributed to the early declines in casual/multiple sexual partnerships and HIV incidence and, along with other factors including condom use, to the subsequent sharp decline in HIV prevalence. Yet the debate over “what happened in Uganda” continues, often involving divisive abstinence-versus-condoms rhetoric, which appears more related to the culture wars in the USA than to African social reality

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The Occurrence of Rocky Habitable-zone Planets around Solar-like Stars from Kepler Data

We present the occurrence rates for rocky planets in the habitable zones (HZs) of main-sequence dwarf stars based on the Kepler DR25 planet candidate catalog and Gaia-based stellar properties. We provide the first analysis in terms of star-dependent instellation flux, which allows us to track HZ planets. We define η⊕ as the HZ occurrence of planets with radii between 0.5 and 1.5 R⊕ orbiting stars with effective temperatures between 4800 and 6300 K. We find that η⊕ for the conservative HZ is between 0.37^(+0.48)_(−0.21) (errors reflect 68% credible intervals) and 0.60^(+0.90)_(−0.36) planets per star, while the optimistic HZ occurrence is between 0.58^(+0.73)_(−0.33) and 0.88^(+1.28)_(−0.51) planets per star. These bounds reflect two extreme assumptions about the extrapolation of completeness beyond orbital periods where DR25 completeness data are available. The large uncertainties are due to the small number of detected small HZ planets. We find similar occurrence rates between using Poisson likelihood Bayesian analysis and using Approximate Bayesian Computation. Our results are corrected for catalog completeness and reliability. Both completeness and the planet occurrence rate are dependent on stellar effective temperature. We also present occurrence rates for various stellar populations and planet size ranges. We estimate with 95% confidence that, on average, the nearest HZ planet around G and K dwarfs is ~6 pc away and there are ~4 HZ rocky planets around G and K dwarfs within 10 pc of the Sun

The Occurrence of Rocky Habitable Zone Planets Around Solar-Like Stars from Kepler Data

We present occurrence rates for rocky planets in the habitable zones (HZ) of main-sequence dwarf stars based on the Kepler DR25 planet candidate catalog and Gaia-based stellar properties. We provide the first analysis in terms of star-dependent instellation flux, which allows us to track HZ planets. We define $\eta_\oplus$ as the HZ occurrence of planets with radius between 0.5 and 1.5 $R_\oplus$ orbiting stars with effective temperatures between 4800 K and 6300 K. We find that $\eta_\oplus$ for the conservative HZ is between $0.37^{+0.48}_{-0.21}$ (errors reflect 68\% credible intervals) and $0.60^{+0.90}_{-0.36}$ planets per star, while the optimistic HZ occurrence is between $0.58^{+0.73}_{-0.33}$ and $0.88^{+1.28}_{-0.51}$ planets per star. These bounds reflect two extreme assumptions about the extrapolation of completeness beyond orbital periods where DR25 completeness data are available. The large uncertainties are due to the small number of detected small HZ planets. We find similar occurrence rates using both a Poisson likelihood Bayesian analysis and Approximate Bayesian Computation. Our results are corrected for catalog completeness and reliability. Both completeness and the planet occurrence rate are dependent on stellar effective temperature. We also present occurrence rates for various stellar populations and planet size ranges. We estimate with $95\%$ confidence that, on average, the nearest HZ planet around G and K dwarfs is about 6 pc away, and there are about 4 HZ rocky planets around G and K dwarfs within 10 pc of the Sun.Comment: To appear in The Astronomical Journa

Movements and Population Structure of Humpback Whales in the North Pacific

Despite the extensive use of photographic identification methods to investigate humpback whales in the North Pacific, few quantitative analyses have been conducted. We report on a comprehensive analysis of interchange in the North Pacific among three wintering regions (Mexico, Hawaii, and Japan) each with two to three subareas, and feeding areas that extended from southern California to the Aleutian Islands. Of the 6,413 identification photographs of humpback whales obtained by 16 independent research groups between 1990 and 1993 and examined for this study, 3,650 photographs were determined to be of suitable quality. A total of 1,241 matches was found by two independent matching teams, identifying 2,712 unique whales in the sample (seen one to five times). Site fidelity was greatest at feeding areas where there was a high rate of resightings in the same area in different years and a low rate of interchange among different areas. Migrations between winter regions and feeding areas did not follow a simple pattern, although highest match rates were found for whales that moved between Hawaii and southeastern Alaska, and between mainland and Baja Mexico and California. Interchange among subareas of the three primary wintering regions was extensive for Hawaii, variable (depending on subareas) for Mexico, and low for Japan and reflected the relative distances among subareas. Interchange among these primary wintering regions was rare. This study provides the first quantitative assessment of the migratory structure of humpback whales in the entire North Pacific basin