Background: Bisphenol A (BPA) is a high-production-volume chemical commonly used in the manufacture of polycarbonate plastic Low-level concentrations of BPA in animals and possibly in humans may ...cause endocrine disruption. Whether ingestion of food or beverages from polycarbonate containers increases BPA concentrations in humans has not been studied. Objectives: We examined the association between use of polycarbonate beverage containers and urinary BPA concentrations in humans. Methods: We conducted a nonrandomized intervention of 77 Harvard College students to compare urinary BPA concentrations collected after a washout phase of 1 week to those taken after an intervention week during which most cold beverages were consumed from polycarbonate drinking bottles. Paired t-tests were used to assess the difference in urinary BPA concentrations before and after polycarbonate bottle use. Results: The geometric mean urinary BPA concentration at the end of the washout phase was 1.2 µg/g creatinine, increasing to 2.0 µg/g creatinine after 1 week of polycarbonate bottle use. Urinary BPA concentrations increased by 69% after use of polycarbonate bottles (p < 0.0001). The association was stronger among participants who reported ≥ 90% compliance (77% increase; p < 0.0001) than among those reporting < 90% compliance (55% increase; p = 0.03), but this difference was not statistically significant (p = 0.54). Conclusions: One week of polycarbonate bottle use increased urinary BPA concentrations by twothirds. Regular consumption of cold beverages from polycarbonate bottles is associated with a substantial increase in urinary BPA concentrations irrespective of exposure to BPA from other sources.
Food insecurity is common among HIV-infected individuals and has been associated with poor health. Little longitudinal research has examined the association of food insecurity with HIV clinical ...outcomes, or the extent to which adherence mediates these associations.
Observational cohort study
HIV-infected homeless and marginally housed individuals in the San Francisco Research on Access to Care in the Homeless cohort completed quarterly structured interviews and blood draws. We measured food insecurity using the validated Household Food Insecurity Access Scale. Primary outcomes were: antiretroviral therapy (ART) nonadherence (<90% adherence), incomplete HIV viral load suppression more than 100 copies/ml, and CD4⁺ cell counts less than 200 cells/μl. We estimated model parameters using generalized estimating equations, adjusting for sociodemographic and clinical variables.
From May 2007 to March 2010, we followed 284 participants for a median of 22 months. At baseline 54.6% of participants were food-insecure. Food insecurity was associated with increased odds of ART nonadherence adjusted odds ratio (AOR) = 1.48; 95% confidence interval (CI), 1.19-1.85, incomplete viral load suppression (AOR = 1.29, 95% CI 1.04-1.61), and CD4⁺ cell counts less than 200 cells/μl (AOR = 1.26, 95% CI 1.01-1.56). When we included ART adherence in adjusted models for incomplete viral suppression and CD4⁺ cell counts less than 200 cells/μl, the magnitude of the effect decreased slightly.
Food insecurity was associated with poor HIV outcomes, including nonadherence, in a longitudinal study of US-based HIV-infected unstably housed individuals. Efforts to address food insecurity should be included in HIV-treatment programs, and may help improve health outcomes.
Nonenzymatic, template-directed synthesis of nucleic acids is a paradigm for self-replicating systems. The evolutionary dynamics of such systems depend on several factors, including the mutation ...rates, relative replication rates, and sequence characteristics of mutant sequences. We measured the kinetics of correct and incorrect monomer insertion downstream of a primer-template mismatch (mutation), using a range of backbone structures (RNA, DNA, and LNA templates and RNA and DNA primers) and two types of 5′-activated nucleotides (oxyazabenzotriazolides and imidazolides, i.e., nucleoside 5′-phosphorimidazolides). Our study indicated that for all systems studied, an initial mismatch was likely to be followed by another error (54–75% of the time), and extension after a single mismatch was generally 10–100 times slower than extension without errors. If the mismatch was followed by a matched base pair, the extension rate recovered to nearly normal levels. On the basis of these data, we simulated nucleic acid replication in silico, which indicated that a primer suffering an initial error would lag behind properly extended counterparts due to a cascade of subsequent errors and kinetic stalling, with the typical mutational event consisting of several consecutive errors. Our study also included different sequence contexts, which suggest the presence of cooperativity among monomers affecting both absolute rate (by up to 2 orders of magnitude) and fidelity. The results suggest that molecular evolution in enzyme-free replication systems would be characterized by large “leaps” through sequence space rather than isolated point mutations, perhaps enabling rapid exploration of diverse sequences. The findings may also be useful for designing self-replicating systems combining high fidelity with evolvability.
Background: Specialty care access is increasingly constrained due to increasing demand for specialty care. Although much attention has been placed on the initial referral decision, much less is known ...about follow-up visit patterns. We examined the patterns of follow-up visits for new patients to a university-based cardiology practice and identified independent predictors of follow-up visits. Methods: This is a retrospective cohort study of new patient visits using electronic medical record data. The primary outcome was a follow-up visit. Results: Substantial variation in practice patterns by provider persisted after accounting for patient and disease factors. Most follow-up care was concentrated in a small population of patients. Conclusion: Specialty care follow-up visits may represent a significant opportunity for standardization and quality improvement, and further studies are warranted to understand follow-up visits in specialty care. Implications: Better understanding of between-provider differences could identify ways to reduce unnecessary follow-up visits. Level of Evidence: Single-institution study.
Background:
Specialty care access is increasingly constrained due to increasing demand for specialty care. Although much attention has been placed on the initial referral decision, much less is known ...about follow-up visit patterns. We examined the patterns of follow-up visits for new patients to a university-based cardiology practice and identified independent predictors of follow-up visits.
Methods:
This is a retrospective cohort study of new patient visits using electronic medical record data. The primary outcome was a follow-up visit.
Results:
Substantial variation in practice patterns by provider persisted after accounting for patient and disease factors. Most follow-up care was concentrated in a small population of patients.
Conclusion:
Specialty care follow-up visits may represent a significant opportunity for standardization and quality improvement, and further studies are warranted to understand follow-up visits in specialty care.
Implications:
Better understanding of between-provider differences could identify ways to reduce unnecessary follow-up visits.
Level of Evidence:
Single-institution study.
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple ...prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed
by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth
and
. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
Ischemia/reperfusion of organ systems in trauma patients with resuscitated hemorrhagic shock (HSR) contributes to tissue injury and organ dysfunction. Previous studies using a murine model of HSR ...showed that remote ischemic preconditioning (RIC) protected against organ injury and that the plasma was able to prevent neutrophil migration in a zebrafish tailfin-cut inflammation model. In this study, we hypothesized that RIC plasma inhibits neutrophil function through a decrease in reactive oxygen species (ROS) production via the upregulation of the transcription factor Nrf2 and downstream antioxidative genes. Plasma from mice subjected to RIC (4 cycles of 5-min hindlimb ischemia/reperfusion) was microinjected into zebrafish. The results show that RIC plasma caused a reduction of ROS generation in response to tail injury. In addition, RIC plasma protected the fish larvae in the survival studies when exposed to either H2O2 or LPS. Oxidative stress PCR Array showed that RIC plasma treatment led to upregulation of antioxidative related genes including hsp70, hmox1a, nqo1 as well as downregulation of duox, the producer of H2O2. To explore the role of nrf2 in RIC, RIC plasma from Nrf2 KO mice were injected to the zebrafish and showed no inhibitory effect on neutrophil migration. Moreover, knockdown of nrf2a attenuated the anti-inflammatory and protective effect of RIC plasma. The downregulation of duox and upregulation of hmox1a were confirmed to require the activation of nrf2a. Therefore, we show that the protective effect of RIC may be related to the elaboration of humoral factors which counter injury-induced ROS generation in a nrf2-dependent fashion.
The temperature dependence of the density of water, ρ(T), is obtained by means of optical scattering data, Raman and Fourier transform infrared, in a very wide temperature range, 30 < T < 373 K. This ...interval covers three regions: the thermodynamically stable liquid phase, the metastable supercooled phase, and the low-density amorphous solid phase, at very low T. From analyses of the profile of the OH stretching spectra, we determine the fractional weight of the two main spectral components characterized by two different local hydrogen bond structures. They are, as predicted by the liquid-liquid phase transition hypothesis of liquid water, the low- and the high-density liquid phases. We evaluate contributions to the density of these two phases and thus are able to calculate the absolute density of water as a function of T. We observe in ρ(T) a complex thermal behavior characterized not only by the well known maximum in the stable liquid phase at T = 277 K, but also by a well defined minimum in the deeply supercooled region at 203 ± 5 K, in agreement with suggestions from molecular dynamics simulations.
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