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Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Multimorbidity is a public health concern and an essential component of aging and healthspan but understudied because investigative tools are lacking that can be translatable to capture similarities and differences of the aging process across species and variability between individuals and individual organs. To help address this need, body organ disease number (BODN) borrowed from human studies was applied to C57BL/6 (B6) and CB6F1 mouse strains at 8, 16, 24 and 32 months of age, as a measure of systems morbidity based on pathology lesions to develop a mouse PathoClock resembling clinically based Body Clock in humans, using Bayesian inference. A mouse PhysioClock was also developed based on measures of physiological domains including cardiovascular, neuromuscular, and cognitive function in the same two mouse strains so that alignment with BODN was predictable. The results revealed between- and within-age variabilities in PathoClock and PhysioClock, as well as between-strain variabilities. Both PathoClock and PhysioClock correlated with chronological age more strongly in CB6F1 than C57BL/6. Prediction models were then developed, designated as PathoAge and PhysioAge, using regression models of pathology and physiology measures on chronological age. PathoAge better predicted chronological age than PhysioAge as the predicted chronological and observed chronological age for PhysioAge were complex rather than linear. In conclusion, PathoClock and PhathoAge can be used to capture biological changes that predict BODN, a metric developed in human, and compare multimorbidity across species. These mouse clocks are potential translational tools that could be used in aging intervention studies.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

An understanding of early-onset mechanisms underlying age-related changes can be obtained by evaluating changes that precede frailty and end of life using histological characterization of age-related lesions. Histopathology-based information as a component of aging studies in mice can complement and add context to molecular, cellular, and physiologic data, but there is a lack of information regarding scoring criteria and lesion grading guidelines. This report describes the validation of a grading system, designated as the geropathology grading platform (GGP), which generated a composite lesion score (CLS) for comparison of histological lesion scores in tissues from aging mice. To assess reproducibility of the scoring system, multiple veterinary pathologists independently scored the same slides from the heart, lung, liver, and kidney from two different strains (C57BL/6 and CB6F1) of male mice at 8, 16, 24, and 32 months of age. There was moderate to high agreement between pathologists, particularly when agreement within a 1-point range was considered. CLS for all organs was significantly higher in older versus younger mice, suggesting that the GGP was reliable for detecting age-related pathology in mice. The overall results suggest that the GGP guidelines reliably distinguish between younger and older mice and may therefore be accurate in distinguishing between experimental groups of mice with more, or less, age-related pathology.

With aging, most older adults are at risk of having more than two diseases, conventionally defined as multimorbidity. We determined body organ disease number (BODN) as a new multimorbidity index. We measured the degree to which each disease level, from mild to severe, predicts longitudinal BODN uncoupled from chronological age. We determined Body Clock using global disease levels burden from all systems predicting longitudinal BODN for each individual, which is a proxy of the personalized rate of biological aging. Change in Body Clock predicts late-life age-related outcomes and can be used for geriatric clinics and clinical trials for precision medicine.

Background Atmospheric particulate matter (PM) has been associated with endothelial dysfunction, an early marker of cardiovascular risk. Our aim was to extend this research to a genetically homogenous, geographically stable rural population using location-specific moving-average air pollution exposure estimates indexed to the date of endothelial function measurement. Methods We measured endothelial function using brachial artery flow-mediated dilation (FMD) in 615 community-dwelling healthy Amish participants. Exposures to PM

Within the past several decades, the emergence of new viral diseases with more severe health complications and mortality, primarily in older adults with comorbidities, is evidence of an age-dependent, compromised bodily response to abrupt stress with concomitant reduced immunity. The emergence of new infectious coronaviruses such as SARS-CoV-2 has resulted in the coronavirus disease 2019 (COVID-19). The result is increased morbidity and mortality in persons with underlying chronic diseases and among those with compromised defense mechanisms, regardless of age and among older adults who are more likely to fit these categories. COVID-19 appears to be primarily an upper respiratory disease. While SARS-CoV-2 is highly virulent, there is variability in the severity of the disease and its complications in humans. Severe pneumonia, acute respiratory distress syndrome (ARDS), lung fibrosis, cardiac t complication, acute kidney injury, hospitalization, and high mortality have been reported in older adults with COVID-19, that result from pathogen-host interactions. Here, we review potential interactions of the coronavirus and host cellular responses in relation to hallmarks of aging including genomic instability, telomere attrition, impaired autophagy, mitochondrial dysfunction, innate immunosenescence, inflammation and inflammasomes, adaptive immunosenescence, and epigenetic alterations, that likely contribute to the increased pathophysiological responses to SARS-CoV-2 among older adults.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Although inflammation is known to influence bone turnover and bone mineral density (BMD), less is known about role of soluble tumor necrosis factor alpha receptor 1 (sTNFα-R1) in changes in bone turnover and BMD in the year after hip fracture. We studied 245 persons (117 men and 128 women) from the Baltimore Hip Studies. Bone turnover markers of resorption (carboxy-terminal type I collagen cross-links [CTX-I]) and formation (amino-terminal propeptide type I collagen [P1NP]), BMD of the contralateral hip, and sTNFα-R1 were measured within 15 days of hospitalization and 2, 6, and 12 months later. Latent class growth modeling was used to determine sTNFα-R1 trajectories. Weighted generalized estimating equations were used to examine the association of sTNFα-R1 trajectories with serum levels of CTX-I and P1NP and BMD; standardized beta coefficients (βˆ) are reported. Higher baseline sTNFα-R1 was significantly associated with a greater rate of CTX-I change (βˆ = 0.26, p = 0.004). Four distinct sTNFα-R1 trajectories were identified. The two groups with higher sTNFα-R1 levels during the year following fracture had faster increasing levels of CTX-I compared to the group with lowest sTNFα-R1 levels (men: group 3: βˆ = 0.76, p = 0.02; group 4: βˆ = 1.4, p

Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury.

Objectives To examine the hypothesis that the inflammatory state of aging is a risk factor for accelerated renal function (RF) decline using inflammatory biomarkers and RF measures collected over 9 years of follow‐up in relatively healthy individuals enrolled in the Invecchiare in Chianti study. Design Longitudinal. Setting Community. Participants Individuals aged 60 and older with baseline estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 and greater and no diabetes mellitus (DM) (N = 687). Measures eGFR, as a proxy for RF, was determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation at baseline and 3‐, 6‐, and 9‐year follow‐up. Incident chronic kidney disease (CKD) was defined as new‐onset eGFR less than 60 mL/min per 1.73 m2 at each follow‐up. Predictors included baseline and time‐dependent inflammatory biomarkers: soluble tumor necrosis factor alpha receptors (sTNFα‐R1 and ‐R2), interleukin (IL)‐6, IL‐18, IL‐1β, IL‐1 receptor antagonist, and high‐sensitivity C‐reactive protein. Results Higher baseline sTNFα‐R1 was significantly associated with lower eGFR over 9 years, independent of DM or blood pressure (baseline: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0001 = −0.39, P = .001; 3‐year: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0002 = −0.26, P = .001; 6‐year: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0003 = −0.36, P = .001; 9‐year: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0004 = −0.47, P = .001). The rate of TNFα‐R1 change was significantly associated with rate of eGFR change (urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0005 = −0.18, P = .001). Baseline sTNFα‐R1 predicted incident CKD (per 1‐standard deviation increment: 3‐year: relative risk (RR) = 1.3, 95% confidence interval (CI) = 1.1–1.5; 6‐year: RR = 1.5, 95% CI = 1.1–2.2; 9‐year RR = 1.6, 95% CI = 1.1–2.2). Similar results were found for sTNFα‐R2. Conclusion Baseline TNFα‐R levels and their rates of change were significantly associated with RF decline and incident CKD in older adults independent of DM or blood pressure.

A geropathology grading platform (GGP) for assessing age-related lesions has been established and validated for in inbred strain of mice. Because nonhuman primates (NHPs) share significant similarities in aging and spontaneous chronic diseases with humans, they provide excellent translational value for correlating histopathology with biological and pathological events associated with increasing age. Descriptive age-associated pathology has been described for rhesus macaques and marmosets, but a grading platform similar to the mouse GGP does not exist. The value of these NHP models is enhanced by considerable historical data from clinical, bio-behavioral, and social domains that align with health span in these animals. Successful adaptation of the mouse GGP for NHPs will include 1) expanding the range of organs examined; 2) standardizing necropsy collection, tissue trimming, and descriptive lesion terminology; 3) expanding beyond rhesus macaques and marmosets to include other commonly used NHPs in research; and 4) creating a national resource for age-related pathology to complement the extensive in-life datasets. Adaptation of the GGP to include translational models other than mice will be crucial to advance geropathology designed to enhance aging research.

Additional file 1 : Table S1. Polynomial distributed lag (PDL) model posterior probabilities obtained from Bayesian model averaging (BMA) for zero-order through 5th order models using 12 lag periods, for PM2.5 and PM10. Table S2. Associations of PM2.5 and PM10 exposure metrics and FMD stratified by age (less than 50 years vs. 50 years and older) and sex for increases in normalized PM2.5 and PM10 exposure in fully adjusted models. Table S3. Associations of PM2.5 and PM10 exposure metrics and FMD across all participants and by sex for a 10 μg m− 3 increment in PM2.5 and PM10 exposure in fully adjusted models. Figure S1. Effect estimates from the six PDL models (zero-order through 5th order) weighted using BMA as discussed in main text, for: A) PM2.5 and B) PM10. The month prior to FMD measurement (lag zero) and 11 months prior are shown, as well as the cumulative effect over all 12 lag periods.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine., Finding a reference metric for the rate of biological aging is key to understanding the molecular nature of the aging process. Defining and validating this metric in humans opens the door to a new kind of medicine that will overcome the limitation of current disease definitions. We will then be able to approach health in a global perspective and bring life course preventative measures to the center of attention.

BackgroundGenetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.MethodsWe combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.FindingsWhen testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P=6.1×10-11; METTL8, rs116951054, MAF 0.09%, P=4.5×10-9; and MATK, rs539182790, MAF 0.05%, P=3.4×10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P=1.2×10-9, nearest gene GATM, and rs71147340, MAF=0.34, P=3.3×10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.InterpretationThis study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

Although the incidence and prevalence of multimorbidity(MM) have surged, there is no consensus on an optimal tool to measure MM as a risk factor for functional decline or as an outcome. Most of the available tools have been developed based on medical reports, hospital administrative records or self-reports. In this study, we assessed a novel tool developed from repeated measures of clinical data collected in the Baltimore Longitudinal Study of Aging. In 900 participants, aged 50–100 years with an average follow-up of 4.5 years, we assessed organ-specific medical examinations and medication use to develop a rigorous index that captures time-dependent accumulative MM effects on accelerated aging. A weighted index using longitudinal data provides a time-dependent weighted association, a novel multi-dimensional index that significantly predicts accelerated age-related adverse outcomes.

E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine whole genome sequencing data in 2249 African Americans (AAs) from the Jackson Heart Study, we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in Fucosyltransferase 6 (FUT6; rs17855739,p.Glu274Lys, P = 9.02 × 10(−24)) with higher soluble E-selectin levels. This variant is considerably more common in populations of African ancestry compared to non-African ancestry populations. We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women’s Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an electronic medical record-based phenome-wide association scan of over 9000 AAs.

Wnt1-inducible signaling pathway protein-1 (WISP1) is a novel target of the Wnt pathway for modulating osteogenesis and improving bone strength. However, it is not clear if genetic variants in the WISP1 region are associated with bone mineral density (BMD) in human. The aim of this study is to investigate the role of genetic variation in WISP1 gene as a determinant of BMD in 1,510 Old Order Amish (OOA). We performed regional association analysis of 58 tag variants within 5 kb upstream and downstream to WISP1 with BMD and found 5 variants that were associated with BMD at multiple skeletal sites (P values from 2.89 × 10−6 to 1.62 × 10−2), with some significant associations even after adjustment for multiple comparisons. To replicate these results in an independent dataset, we performed a look-up of BMD associations with these variants in European ancestry subjects from the large GEFOS Consortium and observed the nominal associations of two of these variants with BMD (P values: 0.031 to 0.048). In conclusion, we have demonstrated that genetic variants surrounding WISP1 are associated with BMD at multiple skeletal sites in the OOA, thus influencing osteoporosis risk. These results support a role for the WISP1 gene on influencing variation in BMD.

AEOL 10150 is a catalytic metalloporphyrin superoxide dismutase mimic being developed as a medical countermeasure for radiation-induced lung injury (RILI). The efficacy of AEOL 10150 against RILI through a reduction of oxidative stress, hypoxia and pro-apoptotic signals has been previously reported. The goal of this study was to determine the most effective dose of AEOL 10150 (daily subcutaneous injections, day 1–28) in improving 180-day survival in CBA/J mice after whole-thorax lung irradiation (WTLI) to a dose of 14.6 Gy. Functional and histopathological assessments were performed as secondary end points. Estimated 180-day survival improved from 10% in WTLI alone to 40% with WTLI-AEOL 10150 at 25 mg/kg (P = 0.065) and to 30% at 40 mg/kg (P = 0.023). No significant improvement was seen at doses of 5 and 10 mg/kg or at doses between 25 and 40 mg/kg. AEOL 10150 treatment at 25 mg/kg lowered the respiratory function parameter of enhanced pause (Penh) significantly, especially at week 16 and 18 (P = 0.044 and P = 0.025, respectively) compared to vehicle and other doses. Pulmonary edema/congestion were also significantly reduced at the time of necropsy among mice treated with 25 and 40 mg/kg AEOL 10150 compared to WTLI alone (P < 0.02). In conclusion, treatment with AEOL 10150 at a dose of 25 mg/kg/day for a total of 28 days starting 24 h after WTLI in CBA/J mice was found to be the optimal dose with improvement in survival and lung function. Future studies will be required to determine the optimal duration and therapeutic window for drug delivery at this dose.

Although inflammation is known to influence bone turnover and bone mineral density (BMD), less is known about role of soluble tumor necrosis factor alpha receptor 1 (sTNFα-R1) in changes in bone turnover and BMD in the year after hip fracture. We studied 245 persons (117 men and 128 women) from the Baltimore Hip Studies. Bone turnover markers of resorption (carboxy-terminal type I collagen cross-links [CTX-I]) and formation (amino-terminal propeptide type I collagen [P1NP]), BMD of the contralateral hip, and sTNFα-R1 were measured within 15 days of hospitalization and 2, 6, and 12 months later. Latent class growth modeling was used to determine sTNFα-R1 trajectories. Weighted generalized estimating equations were used to examine the association of sTNFα-R1 trajectories with serum levels of CTX-I and P1NP and BMD; standardized beta coefficients (βˆ) are reported. Higher baseline sTNFα-R1 was significantly associated with a greater rate of CTX-I change (βˆ = 0.26, p = 0.004). Four distinct sTNFα-R1 trajectories were identified. The two groups with higher sTNFα-R1 levels during the year following fracture had faster increasing levels of CTX-I compared to the group with lowest sTNFα-R1 levels (men: group 3: βˆ = 0.76, p = 0.02; group 4: βˆ = 1.4, p 0.001; women: group 3; βˆ = 0.67, p = 0.02; group 4: βˆ = 1.3, p = 0.004). Men in the highest sTNFα-R1 group had a greater decline in BMD compared to the lowest sTNFα-R1 group (2-month βˆ = -0.01, p = 0.01; 6-month: βˆ = -0.09, p = 0.001; 12-months: βˆ = -0.1, p 0.001). An increasing rate of CTX-I was associated with a steeper decline in total hip BMD in those within higher sTNFα-R1 trajectory groups (p 0.001). CTX-I was significantly increased with sTNFα-R1 in both sexes. CTX-I and the highest sTNFα-R1 trajectory were significantly associated with declines in total hip BMD in men. Interventions that reduce systemic inflammation should be explored to reduce bone resorption and prevent a decline in BMD after hip fracture. © 2018 American Society for Bone and Mineral Research.

ObjectiveWe sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.MethodsWe performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.ResultsWe detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10−8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10−8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10−4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10−3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10−6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease– (UNC5D) and Parkinson disease–associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.ConclusionsWhole genome sequence–wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

The recovery after traumatic brain injury (TBI) is hampered by the poor regenerative capacity of the brain. Today there is no treatment available that effectively restores lost brain tissue, but much research is focused on the stimulation of endogenous neural stem cells to viably and functionally repopulate the injured parenchyma. It is crucial that the therapies have a proven long-term effect on both regeneration and functional recovery to be clinically interesting. Here we have studied the induction of stem cell activation in rats at three weeks and six weeks after inducing TBI using controlled cortical impact model at a severe setting. We combined intracerebroventricular growth factor and scaffold treatment in order to accomplish an optimal effect on the stem cell regeneration. Immediately after TBI epidermal growth factor infusion with osmotic minipumps was started and continued for seven days. The pumps were removed and an extracellular matrix scaffold containing vascular endothelial growth factor was deposited into the cortical cavity. Three weeks after injury there was a positive effect of the treatment with a significant increase in neuronal and astrocytic regeneration. However, after six weeks there was no difference in the number of newly generated neurons and astrocytes in treated or untreated rats. Evaluation of tissue loss and spatial learning in the Morris water maze corroborated that the treatment had no effect at the later time point. Our results highlight the importance of long-term studies to ensure that a promising effect on tissue regeneration and functional outcome is not only temporary.

It is likely that the dimension and the scope of stress perception are different in different body systems conditioning their specific rates of aging. Moreover, in addition to between-individual variabilities in body response to stress, there is inter-organs variability in adaptations resulting in pleiotropy of phenotypes evolved with aging. Epigenetic measures may be considered possible readouts of the extent and proxy of the adaptive response to intrinsic and/or extrinsic stress in body organs. It is thus important to disentangle the epigenetic basis of stress, adaptation, and pathology. In this symposium we discuss a combination of the specific DNA methylation patterns relate to the diseases as an intrinsic stressor and adaptation responses imposed to bodily systems, and also accelerated body organ morbidities. We explain the static and dynamic DNA methylation differentiation over time as the “epigenetic code” of accelerated pathology across various age using longitudinal data.

Any stimulus that endangers body integrity (stressor) results in an adaptive response to resolve stressful state and determine adaptive or and maladaptive responses. Both chronic extrinsic and intrinsic stressors can produce long-lasting, epigenetic changes in various organs that can eventually result in accelerated changes in bio-physio-pathology. There is initial evidence that stress response involves mechanisms of the epigenetic basis of adaptation and stress response to biological aging and chronic diseases. With aging, homeostasis stability declines causing augmented vulnerability to the external and internal stress. Individuals in whom vulnerability trespass a certain threshold experience accelerated aging and deterioration of health and/ or “secondary aging” phenomena such as premature mortality. Because of substantial heterogeneity of the rate of decline in homeostatic stability, there is inter-individual variability in the age of appearance of chronic diseases and the increased risk of disability and mortality. Thus, tools for the quantification of a stress response would be clinically valuable. Therefore, this symposium suggests approaches to study the epigenetic basis of molecular adaptations across various age, organs’ health-span, and life-span.

The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of P

Background Platelet activation can lead to enhanced oxidative stress, inflammatory response, and endothelial dysfunction. To quantify the effects of platelet inhibition on endothelial function, we assessed platelet activity of healthy persons before and after clopidogrel administration and evaluated its effects on endothelial function. We hypothesized that clopidogrel, by attenuating platelet activity, would result in enhanced endothelial function. Methods and Results Microcirculatory endothelial function was quantified by laser Doppler flowmetry ( LDF ) mediated by thermal hyperemia ( TH ) and postocclusive reactive hyperemia, respectively, in 287 and 241 relatively healthy and homogenous Old Order Amish persons. LDF and platelet aggregation measures were obtained at baseline and after 7 days of clopidogrel administration. Our primary outcome was percentage change in post‐ versus preclopidogrel LDF measures. Preclopidogrel TH ‐ LDF and platelet aggregation were higher in women than in men ( P TH ‐ LDF in participants with high versus low baseline platelet aggregation (39.4±10.1% versus 17.4±5.6%, P =0.03). Clopidogrel also increased absolute TH ‐ LDF measures in persons with high platelet aggregation (1757±766 to 2154±1055, P =0.03), with a more prominent effect in women (1909±846 to 2518±1048, P =0.001). There was no evidence that clopidogrel influenced postocclusive reactive hyperemia LDF measures. Conclusions The administration of clopidogrel in healthy persons with high baseline platelet aggregation results in improved TH ‐induced microcirculatory endothelial function. These data suggest that clopidogrel may have a beneficial effect on microcirculatory endothelial function, presumably through antiplatelet activity, and may confer additional vascular benefits. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00799396.

In the west, men are twice as likely as women to develop a drug problem, but female users have higher rates of morbidity than male users. Iran has the world highest per capita opiate consumption, but little is known about female drug users. In 2007, we established a free methadone clinic with ancillary services for female drug users in South Tehran. The aim was to explore the characteristics of female drug users seeking treatment for heroin dependence in Iran. Clients were interviewed about demographic characteristics, drug use and treatment history, and drug-related health problems. Urine and blood samples were collected and tested for morphine, HIV, hepatitis C virus (HCV), and sexually transmitted infections (STIs).Between August 2007 and October 2008, 78 women completed a baseline interview. The median age was 37 years, the main ethnic background was Persian (65%), and half of the clients were married. Opium and heroin and opium use was reported by 69% (n=54) and 87% (n=68) of clients, respectively. The mean duration of heroin use problems was 10.5 years, and only 20% of women reported ever having received drug treatment. HIV and HCV seroprevalence was 5% and 24%, respectively. Forty percent were sexually active when interviewed, and one third tested positive for an STI. Women had poor social functioning, high levels of depression, and poor general health.Our clients were dependent users with a multitude of problems who had little or no contact with treatment agencies before this study. Many clients had made a transition from using opium to using heroin, and some had commenced injecting, placing them at risk for HIV and HCV infection. More women-only drug treatment services are needed to facilitate women's entry into drug treatment.

In Iran women are less likely than men to use drugs, but suffer greater morbidity, are stigmatised, and are less likely to seek treatment. In 2007, we established a clinic in Tehran for drug using women. We report here on our study of the 97 women who registered in the first year of operation. We profiled these women: demographics, drug use, risk behaviour, and use of services. The clinic's services were heavily used. We interviewed clients and staff about the clinic and learned that intensive help is needed for women trying to recover from years of drug use. We conclude that female drug users will make use of harm reduction services if they are provided in a setting designed and operated for women.

The ability to categorize has been known as one of the most important cognitive abilities in human beings. When it comes to the topic of categorization type, it seems different people select differently. Some of them categorize on the basis of similarity judgment and some based on the uni-dimensional rule. The present study attempts to evaluate the tendency toward a specific type of categorization as can be observed in a voluntary group of medical students in Iran. Most of the studies in categorization have been conducted in Western world and some of Eastern-Asian people. To the best of our knowledge, this is the first study which has been done in categorization in Iran. The results suggest that Iranians, like Eastern-Asian people, tend to categorize mostly based on similarity. There was not any relationship between the IQ scores of the participants and the type of categorization. We also examined the implications of the words “similarity” and “belonging to” as translated into Persian.

Purpose: To evaluate the effect of topical antiglaucoma medications on the lacrimal drainage system. Methods: In a prospective controlled blind observational case series, 627 eyes of 384 patients (219 males, 165 females) were screened. Data recording (demographics and history taking), allocation in case (on topical antiglaucoma medications) and control (no glaucoma) groups, and examinations (eye examination and dye disappearance test) were performed by a senior ophthalmology resident. Exclusion criteria were epiphora prior to onset of treatment with topical antiglaucoma medication (only for case group), history of long-term use of topical medications (other than antiglaucoma medications in the case group), and previous ocular and periocular disorders. Diagnostic probing and irrigation of the lacrimal drainage system were performed by an oculoplastic surgeon masked to a patient’s status as case or control. Results: After exclusion, there were 130 eyes from 98 patients and 280 eyes from 178 patients in the case and control groups, respectively. Case and control groups were matched. There was significantly more lacrimal drainage system obstruction in the case group (26 of 130, 20%) than in the control group (24 of 280, 8.57%) (p = 0.002). Upper lacrimal drainage system obstruction was significantly more in the case group (p = 0.018). Increasing age was associated with significantly more obstruction in the control group only (p = 0.029). Statistically significant obstruction was found in the patients taking timolol + dorzolamide (p = 0.021) and timolol + dorzolamide + pilocarpine (p = 0.017) with a duration of 2 weeks to 156 months. Conclusion: Patients taking a combination of topical antiglaucoma medications showed significantly increased risk of developing lacrimal drainage system obstruction. Both total and upper obstruction was significantly more frequent in patients on topical antiglaucoma medications.

In order to fabricate efficient pH optical sensors, the characteristic features of the UV–vis spectra of six synthesized hydroxyazobenzene dyes were studied at different pH(s). Two optical pH sensors were developed using 4-[(p-nitrophenyl)azo]phenol and 2-methoxy-4-[(4-nitrophenyl)azo]phenol dyes immobilized on transparent triacetylcellulose (TAC) membrane, which showed reversible responses within the dynamic ranges of 8.5–10.5 and 6.5–8.5, respectively. A new optical pH sensor with a linear response over a range of 4.5 pH units (7–11.5) was also developed by immobilization of a mixture of the aforementioned dyes on a TAC membrane. All the fabricated optodes showed fast response time (less than 20 s), sharp and clear color change as well as excellent long-term stability (at least 3 months) under the applied conditions.

Objective: To determine the impact of sumatriptan prophylaxis on acute mountain sickness (AMS) and altitude headache development within 24 hours of ascent, we designed a double-blind, randomized, clinical trial. Methods: A prospective, double-blind, randomized, placebo-controlled trial was conducted in Tochal Mountain Hotel at an altitude of 3,500 meters above sea level during October 2006 to November 2006. A total of 102 Iranian adults were assigned to receive either sumatriptan succinate (50mg) or placebo within 1 hour of ascent. AMS incidence was measured by Lake Louise AMS score 3 with headache and one other symptom. Secondary outcome measures included severity of syndrome (Lake Louise scores 5), incidence of headache, and severity of headache. Results: Based on intention-to-treat analysis, AMS was more prevalent in placebo group (n 23 [45.1%]) than sumatriptan group (n 12 [23.5%]; p 0.02). Headache also had a greater rate for placebo users (placebo vs sumatriptan group: 29 [56.9%] vs 17 [33.3%]; p 0.02). No association was detected between sumatriptan prophylaxis and AMS or altitude headache severity. Discussion: Sumatriptan prophylaxis is effective to prevent AMS development. Furthermore, our findings confirm cerebral vasodilative and edematous mechanisms of AMS progression, whereas sumatriptan is a selective 5-hydroxytryptamine1 receptor subtype agonist and a selective cerebral vasoconstrictor as a result (http://www.controlled-trials.com/ISRCTN87201238/). Ann Neurol 2007;62:273–277

Background Impairment in glomerular endothelial function likely plays a major role in the development of albuminuria and CKD progression. Glomerular endothelial dysfunction may reflect systemic microvascular dysfunction, accounting in part for the greater cardiovascular risk in patients with albuminuria. Prior studies of vascular function in CKD have focused on conduit artery function or those with ESRD, and have not examined microvascular endothelial function with albuminuria. Methods We conducted a cross-sectional study among older hypertensive male veterans with stage 1–4 CKD, and hypertensive controls without CKD. Microvascular function was quantified by two distinct Laser-Doppler flowmetry (LDF) measures: peak responses to 1) post-occlusive reactive hyperemia (PORH) and 2) thermal hyperemia (TH), measured on forearm skin. Associations of each LDF measure with albuminuria, eGFR, and CKD status were estimated using correlation coefficients and multiple linear regression, accounting for potential confounders. Results Among 66 participants (mean age 69.2 years), 36 had CKD (mean eGFR 46.1 cc/min/1.73 m2; 30.6 % with overt albuminuria). LDF responses to PORH and TH were 43 and 39 % significantly lower in multivariate analyses among those with macroalbuminuria compared to normoalbuminuria, (β= − 0.42, p = 0.009 and β= −0.37, p = 0.01, respectively). Those with CKD had a 23.9 % lower response to PORH compared to controls (p = 0.02 after adjustment). In contrast, TH responses did not differ between those with and without CKD. Conclusions Microvascular endothelial function was strongly associated with greater albuminuria and CKD, independent of diabetes and blood pressure. These findings may explain in part the excess systemic cardiovascular risk associated with albuminuria and CKD.

To determine the association of intimate partner violence with maternal cigarette smoking before and during pregnancy.Data were obtained for 196,391 U.S. mothers who delivered live neonates from 2004-2008 and completed the Pregnancy Risk Assessment Monitoring System survey 2-9 months postpartum. Intimate partner violence was defined as being physically hurt by a current or expartner in the year before or during pregnancy. Weighted descriptive and multivariate analyses were performed.Compared with nonphysically abused women, those who experienced physical abuse were 2.1 times more likely to smoke before pregnancy (44.0% compared with 21.0%, P.001) and 2.6 times more likely to smoke during pregnancy (29.6% compared with 11.4%, P.001). Smoking prevalence during pregnancy was highest for abused women who were non-Hispanic white (42.3% smoked) and lowest for nonabused college graduates (2.2% smoked). Smoking rates more than tripled for college graduates in abusive relationships (2.2% compared with 7.1%). After adjusting for potential confounding factors, abused women were significantly more likely to smoke during pregnancy than nonabused women (adjusted odds ratio 1.95, P.001, 95% confidence interval 1.80-2.12).Women who experienced intimate partner violence had significantly higher rates of smoking before pregnancy and were less likely to quit during pregnancy than women who did not experience intimate partner violence. The American College of Obstetricians and Gynecologists and the U.S. Public Services Task Force recommend routine intimate partner violence screening with appropriate interventions to prevent violence against women, optimize safety, and improve health. Additional and targeted intimate partner violence assessment of women who smoke during pregnancy may prove especially beneficial.

A simple and rapid microwave-assisted extraction (MAE) procedure was developed and optimized for two common color pigments, alizarin and purpurin, in various samples of Rubiaceae plants. Several variables that can potentially affect the extraction efficiency, namely temperature, methanol concentration in the extractant mixture, time, and solvent volume were optimized by means of a central composite design approach. The results suggest that temperature and methanol concentration in the solvent mixture are statistically the most significant factors. The separation and quantitative determination of the pigments was carried out in less than 6 min by a developed high-performance liquid chromatographic method with UV detection at 250 nm. Under optimum operating conditions, MAE showed significantly higher recoveries than those obtained by the conventional extraction methods (ultrasonic and reflux extraction), ranging from 84 to 94%. In addition, a drastic reduction of the extraction time (20 min versus 6 h) and solvent consumption (20 versus 100 mL) was achieved with a reproducibility (RSDs < 10%) comparable with that provided by the reflux extraction as a reference method.

Hexadecylpyridinium bromide (HDPB) was used as an excellent carrier for the uphill transport of palladium(II) as PdBr42− complex anion through a chloroform bulk liquid membrane. The transport efficiency of palladium(II) by HDPB was investigated under various experimental conditions such as pH and concentration of NaBr in source phase, concentration of surfactant (HDPB) in membrane, HBr and thiourea (as stripping agent) concentration in receiving phase and equilibrium time. In the optimum conditions, transport efficiency of palladium(II) for the ten replicate measurements after 110 min was 97.9±1.1%. The selectivity of palladium(II) transport from aqueous solutions containing Sr2+, Ca2+, Ba2+, Co2+, Ni2+, Zn2+, Cu2+, Cd2+, Mn2+ and Hg2+ ions was investigated and found that none of cations used, interfere the palladium(II) transport (at Mn+/Pd2+ mole ratio of 10).The proposed method has been applied to separation of palladium in Silicon–Alumina catalysts. The transport efficiency after 120 min was 98%.

This study examines the relationship between postpartum depression (PPD) and cigarette smoking from prior to pregnancy to postpartum.The study sample consisted of 29,654 U.S. women who reported smoking in the 3months prior to pregnancy and for whom data on PPD were available from the Pregnancy Risk Assessment Monitoring System (PRAMS). Two sets of analyses were conducted. The first compared smoking at 2 time points (prior to pregnancy and postpartum) and the second at 3 time points (prior to pregnancy, during pregnancy, and postpartum). PPD was defined as responses of "often" or "always" to 2 questions: "Since your baby was born, how often have you felt down, depressed, or sad?" and "Since your new baby was born, how often have you had little interest or little pleasure in doing things?"Overall, 22% of the sample endorsed PPD symptoms. In the 2 time-point analysis, controlling for known confounders, participants whose smoking was reduced or unchanged postpartum were about 30% more likely to have PPD compared to those who quit (OR: 1.34; 95% CI=1.10-1.60, p=0.001; OR:1.32; 95% CI: 1.10-1.50, p0.001 respectively). Participants who increased smoking postpartum were 80% more likely to have PPD compared those who quit (OR: 1.80; 95% CI: 1.50-2.30, p0.001). In the 3 time-point analysis, participants who continued smoking at any level during pregnancy and postpartum had 1.48 times the odds of reporting PPD (95% CI: 1.26, 1.73) compared to those who quit during pregnancy and remained quit postpartum. Participants who quit during pregnancy but resumed postpartum had 1.28 times the odds of reporting PPD (95% CI: 1.06, 1.53) compared to those who quit during pregnancy and remained quit postpartum.Results suggest an association among women who smoke cigarettes prior to pregnancy between PPD and continued smoking during pregnancy and postpartum.

Primary adrenal lymphoma is extremely rare. We report a case with primary bilateral adrenal lym-phoma in a young male patient. He presented with abdominal pain and weight loss. Pathologic study revealed malignant lymphoma, diffuse large cell type (T- cell origin). Patient recieved combination chemotherapy and radiation therapy but 22 months after diagnosis died because of progression of dis¬ease

Background: Leukocytosis is a powerful predictor of incident chronic kidney disease (CKD) and related outcomes. However, the association between periodontitis measures and increased leukocytosis in the context of CKD has not been well described. We sought to identify which individual measures of periodontal disease may best associate with reduced estimated glomerular filtration rate (eGFR) and albuminuria, and to test if these measures were associated with increased leukocytosis in subjects with established CKD. Methods: We estimated, among 13,270 participants in the National Health and Nutrition Examination Survey III study, the associations between case-based definition of periodontitis, clinical attachment loss (CAL) and pocket depth (PD) as individual measures of periodontal disease, with renal function measures and leukocytosis. Results: In adjusted multivariate analyses, case-based definition of severe periodontitis was associated with albuminuria (β = 0.003, p = 0.01) but not with eGFR. However, CAL and PD were all individually associated with both albuminuria (β = 0.08, p < 0.001 and β = 0.06, p < 0.001, respectively) and eGFR (β = -0.05, p < 0.001 and β = -0.03, p < 0.001, respectively). We found significant associations between elevated CAL and PD with leukocytosis. Lastly, we found a marked association between the joint presence of CKD and elevated CAL or PD with leukocytosis (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.4-7.5 and OR 3.2, 95% CI 1.1-9.7, respectively). Conclusion: Individual measures of periodontal disease are associated with renal function and heightened leukocytosis in CKD subjects. The significantly added inflammatory burden noted in CKD subjects with periodontal disease argue for targeting periodontitis treatment as part of our multifaceted approach to CKD patients.

Kate Dolan1, Shabnam Salimi2, Bijan Nassirimanesh3, Setareh Mohsenifar2, David Allsop1, Azarakhsh Mokri21Program of International Research and Training, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia; 2Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; 3Persepolis Centre, Tehran, IranBackground: In general, information about women who use drugs comes from studies performed in the West. Whether women in countries such as Iran are likely to enter drug treatment or how they will respond is not known.Purpose: To examine the short-term impact of methadone maintenance treatment (MMT) on drug use, dependence, social functioning, crime, and human immunodeficiency virus (HIV) and hepatitis C virus (HCV) risk behavior and seroincidence in female drug users in Iran.Methods: Women were eligible for inclusion in the study if they were assessed as dependent on opiates according to the International Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10). The sample comprised 78 female heroin or opium users who attended the Persepolis women's drug treatment clinic in Tehran between 2007 and 2008. Participants were followed up in 2009/2010. Heroin and the use of other drugs, social functioning, involvement in crime, and involvement in HIV and HCV risk behavior were measured by self-report. The prevalence and incidence of HIV and HCV were measured by serology and self-report.Findings: Of the 78 women recruited, 40 were followed up, and this occurred approximately 7 months later. One in four women reported a history of drug injection. At follow-up there were significant reductions in self-reported heroin use on ICD-10 dependence scores. Subjects with more severe drug dependence at baseline were significantly more likely to be criminally active than less severely dependent subjects. Baseline prevalence for HIV and HCV was 5% and 24%, respectively. At follow-up, no one had acquired HIV infection, but one participant had acquired HCV, giving an incidence rate of 7.1 per 100 person-years.Conclusion: This research provides the first evidence that Iranian female drug users can enter MMT and respond well. Within a few months of entering MMT, improvements occurred in heroin use, levels of dependence, social functioning, and HIV risk behavior. While the incidence of blood-borne viral infections was low, there was a serious risk of HIV transmission among this cohort and also to participants' needle and sexual contacts. In a country with high levels of drug use, the high levels of HCV among female drug users require more women to enter drug treatment if an HIV epidemic is to be avoided. Many participants had a chronic drug problem and had had little or no previous exposure to MMT. The introduction or expansion of women-only drug treatment services is urgently needed in order to engage more women in treatment.Keywords: women drug users, Iran, drug treatment clinic, risk behavior

A randomized, double-blind, placebo-controlled clinical trial was conducted among 44 subjects to assess the efficacy of EMLA cream application without occlusive dressing on pain on needling (PN) and pain on injection (PI) felt during multiple botulinum toxin type A (BTA) injections for correction of hyperkinetic upper facial lines. Mean PN score was less than PI score with high correlation and no significant difference. Although both PN and PI scores (visual analog) were less in the EMLA than placebo group, the difference was only statistically significant for PN score. Time intervals between the cream application and BTA injections beyond 60 minutes did not show lower pain score in either type of the pain.

Headache is the most prevalent symptom of acute mountain sickness. We conducted a pilot clinical trial at an altitude of 3500 m to evaluate the efficacy of gabapentin in treatment of high-altitude headache (HAH). Twenty-four adult HAH patients (10 female, 14 male; age 18–50 years) were randomly assigned to receive either 300 mg of gabapentin capsule or identical placebo. After 1 h the presence of HAH and need to receive supplementary analgesic were assessed. The duration of the HAH-free phase after taking additional analgesic was also registered. Four patients in the gabapentin group asked for additional analgesics, whereas nine placebo recipients did not find primary medication satisfactory after the first hour of treatment ( P = 0.04). The mean HAH-free period was 17.10 h in the gabapentin group, which was significantly higher than in the placebo group with a mean of 10.08 h ( P = 0.02). This preliminary observation indicates that gabapentin is effective in treatment and alleviation of HAH.

BACKGROUND Being overweight, a constituent of the metabolic syndrome, is also an important contributing factor to the development of coronary artery disease in younger patients, compared with the older patient population. Owing to the above-mentioned fact, we sought to assess the association of the metabolic syndrome with premature coronary artery disease. METHODS In an analytic cross-sectional study, 940 patients (553 women

A simple and rapid liquid-liquid extraction of palladium has been studied involving ion-pairing of bromocomplexes of palladium(II) with hexadecylpyridinium bromide (HDPB) dissolved in chloroform. The stoichiometry and distribution of (HDP)2PdBr4 between the aqueous and organic phase was investigated by spectrophotometric mole ratio method. The extraction efficiency of palladium(II) by HDPB was studied as a function of several variables: acid, salt, surfactant concentration and equilibrium time. The results showed that PdBr4(2-) extraction could be explained by assuming the formation of (HDP)2PdBr4 complexes in the aqueous solution and transfer to organic phase. The extraction was fast and the shaking time was only a few min. The average recovery of palladium(II) from an aqueous solution containing 10 microg/ml of analyte was 99% with an RSD% of 0.95. The percentage recovery of 0.2 microg/ml palladium(II) was 96%.

s / Drug and Alcohol Dependence 140 (2014) e169–e251 e193 Post-retrieval propranolol may alter reconsolidation of trauma memory in individuals with PTSD and comorbid alcohol dependence Michael E. Saladin1, K. Gray1, T. Abbott1, S. LaRowe1,2, Aimee McRae-Clark1, S. DeSantis1, N. Baker1, S. Back1, Karen Hartwell1,2, Kathleen T. Brady1,2 1 Medical University of South Carolina, Charleston, SC, United States 2 Ralph H. Johnson VAMC, Charleston, SC, United States Aims:We recently completed a laboratory studyof anovelmedication intervention that targeted attenuation of trauma related distress by altering trauma memory reconsolidation in individuals with PTSD and comorbid alcohol dependence (AD). The medication intervention consisted of the administration of the -blocking agent, propranolol, immediately following thepresentation trauma cues (the cues initiate the reconsolidation). A placebo control group was also employed. In a test session performed the next day, we examined subjective distress and alcohol craving to both trauma and alcohol cues. It was hypothesized that propranolol-treated PTSD+AD individuals would evidence lower distress and craving during the test session than placebo-treated individuals. Methods: PTSD+AD participants received either 40mg propranolol (n=21) or placebo (n=23) immediately after trauma cue exposure (description of participant’s worst trauma presented via headphones). After remaining overnight in an alcohol-free environment, participants received a ‘test’ session of cue exposure that was identical to the first session except (a) trauma cue exposure was followed by alcohol cue exposure, and (b) no medication was administered. Subjective distress and craving were measured (100 point scale) prior to, during, and following cue exposure in both sessions. Results: Compared to placebo-treated participants (M=56.0, se =3.7), propranolol-treated (M=42.8, se =4.0) participants evidenced significantly lower distress to the combined traumaalcohol cues presented during the test session (p= .03). The groups did not evidence any difference in craving. Conclusions: This study provides the first evidence that propranolol administration following trauma cue exposuremaymodulate traumamemories in PTSD+ADhumans. Implications for basic neuroscience and drug addiction treatment will be noted. Financial support: NIAAA grant 5RC1AA019019 (M. E. Saladin, PI), USPHS grant M01 RR01070 and NIH Grant Numbers UL1 RR029882 and UL1 TR000062. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.538 The relationship between postpartum depression and change in perinatal alcohol use: An analysis of prams data S. Salimi1, M. Chisolm2, D. Cheng3, M. Terplan4 1 Department of Medicine, University of Maryland, Baltimore, MD, United States 2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States 3 Bureau for Maternal and Child Health, Maryland Department of Health and Mental Hygiene, Baltimore, MD, United States 4 Obstetrics, Gynecology and Reproductive Sciences and Epidemiology and Public Health, University of Maryland, Baltimore, MD, United States Aims: Postpartum depression (PPD) is common andmore likely to affect women with drug and alcohol problems. Although most womenquit drinkingduringpregnancy, approximately 10%continues. This study investigated the relationship between postpartum depression and change in perinatal alcohol use. Methods: The study population was from the Pregnancy Risk Assessment Monitoring System, 2004–2008 births which is a population-based surveillance and collects data from postpartum women on health behaviors before, during, and shortly after pregnancy. Women who self-reported any alcohol use during the 3 months before pregnancywere included in analysis. Overall change in alcohol use (difference between self-reported use in 3 months before and last 3 months of pregnancy) was compared between those with and without PPD. Also, change in heavy (7 or more drinks/week) and binge drinking (5 or more drinks/sitting) by PPD status were examined. Bivariate analysis and logistic regression were performed using the weight functions. Results: The study sample consisted of 64,595women of whom 10% reported PPD. Most women (87%) quit drinking during pregnancy, although 1.4% and 0.4% reported binge and heavy drinking, respectively, in the last 3months of pregnancy. PPDwasmore common among women who continued drinking compared to who quit or reduced use (AOR 1.30 [95% CI: 1.07, 1.55]). Moreover, any binge drinking during pregnancy was associated with PPD (AOR 1.53 [95%CI: 1.06, 2.20]), whereas heavy drinking was not (AOR 0.90 [95% CI: 0.43, 1.88]). Conclusions: These findings suggest several associations between postpartum depression and change in perinatal alcohol use, highlighting the need for vigorous screening and treatment for both PPD and alcohol use in this population. Financial support: None. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.539 Preclinical investigation of the abused synthetic cannabinoid CP47,497 Kimberly L. Samano1, A. Poklis2, A.H. Lichtman1 1 Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States 2 Pathology, Virginia Commonwealth University, Richmond, VA, United States Aims: CP47,497 and other synthetic cannabinoid compounds were incipiently synthesized as research tools to investigate mechanismsbywhichmarijuanaaffects thebrainand for thedevelopment of potential therapeutic drugs. Over the past few years, these compoundshave resurfacedon thedesigner drugmarket. The

A bilateral simultaneous cataract surgery (BSCS) was performed on a 67-year-old man. The surgeon had not changed the surgical settings in between the two procedures for the two eyes. The patient developed fulminant bilateral endophthalmitis a day following the BSCS. Intravitreal culture grew Pseudomonas aeruginosa . The source of infection was not found. Immediate bilateral vitrectomy and intravitreal, subconjunctival, topical and systemic antibiotic did not save the eyes. Patient ended up with bilateral visual loss.