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Aim: To determine if a defined set of echocardiographic parameters at entry and exit of a longitudinal study over 5 years showed changes with aging. Methods: The cohort consisted of 484 randomly recruited women aged 40-80. They were examined by two echocardiography cardiologists, independent of the medical information for these women. Results: Across the age decades (40-49, 50-59, 60-69, 70-79 years), body weight and body surface area (BSA) did not vary, and diastolic blood pressure (DBP) was stable; systolic blood pressure (SBP) progressively increased. There was gradual decline in left ventricular (LV) diastolic function, increase in LV muscle mass, and decrease in LV end-diastolic volume (LVEDV). The serial decrease in rate of change over 5 years in ejection fraction (ET) was small but significant across the four age decades. Conclusions: As expected, there were age-related changes in cardiac structure and function over time in women who showed no apparent cardiovascular disease (CVD) at entry to the study. The direction of these serial changes was toward the development of LV stiffness and likelihood of subsequent heart failure. The clinical significance of the decrease in rate of change in EF remains unclear. [ABSTRACT FROM AUTHOR]

Background: Medical treatment of the rare interstitial ectopic pregnancy with methotrexate has been considered an alternative to surgical resection. Aim: To determine the treatment success rate with a single-dose intravenous methotrexate/folinic acid regimen and to identify predictors of treatment outcome. Methods: A 5-year audit (April 2000-August 2005) was carried out, collecting clinical imaging data and serum beta-human chorionic gonadotrophin (beta-hCG). Time taken for complete beta-hCG resolution was recorded, and a negative beta-hCG result was used as an endpoint of successful outcome. Results: Of the 13 cases, two required urgent surgery for rupture on presentation. In the remaining 11 cases, intravenous methotrexate (300 mg) was used, with oral folinic acid rescue (15 mg x 4 doses). There were no side-effects. Complete beta-hCG resolution was achieved in 10 of the 11 medically treated cases (91% success rate), requiring 21-129 days. Successful outcome was seen with initial beta-hCG level as high as 106 634 IU/L and gestation sac as large as 6 cm and a live fetus. Conclusion: The methotrexate/folinic acid regimen used as a one-dose treatment is safe and effective for unruptured interstitial pregnancy, with no side-effects and the advantage of avoiding invasive surgery. Subsequent tubal patency and reproductive function are yet to be ascertained. [ABSTRACT FROM AUTHOR]

RATIONALE: The majority of previous studies investigating asthma genetics have focused on cohorts with stable disease and have not defined mechanisms important during acute asthma. CD14 and CC16 each play a key role in biologically important inflammatory pathways and the gene of each has a functional promoter-region polymorphism. OBJECTIVES: This study was designed to determine the influence of these polymorphisms on plasma levels of their products and clinical disease during acute asthma. We hypothesized that genotype-related differences in CD14 and CC16 production would be more marked during acute asthma and related to disease severity. METHODS: We studied 148 children on presentation with acute asthma and again in convalescence. CD14 C-159T and CC16 A38G genotypes were determined, and plasma levels of soluble CD14 (sCD14) and CC16 were measured at both times. MEASUREMENTS AND MAIN RESULTS: During acute asthma, plasma sCD14 levels were higher for the whole group (p = 0.003), but increases were only in subjects with CD14 -159TT (p = 0.003) and -159CT (p = 0.004), and not in those with -159CC. Plasma CC16 levels were also elevated acutely for the whole group (p = 0.013), but only in those with CC16 38GG (p = 0.043) and 38AG (p = 0.014), and not in those with CC16 38AA. Subjects with CD14 -159CC and CC16 38AA were more likely to have moderate or severe acute asthma. CONCLUSIONS: Plasma levels of sCD14 and CC16 were higher during acute asthma in the subjects. Those with CD14 -159CC and CC16 38AA had no change in sCD14 and CC16 levels and more severe asthma. [ABSTRACT FROM AUTHOR]

AIM: To study the biocompatibility of surgical meshes for use in pelvic reconstructive surgery using an animal model. METHODS: Eight different types of mesh: Atrium, Dexon, Gynemesh, IVS tape, Prolene, SPARC tape, TVT tape and Vypro II, were implanted into the abdominal walls of rats for 3 months' duration. Explanted meshes were assessed, using light microscopy, for parameters of rejection and incorporation. RESULTS: Type 1 (Atrium, Gynemesh, Prolene, SPARC and TVT) and type 3 (Vypro II, Dexon and IVS) meshes demonstrated different biocompatible properties. Inflammatory cellular response and fibrosis at the interface of mesh and host tissue was most marked with Vypro II and IVS. All type 1 meshes displayed similar cellular responses despite markedly different mesh architecture. CONCLUSIONS: The inflammatory response and fibrous reaction in the non-absorbable type 3 meshes tested (IVS and Vypro II) was more marked than the type 1 meshes. The increased inflammatory and fibrotic response may be because of the multifilamentous polypropylene components of these meshes. Material and filament composition of mesh is the main factor in determining cellular response. [ABSTRACT FROM AUTHOR]

Background: Impaired interferon response and allergic sensitization may contribute to virus-induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity as critical producers of type I interferons. pDCs also express the high-affinity IgE receptor through which type I interferon production may be negatively regulated. Whether antiviral function of pDCs is associated with recurrent episodes of wheeze in young children is not well understood., Objective: We sought to evaluate the phenotype and function of circulating pDCs in children with a longitudinally defined wheezing phenotype., Methods: We performed multiparameter flow cytometry on PBMCs from 38 children presenting to the emergency department with an acute episode of respiratory wheeze and 19 controls. RNA sequencing on isolated pDCs from the same individuals was also performed. For each subject, their longitudinal exacerbation phenotype was determined using the Western Australia public hospital database., Results: We observed a significant depletion of circulating pDCs in young children with a persistent phenotype of wheeze. The same individuals also displayed upregulation of the FcεRI on their pDCs. Based on transcriptomic analysis, pDCs from these individuals did not mount a robust systemic antiviral response as observed in children who displayed a nonrecurrent wheezing phenotype., Conclusions: Our data suggest that circulating pDC phenotype and function are altered in young children with a persistent longitudinal exacerbation phenotype. Expression of high-affinity IgE receptor is increased and their function as major interferon producers is impaired during acute exacerbations of wheeze., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The menopausal transition is widely believed to increase the risk of cardiovascular disease, based on the notion that estrogen is cardioprotective in women. While aortic stiffness is an independent predictor of cardiovascular disease, it has been unclear whether this risk increases during menopause., Objective: This study aimed to determine the association between changes in menopausal status and aortic stiffness., Main Outcome Measures: Menopausal status was classified using the Stages of Reproductive Aging in Women criteria in a stratified random sample of Australian women aged 40-80 years, at three time-points over 14 years (n = 469 in 2001-02 and 2005, and n = 323 in 2014). Aortic stiffness was measured non-invasively via carotid-femoral pulse wave velocity at each time point. Mixed modeling was employed to determine the independent associations between menopausal status and aortic stiffness accounting for multiple covariates including age, systolic blood pressure, heart rate, medications, cholesterol, waist circumference, smoking and diabetes status., Results: There was no evidence to support an association between the menopausal transition and an acceleration of aortic stiffness. However, there was an acceleration of aortic stiffness in the late (8+ years) postmenopause phase, after accounting for age and traditional cardiovascular risk factors (0.122 [95%CI: 0.106, 0.139] m/s/year; p < 0.001)., Conclusions: The menopausal transition is not associated with major changes in aortic stiffness beyond normal age-related effects. However, the clinically significant acceleration in aortic stiffness observed in late postmenopause may contribute to greater cardiovascular risk in this later life phase. Study registered in the Australian and New Zealand Clinical Trials Registry, reference ACTRN12618000005257., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Post-traumatic stress disorder (PTSD) is associated with osteopenia, osteoporosis and increased fracture risk in the clinical population. Yet, the development of preclinical models to study PTSD-induced bone loss remains limited. In this study, we present a previously unreported model of PTSD in adult female C57BL/6 mice, by employing inescapable foot shock and social isolation, that demonstrates high face and construct validity. A subset of mice exposed to this paradigm (i.e. PTSD mice) display long-term alterations in behavioral and inflammatory indices. Using three-dimensional morphometric calculations, cyclic reference point indentation (cRPI) testing and histological analyses, we find that PTSD mice exhibit loss of trabecular bone, altered bone material quality, and aberrant changes in bone tissue architecture and cellular activity. This adult murine model of PTSD exhibits clinically relevant changes in bone physiology and provides a valuable tool for investigating the cellular and molecular mechanisms underlying PTSD-induced bone loss., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Objective: To determine whether changes in fat and lean mass over time, quantified using dual-energy x-ray absorptiometry (DXA), are related to incident cardiovascular events. Previous studies using surrogate anthropometric methods have had inconsistent findings., Study Design: Prospective, longitudinal observational study of women aged 40 to 80 randomly selected from the electoral roll and stratified into decades: 40-49, 50-59, 60-69 and 70-79 years., Main Outcome Measures: Changes in anthropometric measurements (body mass index and waist-to-hip ratio) and DXA-quantified fat mass and lean mass between the first and fifth years of the study. Incident cardiovascular events recorded from the sixth to the 12th year., Results: In total 449 participants (87.9 %) were analyzed. A 10 % or greater decrease in total fat mass index was associated with a 67 % lower likelihood of any cardiovascular event (OR = 0.33, 95%CI 0.15-0.71); no association was observed for an increase. A 10 % or greater decrease in abdominal fat mass index was associated with a 62 % lower likelihood of incident stroke (OR = 0.38, 95%CI 0.16-0.91); no association was observed for an increase. A 10 % or greater decrease in appendicular lean mass index resulted in increased odds ratio of 2.91 for incident peripheral artery events (OR = 2.91, 95%CI 1.18-7.20)., Conclusions: Reducing fat mass for women in midlife and beyond may decrease the risk of cardiovascular events. An increase in fat mass may not contribute to additional cardiovascular events. A reduction in limb muscle mass may provide an independent marker for cardiometabolic risk and peripheral artery disease. No independent association was found using anthropometric measurements and incident cardiovascular events., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS., (© 2023. The Author(s).)

Background: Malaria is a deadly disease caused by Plasmodium spp. Several blood phenotypes have been associated with malarial resistance, which suggests a genetic component to immune protection., Methods: One hundred and eighty-seven single nucleotide polymorphisms (SNPs) in 37 candidate genes were genotyped and investigated for associations with clinical malaria in a longitudinal cohort of 349 infants from Manhiça, Mozambique, in a randomized controlled clinical trial (RCT) (AgeMal, NCT00231452). Malaria candidate genes were selected according to involvement in known malarial haemoglobinopathies, immune, and pathogenesis pathways., Results: Statistically significant evidence was found for the association of TLR4 and related genes with the incidence of clinical malaria (p = 0.0005). These additional genes include ABO, CAT, CD14, CD36, CR1, G6PD, GCLM, HP, IFNG, IFNGR1, IL13, IL1A, IL1B, IL4R, IL4, IL6, IL13, MBL, MNSOD, and TLR2. Of specific interest, the previously identified TLR4 SNP rs4986790 and the novel finding of TRL4 SNP rs5030719 were associated with primary cases of clinical malaria., Conclusions: These findings highlight a potential central role of TLR4 in clinical malarial pathogenesis. This supports the current literature and suggests that further research into the role of TLR4, as well as associated genes, in clinical malaria may provide insight into treatment and drug development., (© 2023. The Author(s).)

Rpc31 is a subunit in the TFIIE-related Rpc82/34/31 heterotrimeric subcomplex of Saccharomyces cerevisiae RNA polymerase III (pol III). Structural analyses of pol III have indicated that the N-terminal region of Rpc31 anchors on Rpc82 and further interacts with the polymerase core and stalk subcomplex. However, structural and functional information for the C-terminal region of Rpc31 is sparse. We conducted a mutational analysis on Rpc31, which uncovered a functional peptide adjacent to the highly conserved Asp-Glu-rich acidic C-terminus. This C-terminal peptide region, termed 'pre-acidic', is important for optimal cell growth, tRNA synthesis, and stable association of Rpc31 in the pre-initiation complex (PIC). Our site-directed photo-cross-linking to map protein interactions within the PIC reveal that this pre-acidic region specifically targets Rpc34 during transcription initiation, but also interacts with the DNA entry surface in free pol III. Thus, we have uncovered a switchable Rpc31 C-terminal region that functions in an initiation-specific protein interaction for pol III transcription., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Src homology-2 domain-containing phosphatase 2 (SHP2) is a ubiquitously expressed phosphatase that is vital for skeletal development and maintenance of chondrocytes, osteoblasts, and osteoclasts. Study of SHP2 function in small animal models has led to insights in phenotypes observed in SHP2-mutant human disease, such as Noonan syndrome. In recent years, allosteric SHP2 inhibitors have been developed to specifically target the protein in neoplastic processes. These inhibitors are highly specific and have great potential for disease modulation in cancer and other pathologies, including bone disorders. In this review, we discuss the importance of SHP2 and related signaling pathways (e.g., Ras/MEK/ERK, JAK/STAT, PI3K/Akt) in skeletal development. We review rodent models of pathologic processes caused by germline mutations that activate SHP2 enzymatic activity, with a focus on the skeletal phenotype seen in these patients. Finally, we discuss SHP2 inhibitors in development and their potential for disease modulation in these genetic diseases, particularly as it relates to the skeleton., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Collagen degradation can lead to early postoperative weakness in colorectal anastomosis. Matrix metalloproteinase inhibitors (MMPIs) are shown to decrease collagen breakdown and enhance healing in anastomosis in animal models. Here, we evaluated the effectiveness of a novel anastomotic augmentation ring (AAR) that releases doxycycline, an MMPI, from a poly(lactic-co-glycolic) acid ring in porcine anastomoses., Methods: Two end-to-end stapled colorectal anastomoses were performed in 20 Yorkshire-Hampshire pigs. AAR was randomly incorporated into either the proximal or distal anastomosis as treatment, while nonaugmented anastomosis served as a control. Animals were then euthanized on days 3, 4, and 5 before anastomosis explantation and burst pressure measurement. Each anastomosis site was also collected for histology, hydroxyproline content, and gene expression microarray analyses., Results: No abscess or anastomotic leak was detected. Average burst pressures were not significantly different at any time point. There is no statistical difference in collagen content between the treatment group and controls. Gene expression analysis revealed no statistically significant in differentially expressed genes. However, genes related to inflammation, such as C-C motif chemokine ligand 11 (CCL11), CD70, and C-X-C motif chemokine ligand 10 (CXCL10), were upregulated (not statistically significant) in AAR compared to non-AAR anastomosis sites on days 3 and 4., Conclusions: This pilot study shows that doxycycline-release AAR is feasible and safe. While burst pressure and collagen content did not change significantly with doxycycline treatment, upregulating genes related to the inflammatory process for pathogen and debris clearance in AAR may improve the early stage of colorectal anastomotic healing., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The primary purpose of this study was to investigate the immediate and long-term effects of Nordic Walking (NW) exercise on walking function, motor/non-motor Parkinson's Disease (PD) symptoms, and serum brain-derived neurotrophic factor (BDNF) in persons with idiopathic PD., Methods: Twelve community-dwelling participants with mild to moderate idiopathic PD and varied degrees of gait dysfunction were recruited for this prospective, repeated measures design that examined clinical measures and BDNF levels at baseline (T0), post-intervention (T1) and 3-month follow-up (T2). Participants engaged in 6 weeks of supervised NW exercise training with individualized instruction, followed by 14 weeks of independent NW exercise with remote coaching. Outcome measurements included daily step counts, 6-Minute Walk Test (6-MinWT), 10-Meter Walk Test (10MWT), spatiotemporalparameters, Timed Up and Go Test (TUG), dual-task TUG, Revised-Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Revised-Freezing of Gait Questionnaire, MDS-Nonmotor Symptom scale (NMS), Parkinson's Fatigue Scale, and serum BDNF levels. The Friedman test with post hoc Wilcoxon sign-ranked pairwise comparisons were used to compare baseline to T1, baseline to T2, and T1 to T2 timepoints with a Benjamini-Hockberg correction applied., Results: Statistically significant improvements found post-training and retained at 3-month follow-up included 6-MinWT, daily step count, 10mWT, MDS-UPDRS, and TUG with effect sizes of 0.57 to 1.03. Serum BDNF at T2 was significantly greater than T0 and T1. Although no statistically significant improvements were observed in the MDS-NMS, 9 of 12 participants had improved non-motor symptoms. There was good adherence, sustained independent exercise engagement, and no adverse events over the 5-month study duration., Conclusions: This study demonstrated that NW exercise was a safe, feasible, and sustainable mode of aerobic exercise for this sample of participants with varied Parkinson's disease duration and severity. Following an individualized and progressive NW training intervention, significant improvements in walking function, daily activity level, and motor function were observed. Following the supervised NW training phase, independent three-month engagement in NW exercise was sustained with long-term retention of these clinical improvements and an increase in serum BDNF levels over this five-month NW exercise trial., Impact: Nordic walking exercise may be a safe, feasible and sustainable mode of independent exercise for improving daily ambulatory activity, gait and motor function, and serum BDNF in individuals with mild to moderate PD with varied gait abilities., Clinical Trials Registry Id: 20-101-H., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Harro, Shoemaker, Coatney, Lentine, Lieffers, Quigley, Rollins, Stewart, Hall and Khoo.)

Human rhinovirus (RV)-induced exacerbations of asthma and wheeze are a major cause of emergency room presentations and hospital admissions among children. Previous studies have shown that immune response patterns during these exacerbations are heterogeneous and are characterized by the presence or absence of robust interferon responses. Molecular phenotypes of asthma are usually identified by cluster analysis of gene expression levels. This approach however is limited, since genes do not exist in isolation, but rather work together in networks. Here, we employed personal network inference to characterize exacerbation response patterns and unveil molecular phenotypes based on variations in network structure. We found that personal gene network patterns were dominated by two major network structures, consisting of interferon-response versus FCER1G-associated networks. Cluster analysis of these structures divided children into subgroups, differing in the prevalence of atopy but not RV species. These network structures were also observed in an independent cohort of children with virus-induced asthma exacerbations sampled over a time course, where we showed that the FCER1G-associated networks were mainly observed at late time points (days four-six) during the acute illness. The ratio of interferon- and FCER1G-associated gene network responses was able to predict recurrence, with low interferon being associated with increased risk of readmission. These findings demonstrate the applicability of personal network inference for biomarker discovery and therapeutic target identification in the context of acute asthma which focuses on variations in network structure.

Background: Acute wheezing is one of the most common hospital presentations for young children. Respiratory syncytial virus (RSV) and rhinovirus (RV) species A, B and the more recently described species C are implicated in the majority of these presentations. However, the relative importance and age-specificities of these viruses have not been defined. Hence, this study aimed to establish these relationships in a large cohort of prospectively recruited hospitalized children., Methods: The study cohort was 390 children 0-16 years of age presenting with acute wheezing to a children's emergency department, 96.4% being admitted. A nonwheezing control population of 190 was also recruited. Nasal samples were analyzed for viruses., Results: For the first 6 months of life, RSV was the dominant virus associated with wheezing (P < 0.001). From 6 months to 2 years, RSV, RV-A and RV-C were all common but none predominated. From 2 to 6 years, RV-C was the dominant virus detected (50-60% of cases), 2-3 times more common than RV-A and RSV, RSV decreasing to be absent from 4 to 7 years. RV-B was rare at all ages. RV-C was no longer dominant in children more than 10 years of age. Overall, RV-C was associated with lower mean oxygen saturation than any other virus (P < 0.001). Controls had no clear age distribution of viruses., Conclusion: This study establishes a clear profile of age specificity of virus infections causing moderate to severe wheezing in children: RSV as the dominant cause in the first 6 months and RV-C in preschool-age children., Competing Interests: Supported by an NHMRC program grant (#458513), NHMRC project grant (#1045760), the West Australian Institute of Medical Research and the Asthma Foundation of Western Australia (AFWA). Fellowship support was also provided for S.W.C.O. (Telethon Research Fellowship and Princess Margaret Hospital Foundation Clinical Fellowship), I.A.L. (Australian Respiratory Council Ann Woolcock Research Fellowship) and J.A.B. (Thoracic Society of Australia and New Zealand/AstraZeneca Respiratory Research Fellowship and AFWA). The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Altered host immune responses are considered to play a key role in the pathogenesis of acute lower respiratory infections (ALRI). The existing literature on cytokine responses in ALRI is largely focussed on adults from developed countries and there are few reports describing the role of cytokines in childhood ALRI, particularly in African or human immunodeficiency virus (HIV)-infected populations. To measure systemic cytokine levels in blood plasma from young South African children with and without ALRI and with and without HIV to determine associations between cytokine responses and disease status and respiratory viral identification. Blood plasma samples were collected from 106 hospitalized ALRI cases and 54 non-ALRI controls less than 2 years of age. HIV status was determined. Blood plasma concentrations of 19 cytokines, 7 chemokines, and 4 growth factors (epidermal growth factor, fibroblast growth factor-basic, hepatocyte growth factor, and vascular endothelial) were measured using The Human Cytokine 30-Plex Panel. Common respiratory viruses were identified by PCR. Mean cytokine concentrations for G-CSF, interferon (IFN)-γ, interleukin (IL)-5, and MCP-1 were significantly higher in ALRI cases than in nonrespiratory controls. Within the ALRI cases, several cytokines were higher in children with a virus compared with children without a virus. Mean cytokine concentrations for IFN-α, IFN-γ, IL-4, IL-5, IL-13, tumour necrosis factor-α, and MIP-1α were significantly lower in HIV-infected cases than in HIV-uninfected cases, while IP-10 and monokine induced by interferon-γ were significantly higher in HIV-infected cases than in HIV-uninfected cases. Certain cytokines are likely to play an important role in the host immune response to ALRI. HIV-infected children have impaired inflammatory responses to respiratory infections compared with HIV-uninfected children., (© 2020 Wiley Periodicals LLC.)

Background: Accurate obesity classification is important so that appropriate intervention can be instituted to modify metabolic risk factors. Commonly utilized body mass index (BMI) and percentage body fat (PBF) are influenced by lean mass whereas fat mass index (FMI) measures only body fat. This study compares the prevalence of obesity and metabolic risk factors with FMI, BMI and PBF using DXA (dual-energy x-ray absorptiometry)., Methods: 489 women randomly recruited from the electoral roll were stratified into 4 age groups; 40-49, 50-59, 60-69 and 70-79 years from 2000 to 2001. Clinical data and DXA body composition were obtained. Statistical analyses were performed using Medcalc v15 (Ostend, Belgium) with significance level at p = 0.05 (two-tailed)., Results: There was higher prevalence of obesity using PBF compared to BMI and FMI (p<0.001). This difference was greater from age 50-59 (p<0.05) which may be explained by age-related lean mass loss. PBF over-classified obesity in over 35% of normal and 95% of overweight categories compared to FMI and BMI. BMI has a sensitivity of 78.9% and specificity of 98.3% for obesity using FMI as the standard. BMI under-classified obesity in the overweight category by 14.9% compared to FMI. There was no difference in diabetes, dyslipidemia, hypertension and metabolic syndrome prevalence within the BMI-obesity and FMI-obesity categories (p>0.05)., Conclusion: PBF classified more obesity than BMI and FMI because of its low pre-determined threshold. The greater difference with PBF compared to BMI and FMI from the 50-59 decade onwards can be attributed to age-related lean mass loss. BMI had the lowest sensitivity for obesity diagnosis. BMI under-classified obesity in the overweight category compared to FMI due to its inability to differentiate lean mass. However, there was no significant difference in the prevalence of metabolic risk factors between BMI and FMI-obesity categories indicating that fat location may influence metabolic dysregulation., Competing Interests: The authors have declared that no competing interests exist.

Background: Tetraspanin CD82 is a tumor metastasis suppressor that is known to down regulate in various metastatic cancers. However, the exact mechanism by which CD82 prevents cancer metastasis is unclear. This study aims to identify genes that are regulated by CD82 in human prostate cell lines., Methods: We used whole human genome microarray to obtain gene expression profiles in a normal prostate epithelial cell line that expressed CD82 (PrEC-31) and a metastatic prostate cell line that does not express CD82 (PC3). Then, siRNA silencing was used to knock down CD82 expression in PrEC-31 while CD82 was re-expressed in PC3 to acquire differentially-expressed genes in the respective cell line., Results: Differentially-expressed genes with a P < 0.05 were identified in 3 data sets: PrEC-31 (+CD82) vs PrEC-31(-CD82), PC3-57 (+CD82) vs. PC3-5 V (-CD82), and PC3-29 (+CD82) vs. PC3-5 V (-CD82). Top 25 gene lists did not show overlap within the data sets, except (CALB1) the calcium binding protein calbindin 1 which was significantly up-regulated (2.8 log fold change) in PrEC-31 and PC3-29 cells that expressed CD82. Other most significantly up-regulated genes included serine peptidase inhibitor kazal type 1 (SPINK1) and polypeptide N-acetyl galactosaminyl transferase 14 (GALNT14) and most down-regulated genes included C-X-C motif chemokine ligand 14 (CXCL14), urotensin 2 (UTS2D), and fibroblast growth factor 13 (FGF13). Pathways related with cell proliferation and angiogenesis, migration and invasion, cell death, cell cycle, signal transduction, and metabolism were highly enriched in cells that lack CD82 expression. Expression of two mutually inclusive genes in top 100 gene lists of all data sets, runt-related transcription factor (RUNX3) and trefoil factor 3 (TFF3), could be validated with qRT-PCR., Conclusion: Identification of genes and pathways regulated by CD82 in this study may provide additional insights into the role that CD82 plays in prostate tumor progression and metastasis, as well as identify potential targets for therapeutic intervention.

Purpose From an anthropological perspective of hominin communication, the human auditory system likely evolved to enable special sensitivity to sounds produced by the vocal tracts of human conspecifics whether attended or passively heard. While numerous electrophysiological studies have used stereotypical human-produced verbal (speech voice and singing voice) and nonverbal vocalizations to identify human voice-sensitive responses, controversy remains as to when (and where) processing of acoustic signal attributes characteristic of "human voiceness" per se initiate in the brain. Method To explore this, we used animal vocalizations and human-mimicked versions of those calls ("mimic voice") to examine late auditory evoked potential responses in humans. Results Here, we revealed an N1b component (96-120 ms poststimulus) during a nonattending listening condition showing significantly greater magnitude in response to mimics, beginning as early as primary auditory cortices, preceding the time window reported in previous studies that revealed species-specific vocalization processing initiating in the range of 147-219 ms. During a sound discrimination task, a P600 (500-700 ms poststimulus) component showed specificity for accurate discrimination of human mimic voice. Distinct acoustic signal attributes and features of the stimuli were used in a classifier model, which could distinguish most human from animal voice comparably to behavioral data-though none of these single features could adequately distinguish human voiceness. Conclusions These results provide novel ideas for algorithms used in neuromimetic hearing aids, as well as direct electrophysiological support for a neurocognitive model of natural sound processing that informs both neurodevelopmental and anthropological models regarding the establishment of auditory communication systems in humans. Supplemental Material https://doi.org/10.23641/asha.12903839.

Objective: Most studies of the age-related changes in body composition are cross-sectional in design: there have been few longitudinal studies. The aim of this 5-year study was to document body composition changes in perimenopausal and older women., Study Design: Prospective, longitudinal observational study., Methods: 489 women were randomly selected from the electoral roll and stratified into 4 age groups by decade: 40-49, 50-59, 60-69 and 70-79 years. Dual-energy x-ray absorptiometry (DXA) was performed in the first and fifth years of the study. Total body mass (TBM), total fat mass (TFM), total lean mass (TLM), abdominopelvic fat mass, and appendicular fat and lean mass were determined., Results: There were significant increases in TBM (p < 0.001), TFM (p < 0.01), TLM (p < 0.05), arm fat mass (p < 0.05), leg fat mass (p < 0.001) and leg lean mass (p < 0.05) within the 40-49 age decade. TBM, TFM and abdominopelvic fat started to decline from the 50-59 decade. Abdominopelvic fat reduction was significant from the 50-59 decade to the later decades (p = 0.05 to p < 0.001). Arm lean mass showed a significant reduction from the 50-59 decade (p < 0.01). Leg lean mass declined from the 60-69 decade, reaching significance in the 70-79 decade (p = 0.05)., Conclusion: TFM and abdominopelvic fat declined from the 50-59 age decade, which is earlier than is suggested in the literature. Conversely, the decline in appendicular lean mass with age occurred later, from the 50-59 decade, with earlier and greater loss in the arms, which has implications for exercise strategies to maintain muscle mass from midlife on., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute viral wheeze in children is a major cause of hospitalisation and a major risk factor for the development of asthma. However, the role of the respiratory tract microbiome in the development of acute wheeze is unclear. To investigate whether severe wheezing episodes in children are associated with bacterial dysbiosis in the respiratory tract, oropharyngeal swabs were collected from 109 children with acute wheezing attending the only tertiary paediatric hospital in Perth, Australia. The bacterial community from these samples was explored using next generation sequencing and compared to samples from 75 non-wheezing controls. No significant difference in bacterial diversity was observed between samples from those with wheeze and healthy controls. Within the wheezing group, attendance at kindergarten or preschool was however, associated with increased bacterial diversity. Rhinovirus (RV) infection did not have a significant effect on bacterial community composition. A significant difference in bacterial richness was observed between children with RV-A and RV-C infection, however this is likely due to the differences in age group between the patient cohorts. The bacterial community within the oropharynx was found to be diverse and heterogeneous. Age and attendance at day care or kindergarten were important factors in driving bacterial diversity. However, wheeze and viral infection were not found to significantly relate to the bacterial community. Bacterial airway microbiome is highly variable in early life and its role in wheeze remains less clear than viral influences., Competing Interests: The authors have declared that no competing interests exist.

Background: The human body is a home to thousands of microbiotas. It is defined as a community of symbiotic, commensal and pathogenic microorganisms that have existed in all exposed sites of the body, which have co-evolved with diet, lifestyle, genetic factors and immune factors. Human microbiotas have been studied for years on their effects with relation to health and diseases., Methods: Relevant published studies, literature and reports were searched from accessible electronic databases and related institutional databases. We used keywords, viz; microbiome, microbiota, microbiome drug delivery and respiratory disease. Selected articles were carefully read through, clustered, segregated into subtopics and reviewed., Findings: The traditional belief of sterile lungs was challenged by the emergence of culture-independent molecular techniques and the recently introduced invasive broncho-alveolar lavage (BAL) sampling method. The constitution of a lung microbiome mainly depends on three main ecological factors, which include; firstly, the immigration of microbes into airways, secondly, the removal of microbes from airways and lastly, the regional growth conditions. In healthy conditions, the microbial communities that co-exist in our lungs can build significant pulmonary immunity and could act as a barrier against diseases, whereas, in an adverse way, microbiomes may interact with other pathogenic bacteriomes and viromes, acting as a cofactor in inflammation and host immune responses, which may lead to the progression of a disease. Thus, the use of microbiota as a target, and as a drug delivery system in the possible modification of a disease state, has started to gain massive attention in recent years. Microbiota, owing to its unique characteristics, could serve as a potential drug delivery system, that could be bioengineered to suit the interest. The engineered microbiome-derived therapeutics can be delivered through BC, bacteriophage, bacteria-derived lipid vesicles and microbe-derived extracellular vesicles. This review highlights the relationships between microbiota and different types of respiratory diseases, the importance of microbiota towards human health and diseases, including the role of novel microbiome drug delivery systems in targeting various respiratory diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Vascular dementia (VaD) is cognitive decline linked to reduced cerebral blood perfusion, yet there are few therapeutic options to protect cognitive function following cerebrovascular accidents. The purpose of this study was to profile gene expression changes unique to VaD to identify and characterize disease relevant changes that could offer clues for future therapeutic direction. Microarray-based profiling and validation studies of postmortem frontal cortex samples from VaD, Alzheimer disease, and age-matched control subjects revealed that the oxytocin receptor (OXTR) was strongly and differentially upregulated in VaD. Further characterization in fixed tissue from the same cases showed that OXTR upregulation occurs de novo around and within microinfarcts in peri-infarct reactive astrocytes as well as within vascular profiles, likely on microvascular endothelial cells. These results indicate that increased OXTR expression in peri-infarct regions may be a specific response to microvascular insults. Given the established OXTR signaling cascades that elicit antioxidant, anti-inflammatory, and pro-angiogenic responses, the present findings suggest that de novo OXTR expression in the peri-infarct space is a tissue-protective response by astroglial and vascular cells in the wake of ischemic damage that could be exploited as a therapeutic option for the preservation of cognition following cerebrovascular insults., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma., Competing Interests: Conflict of interest statement: F.S., Z.W., and Z.X. are employees and H.E.X. is a consultant of Palo Alto Pharmaceutics Inc.

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7 hi versus IRF7 lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ. The two phenotypes also produced distinct clinical phenotypes. For IRF7 lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms ( p = 0.011) and nearly three times as long for cough ( p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold ( p = 0.018), and time to recurrence was shorter ( p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7 hi versus IRF7 lo phenotypes with associated differences in clinical phenotypes., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Using a well-designed longitudinal cohort, we aimed to identify cytokines that were protective against malaria and to explore how they were influenced by genetic and immunological factors. 349 Mozambican pregnant women and their newborn babies were recruited and followed up for malaria outcomes until 24 months of age. Six Th1 cytokines in cord blood were screened for correlation with malaria incidence, of which IL-12 was selected for further analyses. We genotyped IL-12 polymorphisms in children/mothers and evaluated the genotype-phenotype associations and genetic effects on IL-12 levels. Maternal IL-12 concentrations were also investigated in relation to Plasmodium infections and cord blood IL-12 levels. Our data showed that high background IL-12 levels were prospectively associated with a low incidence of clinical malaria, while IL-12 production after parasite stimulation had the opposite effect on malaria incidence. IL-12 genotypes (IL-12b rs2288831/rs17860508) and the haplotype CGTTAGAG distribution were related to malaria susceptibility and background IL-12 levels. Maternal genotypes also exhibited an evident impact on host genotype-phenotype associations. Finally, a positive correlation in background IL-12 levels between maternal and cord blood was identified. Thus, cord blood background IL-12 concentrations are important for protecting children from clinical malaria, likely mediated by both genotypes (children&mothers) and maternal immunity.

Background: Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin-33 (IL-33) is a major contributor to type-2 inflammation in acute asthma. However, the link between IL-33 and type-2 inflammation has not been shown in naturally occurring asthma exacerbations., Objectives: To determine if airway IL-33 is associated with type-2 inflammation measured by type-2 cytokines, FeNO and sputum eosinophils in patients presenting to the Emergency Department with an asthma exacerbations., Methods: Adult patients hospitalized due to acute asthma were enrolled. Upper airways were sampled with nasal swabs and lower airways with induced sputum. Cytokines were measured at protein level using a Luminex ® assay and mRNA expression level using droplet-digital-PCR. Airway sampling was repeated four weeks after exacerbation., Results: At the time of exacerbation, upper airway IL-33 correlated with upper airway IL-5 and IL-13 (R = 0.84, p < 0.01 and R = 0.76, p < 0.01, respectively) and with lower airway IL-13 (R = 0.49, p = 0.03). Similar associations were observed for mRNA expression. Lower airway IL-33 positively correlated with lower airway IL-13 (R = 0.84, p < 0.01). IL-13 and IL-33 were positively correlated with FeNO, and IL-5 with eosinophils. The association between IL-33 and type-2 cytokines were still present four weeks after exacerbation., Conclusion: This is the first study to demonstrate that airway IL-33 is associated with type-2 cytokines in naturally occurring asthma exacerbations in adults, providing in vivo evidence supporting that IL-33 may be driving type-2 inflammation in acute asthma. Thus supporting IL-33 as a potential future drug target due to its role, upstream in the immunological cascade., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

To assess if the difference in species-specific immune response to RV-C correlates with a higher frequency of reinfection, shorter time to reinfection, or different symptom severity than infections with RV-A or RV-B. Forty-three patients were enrolled of which 34 were successfully tracked longitudinally over 3 months, with nasal swabs and symptom questionnaires provided every 2 weeks to identify rhinovirus (RV) strains and the concurrent symptomatology. No difference was found in the time to reinfection with an RV species between RV-C and RV-A or RV-B (p = 0.866). There was a trend toward more rapid reinfection with the same species in RV-C than RV-A (55.1 days vs. 67.9 days), but this failed to reach statistical significance (p = 0.105). RV infections were generally associated with only minor symptoms, with rhinorrhea being the only significantly associated symptom (p = 0.01). RV-C was shown to have higher levels of lethargy and wheeze than other RV species. Time to reinfection with subsequent RV is not influenced by the species of the preceding RV.

Rpc82 is a TFIIE-related subunit of the eukaryotic RNA polymerase III (pol III) complex. Rpc82 contains four winged-helix (WH) domains and a C-terminal coiled-coil domain. Structural resolution of the pol III complex indicated that Rpc82 anchors on the clamp domain of the pol III cleft to interact with the duplex DNA downstream of the transcription bubble. However, whether Rpc82 interacts with a transcription factor is still not known. Here, we report that a structurally disordered insertion in the third WH domain of Rpc82 is important for cell growth and in vitro transcription activity. Site-specific photo-crosslinking analysis indicated that the WH3 insertion interacts with the TFIIB-related transcription factor Brf1 within the pre-initiation complex (PIC). Moreover, crosslinking and hydroxyl radical probing analyses revealed Rpc82 interactions with the upstream DNA and the protrusion and wall domains of the pol III cleft. Our genetic and biochemical analyses thus provide new molecular insights into the function of Rpc82 in pol III transcription.