Gene expression and matrix turnover in overused and damaged tendons

Chronic, painful conditions affecting tendons, frequently known as tendinopathy, are very common types of sporting injury. The tendon extracellular matrix is substantially altered in tendinopathy, and these changes are thought to precede and underlie the clinical condition. The tendon cell response to repeated minor injuries or “overuse” is thought to be a major factor in the development of tendinopathy. Changes in matrix turnover may also be effected by the cellular response to physical load, altering the balance of matrix turnover and changing the structure and composition of the tendon. Matrix turnover is relatively high in tendons exposed to high mechanical demands, such as the supraspinatus and Achilles, and this is thought to represent either a repair or tissue maintenance function. Metalloproteinases are a large family of enzymes capable of degrading all of the tendon matrix components, and these are thought to play a major role in the degradation of matrix during development, adaptation and repair. It is proposed that some metalloproteinase enzymes are required for the health of the tendon, and others may be damaging, leading to degeneration of the tissue. Further research is required to investigate how these enzyme activities are regulated in tendon and altered in tendinopathy. A profile of all the metalloproteinases expressed and active in healthy and degenerate tendon is required and may lead to the development of new drug therapies for these common and debilitating sports injuries

Time trends, projections, and spatial distribution of low birthweight in Australia, 2009–2030: Evidence from the National Perinatal Data Collection

Introduction: Infants with low birthweight (LBW, birthweight <2500 g) have increased in many high-resource countries over the past two decades. This study aimed to investigate the time trends, projections, and spatial distribution of LBW in Australia, 2009–2030. Methods: We used standard aggregate data on 3 346 808 births from 2009 to 2019 from Australia's National Perinatal Data Collection. Bayesian linear regression model was used to estimate the trends in the prevalence of LBW in Australia. Results: We found that the prevalence of LBW was 6.18% in 2009, which has increased to 6.64% in 2019 (average annual rate of change, AARC = +0.76%). If the national trend remains the same, the projected prevalence of LBW in Australia will increase to 7.34% (95% uncertainty interval, UI = 6.99, 7.68) in 2030. Observing AARC across different subpopulations, the trend of LBW was stable among Indigenous mothers, whereas it increased among non-Indigenous mothers (AARC = +0.81%). There is also an increase among the most disadvantaged mothers (AARC = +1.08%), birthing people in either of two extreme age groups (AARC = +1.99% and +1.53% for <20 years and ≥40 years, respectively), and mothers who smoked during pregnancy (AARC = +1.52%). Spatiotemporal maps showed that some of the Statistical Area level 3 (SA3) in Northern Territory and Queensland had consistently higher prevalence for LBW than the national average from 2014 to 2019. Conclusion: Overall, the prevalence of LBW has increased in Australia during 2009–2019; however, the trends vary across different subpopulations. If trends persist, Australia will not achieve the Sustainable Development Goals (SDGs) target of a 30% reduction in LBW by 2030. Centering and supporting the most vulnerable subpopulations is vital to progress the SDGs and improves perinatal and infant health in Australia

Increased floodplain inundation in the Amazon since 1980

Extensive floodplains throughout the Amazon basin support important ecosystem services and influence global water and carbon cycles. A recent change in the hydroclimatic regime of the region, with increased rainfall in the northern portions of the basin, has produced record-breaking high water levels on the Amazon River mainstem. Yet, the implications for the magnitude and duration of floodplain inundation across the basin remain unknown. Here we leverage state-of-the-art hydrological models, supported by in situ and remote sensing observations, to show that the maximum annual inundation extent along the central Amazon increased by 26% since 1980. We further reveal increased flood duration and greater connectivity among open water areas in multiple Amazon floodplain regions. These changes in the hydrological regime of the world\u27s largest river system have major implications for ecology and biogeochemistry, and require rapid adaptation by vulnerable populations living along Amazonian rivers

DOK3 Negatively Regulates LPS Responses and Endotoxin Tolerance

Innate immune activation via Toll-like receptors (TLRs), although critical for host defense against infection, must be regulated to prevent sustained cell activation that can lead to cell death. Cells repeatedly stimulated with lipopolysaccharide (LPS) develop endotoxin tolerance making the cells hypo-responsive to additional TLR stimulation. We show here that DOK3 is a negative regulator of TLR signaling by limiting LPS-induced ERK activation and cytokine responses in macrophages. LPS induces ubiquitin-mediated degradation of DOK3 leading to SOS1 degradation and inhibition of ERK activation. DOK3 mice are hypersensitive to sublethal doses of LPS and have altered cytokine responses in vivo. During endotoxin tolerance, DOK3 expression remains stable, and it negatively regulates the expression of SHIP1, IRAK-M, SOCS1, and SOS1. As such, DOK3-deficient macrophages are more sensitive to LPS-induced tolerance becoming tolerant at lower levels of LPS than wild type cells. Taken together, the absence of DOK3 increases LPS signaling, contributing to LPS-induced tolerance. Thus, DOK3 plays a role in TLR signaling during both naïve and endotoxin-induced tolerant conditions

Induction of Asthma and the Environment: What We Know and Need to Know

The prevalence of asthma has increased dramatically over the last 25 years in the United States and in other nations as a result of ill-defined changes in living conditions in modern society. On 18 and 19 October 2004 the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences sponsored the workshop “Environmental Influences on the Induction and Incidence of Asthma” to review current scientific evidence with respect to factors that may contribute to the induction of asthma. Participants addressed two broad questions: a) What does the science suggest that regulatory and public health agencies could do now to reduce the incidence of asthma? and b) What research is needed to improve our understanding of the factors that contribute to the induction of asthma and our ability to manage this problem? In this article (one of four articles resulting from the workshop), we briefly characterize asthma and its public health and economic impacts, and intervention strategies that have been successfully used to prevent induction of asthma in the workplace. We conclude with the findings of seven working groups that focus on ambient air, indoor pollutants (biologics), occupational exposures, early life stages, older adults, intrinsic susceptibility, and lifestyle. These groups found strong scientific support for public health efforts to limit in utero and postnatal exposure to cigarette smoke. However, with respect to other potential types of interventions, participants noted many scientific questions, which are summarized in this article. Research to address these questions could have a significant public health and economic impact that would be well worth the investment

Exposure Path Perceptions and Protective Actions in Biological Water Contamination Emergencies

This study extends the Protective Action Decision Model, developed to address disaster warning responses in the context of natural hazards, to “boil water” advisories. The study examined 110 Boston residents’ and 203 Texas students’ expectations of getting sick through different exposure paths for contact with contaminated water. In addition, the study assessed respondents’ actual implementation (for residents) or behavioral expectations (for students) of three different protective actions – bottled water, boiled water, and personally chlorinated water – as well as their demo-graphic characteristics and previous experience with water contamination. The results indicate that people distinguish among the exposure paths, but the differences are small (one-third to one-half of the response scale). Nonetheless, the perceived risk from the exposure paths helps to explain why people are expected to consume (or actually consumed) bottled water rather than boiled or personally chlorinated water. Overall, these results indicate that local authorities should take care to communicate the relative risks of different exposure paths and should expect that people will respond to a boil water order primarily by consuming bottled water. Thus, they should make special efforts to increase supplies of bottled water in their communities during water contamination emergencies

Phase 2 evaluation of parainfluenza type 3 cold passage mutant 45 live attenuated vaccine in healthy children 6-18 months old

© 2004 by the Infectious Diseases Society of America. All rights reserved.A phase 2 evaluation of live attenuated parainfluenza type 3 (PIV3)–cold passage mutant 45 (cp45) vaccine was conducted in 380 children 6–18 months old; 226 children (59%) were seronegative for PIV3. Of the 226 seronegative children, 114 received PIV3-cp45 vaccine, and 112 received placebo. No significant difference in the occurrence of adverse events (i.e., runny nose, cough, or temperature 38°C) was noted during the 14 days after vaccination. There was no difference between groups in the occurrence of acute otitis media or serous otitis media. Paired serum samples were available for 109 of the seronegative vaccine recipients and for 110 of the seronegative placebo recipients; 84% of seronegative vaccine recipients developed a 4-fold increase in antibody titers. The geometric mean antibody titer after vaccination was 1:25 in the vaccine group and <1:4 in the placebo group. PIV3-cp45 vaccine was safe and immunogenic in seronegative children and should be evaluated for efficacy in a phase 3 field trial.Robert B. Belshe, Frances K. Newman, Theodore F. Tsai, Ruth A. Karron, Keith Reisinger, Don Roberton, Helen Marshall, Richard Schwartz, James King, Frederick W. Henderson, William Rodriguez, Joseph M. Severs, Peter F. Wright, Harry Keyserling, Geoffrey A. Weinberg, Kenneth Bromberg, Richard Loh, Peter Sly, Peter McIntyre, John B. Ziegler, Jill Hackell, Anne Deatly, Alice Georgiu, Maribel Paschalis, Shin-Lu Wu, Joanne M. Tatem, Brian Murphy and Edwin Anderso

CCL2 Is Associated with a Faster Rate of Cognitive Decline during Early Stages of Alzheimer's Disease

Chemokine (C-C motif) receptor 2 (CCR2)-signaling can mediate accumulation of microglia at sites affected by neuroinflammation. CCR2 and its main ligand CCL2 (MCP-1) might also be involved in the altered metabolism of beta-amyloid (Aβ) underlying Alzheimer's disease (AD). We therefore measured the levels of CCL2 and three other CCR2 ligands, i.e. CCL11 (eotaxin), CCL13 (MCP-4) and CCL26 (eotaxin-3), in the cerebrospinal fluid (CSF) and plasma of 30 controls and 119 patients with mild cognitive impairment (MCI) at baseline. During clinical follow-up 52 MCI patients were clinically stable for five years, 47 developed AD (i.e. cases with prodromal AD at baseline) and 20 developed other dementias. Only CSF CCL26 was statistically significantly elevated in patients with prodromal AD when compared to controls (p = 0.002). However, in patients with prodromal AD, the CCL2 levels in CSF at baseline correlated with a faster cognitive decline during follow-up (rs = 0.42, p = 0.004). Furthermore, prodromal AD patients in the highest tertile of CSF CCL2 exhibited a significantly faster cognitive decline (p<0.001) and developed AD dementia within a shorter time period (p<0.003) compared to those in the lowest tertile. Finally, in the entire MCI cohort, CSF CCL2 could be combined with CSF Tau, P-tau and Aβ42 to predict both future conversion to AD and the rate of cognitive decline. If these results are corroborated in future studies, CCL2 in CSF could be a candidate biomarker for prediction of future disease progression rate in prodromal AD. Moreover, CCR2-related signaling pathways might be new therapeutic targets for therapies aiming at slowing down the disease progression rate of AD