Abstract
Primary aldosteronism is the most common cause of secondary hypertension. The first-line treatment adrenalectomy resects adrenal nodules and adjacent normal tissue, limiting suitability to ...those who present with unilateral disease. Use of thermal ablation represents an emerging approach as a possible minimally invasive therapy for unilateral and bilateral disease, to target and disrupt hypersecreting aldosterone-producing adenomas, while preserving adjacent normal adrenal cortex. To determine the extent of damage to adrenal cells upon exposure to hyperthermia, the steroidogenic adrenocortical cell lines H295R and HAC15 were treated with hyperthermia at temperatures between 37 and 50°C with the effects of hyperthermia on steroidogenesis evaluated following stimulation with forskolin and ANGII. Cell death, protein/mRNA expression of steroidogenic enzymes and damage markers (HSP70/90), and steroid secretion were analyzed immediately and 7 days after treatment. Following treatment with hyperthermia, 42°C and 45°C did not induce cell death and were deemed sublethal doses while ≥50°C caused excess cell death in adrenal cells. Sublethal hyperthermia (45°C) caused a significant reduction in cortisol secretion immediately following treatment while differentially affecting the expression of various steroidogenic enzymes, although recovery of steroidogenesis was evident 7 days after treatment. As such, sublethal hyperthermia, which occurs in the transitional zone during thermal ablation induces a short-lived, unsustained inhibition of cortisol steroidogenesis in adrenocortical cells in vitro.
Models of infectious disease are increasingly utilising empirical contact data to quantify the number of potentially infectious contacts between age groups. While a growing body of data is being ...collected on contact patterns across many populations, less attention has been paid to the social contacts of young infants. We collected information on the social contacts of primary carers of young infants and investigated their potential for use as a proxy for contacts made by their infant.
We recruited primary carers of infants under one year of age residing in two geographically, demographically and socioeconomically distinct local government areas of Melbourne, Australia - Boroondara and Hume - including a sub-group of Turkish-speaking participants. Participants recorded their own contacts in a paper diary and noted whether their infant was present or absent. Information collected included times at an address; description of location; and details on people contacted at the location. Descriptive summary measures and distributions of contacts by location type, intensity, day of contact and by age are reported.
Of the 226 participants recruited, 220 completed diaries were returned. Participant contact patterns were similar across all groups, with respect to the types of locations, intensity and day of contact, with some variation in the number of unique daily contacts. The infant was present at around 85% of locations at which the primary carer contacted other individuals. The majority of contacts occurring when the infant was present were in Own Home (32%), Retail and Hospitality (18%) and Transport (18%) settings. The mean daily number of unique contacts by infants was estimated as 9.1, 8.7 and 6.5 in Boroondara, Hume (English) and Hume (Turkish), respectively, with a similar age distribution across each of our surveyed groups.
Our demonstration that contact patterns of mothers with infants are reasonably robust to socioeconomic and cultural differences is a step forward in modelling infectious disease transmission. With infants spending most of their time in the company of their mother, contact patterns of mothers are a useful proxy measure of infant contact patterns. The age distribution of contacts made by infants estimated in this study may be used to supplement population-wide contact information commonly used in infectious disease transmission models.
Using baseline data of the Engage Cohort Study, a Canadian study of sexually active gay, bisexual and other men who have sex with men (GBM), we evaluated the association between sexual behavior and ...risk perception among HIV-negative participants and whether HIV treatment optimism moderated this relationship. Participants were recruited by respondent-driven-sampling (RDS). We defined high-risk sexual behavior in the past six months as any condomless anal sex with a casual partner (i.e. not the participant's main partner) with either unknown HIV-status where neither used pre-exposure prophylaxis or with a partner living with HIV having detectable/unknown viral load. We assessed HIV treatment optimism-skepticism using a 12-item scale. RDS-II-weighted adjusted logistic regression models examined associations with risk perception measured by the question "How would you assess your current risk of getting HIV?" (response options were on a 6-point Likert-scale ranging from "very unlikely" to "very likely", dichotomized into "No Perceived Risk" (very unlikely/unlikely) and "Perceived Risk" (somewhat likely/likely/very likely/I think I already have HIV). Of 1961 participants, engagement in high-risk sexual behavior was reported by 155 (17.0%), 62 (12.4%), 128 (17.2%) of participants in Montréal, Toronto, and Vancouver, respectively. High-risk sexual behavior increased the odds of perceived HIV risk (pooled adjusted odds ratio = 2.9, 95%CI = 2.2-3.8). HIV treatment optimism-skepticism scores moderated the relationship: for GBM engaging in high-risk sexual behavior, higher HIV treatment optimism-skepticism scores increased perceived HIV risk. Promoting awareness around advances related to HIV prevention and treatment is important for appropriate risk assessment and for increased engagement in prevention interventions.Using baseline data of the Engage Cohort Study, a Canadian study of sexually active gay, bisexual and other men who have sex with men (GBM), we evaluated the association between sexual behavior and risk perception among HIV-negative participants and whether HIV treatment optimism moderated this relationship. Participants were recruited by respondent-driven-sampling (RDS). We defined high-risk sexual behavior in the past six months as any condomless anal sex with a casual partner (i.e. not the participant's main partner) with either unknown HIV-status where neither used pre-exposure prophylaxis or with a partner living with HIV having detectable/unknown viral load. We assessed HIV treatment optimism-skepticism using a 12-item scale. RDS-II-weighted adjusted logistic regression models examined associations with risk perception measured by the question "How would you assess your current risk of getting HIV?" (response options were on a 6-point Likert-scale ranging from "very unlikely" to "very likely", dichotomized into "No Perceived Risk" (very unlikely/unlikely) and "Perceived Risk" (somewhat likely/likely/very likely/I think I already have HIV). Of 1961 participants, engagement in high-risk sexual behavior was reported by 155 (17.0%), 62 (12.4%), 128 (17.2%) of participants in Montréal, Toronto, and Vancouver, respectively. High-risk sexual behavior increased the odds of perceived HIV risk (pooled adjusted odds ratio = 2.9, 95%CI = 2.2-3.8). HIV treatment optimism-skepticism scores moderated the relationship: for GBM engaging in high-risk sexual behavior, higher HIV treatment optimism-skepticism scores increased perceived HIV risk. Promoting awareness around advances related to HIV prevention and treatment is important for appropriate risk assessment and for increased engagement in prevention interventions.
Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual‐energy X‐ray absorptiometry (DXA) analysis was performed in children with ...intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha‐1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height‐adjusted and weight‐adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height‐adjusted and weight‐adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
The objective of this study was to examine the effects of short-term exercise training, myostatin inhibition (PF-354), and exercise + PF-354, all relative to a vehicle control, on performance and ...metabolic measures in 24-month-old mice. At study termination, PF-354–treated mice exhibited significantly greater muscle weights. Performance measures revealed that exercise + PF-354 increased treadmill running time and distance to exhaustion (more than twofold) and increased habitual activity. Measures of strength were not different; however, all treatment groups demonstrated more than 30% reductions in muscle fatigue. Metabolic measures showed that basal metabolic rates were higher in PF-354– and exercise + PF-354–treated mice, and exercise and exercise + PF-354 groups exhibited significantly greater insulin sensitivity. PF-354 was associated with decreased Smad3 phosphorylation and increased peroxisome proliferator-activated receptor gamma coactivator-1α expression and, similar to exercise, decreased MuRF-1. The data suggest that the combination of exercise training and myostatin blockade may significantly improve physical function and whole-body metabolism in older individuals.
ABSTRACT
Objectives:
To advance our understanding of monogenic forms of intrahepatic cholestasis.
Methods:
Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate ...(ATP)‐binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)‐binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.
Results:
Ninety‐eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations severe and 10 with p.E297G or p.D482G mild), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty‐five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.
Conclusions:
In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype–phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.
Mathematical models of infection that consider targeted interventions are exquisitely dependent on the assumed mixing patterns of the population. We report on a pilot study designed to assess three ...different methods (one retrospective, two prospective) for obtaining contact data relevant to the determination of these mixing patterns.
65 adults were asked to record their social encounters in each location visited during 6 study days using a novel method whereby a change in physical location of the study participant triggered data entry. Using a cross-over design, all participants recorded encounters on 3 days in a paper diary and 3 days using an electronic recording device (PDA). Participants were randomised to first prospective recording method.
Both methods captured more contacts than a pre-study questionnaire, but ascertainment using the paper diary was superior to the PDA (mean difference: 4.52 (95% CI 0.28, 8.77). Paper diaries were found more acceptable to the participants compared with the PDA. Statistical analysis confirms that our results are broadly consistent with those reported from large-scale European based surveys. An association between household size (trend 0.14, 95% CI (0.06, 0.22), P < 0.001) and composition (presence of child 0.37, 95% CI (0.17, 0.56), P < 0.001) and the total number of reported contacts was observed, highlighting the importance of sampling study populations based on household characteristics as well as age. New contacts were still being recorded on the third study day, but compliance had declined, indicating that the optimal number of sample days represents a trade-off between completeness and quality of data for an individual.
The study's location-based reporting design allows greater scope compared to other methods for examining differences in the characteristics of encounters over a range of environments. Improved parameterisation of dynamic transmission models gained from work of this type will aid in the development of more robust decision support tools to assist health policy makers and planners.
Two chromomycin SA analogs, chromomycin SA3 and chromomycin SA2, along with deacetylchromomycin A3 and five previously reported chromomycin analogs were isolated from a marine-derived Streptomyces ...sp. The structures of the new compounds were determined by spectroscopic methods including 1D and 2D NMR techniques, HRMS and chemical methods. Chromomycin SA3 and chromomycin SA2 are the first naturally occuring chromomycin analogs with truncated side-chains. Biological evaluation of chromomycin analogs for cytotoxicity against two non-small cell lung cancer (NSCLC) cell-lines, A549 and HCC44, demonstrated a decrease in cytotoxicity for the truncated sides chain chromomycin analogs.
As a periodic assessment of the mammal collection resource, the Systematic Collections Committee (SCC) of the American Society of Mammalogists undertakes decadal surveys of the collections held in ...the Western Hemisphere. The SCC surveyed 429 collections and compiled a directory of 395 active collections containing 5,275,155 catalogued specimens. Over the past decade, 43 collections have been lost or transferred and 38 new or unsurveyed collections were added. Growth in number of total specimens, expansion of genomic resource collections, and substantial gains in digitization and web accessibility were documented, as well as slight shifts in proportional representation of taxonomic groups owing to increasingly balanced geographic representation of collections relative to previous surveys. While we find the overall health of Western Hemisphere collections to be adequate in some areas, gaps in spatial and temporal coverage and clear threats to long-term growth and vitality of these resources have also been identified. Major expansion of the collective mammal collection resource along with a recommitment to appropriate levels of funding will be required to meet the challenges ahead for mammalogists and other users, and to ensure samples are broad and varied enough that unanticipated future needs can be powerfully addressed.
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