Background: A growing body of evidence has found links between endocrine disruptor phthalates and male reproductive disorders, but the mechanisms underlying these relationships are poorly known. Seminal plasma metabolomes may mediate associations of phthalate exposure with impaired semen quality. Objective: To identify seminal plasma metabolomes associated with poor semen quality and evaluate their associations with urinary phthalate metabolites among 660 Chinese adult men. Method: The seminal plasma metabolic profiles were acquired using an untargeted approach based on liquid chromatography-high resolution mass spectrometry. We explored the differences in seminal plasma metabolites between participants with poor and good semen quality and evaluated cross-sectional associations between discriminatory metabolic biomarkers and urinary phthalate metabolites. Results: Differences between poor and good semen quality groups were observed in relation to 25 seminal plasma metabolites, mostly related to the metabolism of polyunsaturated fatty acids (PUFA) and acylcarnitine (all p < 0.05). After adjusting for various confounders and multiple tests, metabolites were all significantly associated with one or more individual sperm quality parameters (motility, concentration, total count, and morphology) (all p < 0.05). Among identified metabolic biomarkers, seminal plasma L-palmitoylcarnitine, linoelaidyl carnitine, and oleic acid were inversely associated with urinary mono-(2-ethylhexyl) phthalate (MEHP), and seminal plasma L-acetylcarnitine was inversely associated with the proportion of di-(2-ethylhexyl)-phthalate metabolites (DEHP) excreted as MEHP in urine (%MEHP) (all p < 0.05). Mediation analysis revealed that oleic acid and L-acetylcarnitine mediated significant proportions (6.7% and 17%, respectively) of the positive associations between urinary DEHP metabolites and the percentage of spermatozoa with an abnormal head. Conclusions: Elevated urinary phthalate metabolites may impact semen quality by causing metabolic disorders of seminal plasma PUFAs and acylcarnitine. These pathways warrant further investigation.

Amiodarone is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis. Accumulating evidence has demonstrated that myofibroblast differentiation is related to the pathogenesis of pulmonary fibrosis. In the present study, we treated human embryonic lung fibroblasts (HELFs) with amiodarone, and investigated the relative molecular mechanism of amiodarone-induced pulmonary fibrosis and pathway determinants PD98059 (extracellular signal-regulated kinase (ERK) inhibitor) and SB203580 (p38 mitogen-activated protein kinase (MAPK) inhibitor). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8). The secretion of collagen Ⅰ was detected by ELISA. The expressions of α-smooth muscle actin (α-SMA), vimentin, phosphorylated ERK1/2 (p-ERK1/2), ERK1/2, phosphorylated p38 MAPK (p-p38), and p38 MAPK were investigated using Western blot analysis. The levels of α-SMA and vimentin were also determined by immunofluorescence and qRT-PCR. We report that amiodarone promoted cell proliferation and collagen Ⅰ secretion, induced α-SMA and vimentin protein and mRNA expression accompanied by increased phosphorylation of ERK1/2 and p38 MAPK, and furthermore, PD98059 and SB203580 remarkably reduced the proliferative response of HELFs compared with amiodarone group and greatly attenuated α-SMA, vimentin and collagen Ⅰ protein production induced by amiodarone. Taken together, our study suggests that amiodarone regulates cell proliferation and myofibroblast differentiation in HELFs through modulating ERK1/2 and p38 MAPK pathways, and these signal pathways may therefore represent an attractive treatment modality in amiodarone-induced pulmonary fibrosis.

Bottom-up processes, starting at the local government level, are valuable for more-stringent tobacco control measures. The existence of industry-backed state-level tobacco control preemption in states has impeded policy progress within the state and localities/communities. A national public health goal under Healthy People 2020 is to eliminate state-level preemption across the United States. This study explored individual-level perceptions of the impact of state-level preemption in Appalachian Tennessee—a high-smoking, low-income region. During 2015–2016, a community-engagement project to develop a Population Health Improvement Plan (PHIP) involving over 200 stakeholders and 90 organizations was conducted in Appalachian Tennessee to identify policies/programs to address tobacco use. Using a multifaceted framework approach that focused on prevention, protection, and cessation, interviews and meeting discussions were audio-recorded and transcribed. Content analysis using NVivo 11 was conducted to generate themes. Although the central focus of the PHIP was not preemption, the issue emerged naturally in the discussions as a major concern among participants. Cultural and normative factors in Appalachian Tennessee were identified as key rationales for participants’ aversion to state preemption. Thus, repealing preemption would facilitate culturally tailored and region-specific policies/programs to the high tobacco use among Appalachian Tennessee communities where statewide/nationwide policies/programs have not had the intended impacts.

Little attention has been given to differences in obesity risk factors by racial/ethnic groups. Using data from the 2011-2012 California Health Interview Survey, we examined differences in risk factors for obesity among Whites, Latinos, Asians, and African Americans among 42,935 adults (24.8% obese). Estimates were weighted to ensure an unbiased representation of the Californian population. Multiple logistic and linear regression analyses were used to examine the differences in risk factors for obesity. Large ethnic disparities were found in obesity prevalence: Whites (22.0%), Latinos (33.6%), African Americans (36.1%), and Asians (9.8%). Differences in risk factors for obesity were also observed: Whites (gender, age, physical activity, smoking, arthritis, and diabetes medicine intake), Latinos (age, arthritis, and diabetes medicine intake), Asians (age, binge drinking, arthritis, and diabetes medicine intake), and African Americans (gender, physical activity, smoking, binge drinking, and diabetes medicine intake). Females were more likely to be obese among African Americans (odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.05–1.94), but less likely among Whites (OR = 0.80, 95% CI = 0.74–0.87). Race/ethnicity should be considered in developing obesity prevention strategies.

Evidence for putative pathophysiological mechanisms of autism spectrum disorder (ASD), including peripheral inflammation, blood–brain barrier disruption, white matter alterations, and abnormal synaptic overgrowth, indicate a possible involvement of neuroinflammation in the disorder. Neuroinflammation plays a role in the development and maintenance of the dendritic spines involved in glutamatergic and GABAergic neurotransmission, and also influences blood–brain permeability. Cytokines released from microglia can impact the length, location or organization of dendritic spines on excitatory and inhibitory cells as well as recruit and impact glial cell function around the neurons. In this study, gene expression levels of anti- and pro-inflammatory signaling molecules, as well as oligodendrocyte and astrocyte marker proteins, were measured in both gray and white matter tissue in the anterior cingulate cortex from ASD and age-matched typically developing (TD) control brain donors, ranging from ages 4 to 37 years. Expression levels of the pro-inflammatory gene, HLA-DR, were significantly reduced in gray matter and expression levels of the anti-inflammatory gene MRC1 were significantly elevated in white matter from ASD donors as compared to TD donors, but neither retained statistical significance after correction for multiple comparisons. Modest trends toward differences in expression levels were also observed for the pro-inflammatory (CD68, IL1β) and anti-inflammatory genes (IGF1, IGF1R) comparing ASD donors to TD donors. The direction of gene expression changes comparing ASD to TD donors did not reveal consistent findings implicating an elevated pro- or anti-inflammatory state in ASD. However, altered expression of pro- and anti-inflammatory gene expression indicates some involvement of neuroinflammation in ASD. Lay Summary: The anterior cingulate cortex is an integral brain region in modulating social behaviors including nonverbal communication. The study found that inflammatory gene expression levels were altered in this brain region. We hypothesize that the inflammatory changes in this area could impact neuronal function. The finding has future implications in using these molecular markers to identify potential environmental exposures and distinct cell differences in autism.

Background: Clinical factors associated with exclusion from recombinant tissue plasminogen activator in both men and women are not completely understood. The aim of this study is to determine whether there is a gender difference in clinical risk factors that excluded ischemic stroke patients with a history of smoking from recombinant tissue plasminogen activator. Methods: Retrospective data from a stroke registry were analyzed, and multivariable linear regression models were used to determine gender differences. Logistic regression models determined exclusion clinical risk factors for thrombolysis in male and female acute ischemic stroke patients with a history of smoking, while sequentially adjusting for sociodemographic, clinical, and stroke-related variables. The Kaplan–Meier survival analysis was used to determine the exclusion probabilities of men and women with a history of smoking within the stroke population. Results: Of the 1,446 acute ischemic stroke patients eligible for recombinant tissue plasminogen activator, 379 patients with a history of smoking were examined, of which 181 received recombinant tissue plasminogen activator while 198 were excluded from receiving recombinant tissue plasminogen activator. Of the 198 patients, 75 females and 123 males were excluded from receiving recombinant tissue plasminogen activator. After multivariable adjustment for age, National Institutes of Health scores, and stroke-related factors, females who present with weakness/paresis on initial examination (OR = 0.117, 95% CI, 0.025–0.548) and men who present with a history of previous transient ischemic attack (OR = 0.169, 95% CI, 0.044–0.655), antiplatelet medication use (OR = 0.456, 95% CI, 0.230–0.906), and weakness/paresis on initial examination (OR = 0.171, 95% CI, 0.056–0.521) were less likely to be excluded from recombinant tissue plasminogen activator (thrombolysis therapy). Conclusions: In an ischemic stroke population with a history of smoking, female smokers are more likely to be excluded from thrombolysis therapy in comparison to men, even after adjustment for confounding variables.

Introduction: The aging population is a rapidly growing demographic in the United States. Isolation, limited autonomy, and declining physical and mental health render many older adults vulnerable to elder mistreatment (EM). The purpose of this study was to assess the prevalence and correlates of EM among a sample of older adults using legal assistance services in Atlanta, Georgia. Methods: Researchers administered surveys to consenting older adults (aged 60þ) in 5 metro Atlanta community centers that hosted legal assistance information sessions as part of the Elderly Legal Assistance Program. The surveys screened for risk factors and prevalence of EM risk using valid and reliable measures and included additional questions regarding demographics characteristics and healthcare use behaviors. Results: Surveys were completed by 112 participants. Findings reveal that 32 (28.6%) respondents met the criteria for elder abuse / neglect risk; 17 (15.2%) respondents met criteria for depression; and 105 (93.7%) had visited a healthcare provider during the past 6 months. Conclusion: The rates of EM risk in this sample were higher than those previously reported in research. Findings support continued examination of unique risks that may be present among older adults who may be possibly facing legal issues. Additionally, the reported frequency of healthcare visits among participants reveals a promising opportunity to examine development of a more widespread EM screening approach to be conducted in non-emergency settings. Interdisciplinary collaboration is required to inform screening approaches that account for complexities that EM cases present. [West J Emerg Med. 2013;14(4):309–315.]

Sleep problems have been defined using a variety of definitions. No study has assessed the longitudinal association between infant sleep problems and childhood overweight or obesity using existing definitions of sleep problems. This study used longitudinal data (n=895) from the multi-site Study of Early Child Care and Youth Development (SECCYD) to investigate the effects of infant sleep problems on childhood weight status in Grade 6. Infants with sleep problems in Phase I (1991) and with complete data through Phase III (2004) of SECCYD were included. Sleep problems were assessed using maternal reports of night wakings and duration of a waking episode. Sleep problems were defined using Richman (1981), Lozoff et al. (1985), and Zuckerman et al. (1987) definitions. Multinomial logistic regression was used to examine the association between sleep problems during infancy and childhood weight status in Grade 6 while controlling for birth weight, race, sex, breastfeeding, maternal poverty, family structure, and maternal education. After adjusting for all covariates, children with a history of sleep problems were found to be overweight in Grade 6 using Zukerman et al. (Odds ratio (OR)=1.68; 95% confidence interval (CI): 1.11–2.55) and Richman (OR=1.76; 95% CI: 1.05–2.97) definitions, but not using Lozoff et al. definition. Infant sleep problems were not found to be associated with being obese. The study found differential effects of infant sleep problems on childhood overweight in Grade 6 per different definitions of sleep problems. Findings highlight the need to construct a single definition of infant sleep problems.

The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.

The heparan sulfate 6-O-sulfotransferase 3 (HS6ST3) gene is involved in heparan sulphate and heparin metabolism, and has been reported to be associated with diabetic retinopathy in type 2 diabetes. We hypothesized that HS6ST3 gene polymorphisms might play an important role in obesity and related phenotypes (such as triglycerides). We examined genetic associations of 117 single-nucleotide polymorphisms (SNPs) within the HS6ST3 gene with obesity and triglycerides using two Caucasian samples: the Marshfield sample (1442 obesity cases and 2122 controls), and the Health aging and body composition (Health ABC) sample (305 cases and 1336 controls). Logistic regression analysis of obesity as a binary trait and linear regression analysis of triglycerides as a continuous trait, adjusted for age and sex, were performed using PLINK. Single marker analysis showed that six SNPs in the Marshfield sample and one SNP in the Health ABC sample were associated with obesity (P < 0.05). SNP rs535812 revealed a stronger association with obesity in meta-analysis of these two samples (P = 0.0105). The T-A haplotype from rs878950 and rs9525149 revealed significant association with obesity in the Marshfield sample (P = 0.012). Moreover, nine SNPs showed associations with triglycerides in the Marshfield sample (P < 0.05) and the best signal was rs1927796 (P = 0.00858). In addition, rs7331762 showed a strong gene × gender interaction (P = 0.00956) for obesity while rs1927796 showed a strong gene × gender interaction (P = 0.000625) for triglycerides in the Marshfield sample. These findings contribute new insights into the pathogenesis of obesity and triglycerides and demonstrate the importance of gender differences in the aetiology.