Long Term Maternal Diet Transition Recovers Inflammatory Phenotype and Offspring Obesity

As the obesity epidemic continues to affect the chronic disease status of individuals worldwide, research that aims to elucidate the contribution of maternal health status to the perpetuation of the obesity cycle has become increasingly prevalent. We sought to answer how different time point interventions in maternal diet affect characteristics of obesity and presence of inflammation in the visceral adipose tissue of offspring male mice. Addressing this question, female mice were continued on either a high-fat diet or transitioned from a high-fat diet to a low-fat diet at 1, 5 or 9 weeks prior to pregnancy. Offspring male mice were continued on a HFD for 12 weeks post-weaning. Compared to NF group, the H1N group had significantly increased adipocyte diameter indicative of hypertrophy, while the H5N and H9N offspring had rescued adipocyte hypertrophy although the H5N adipocyte was significantly bigger than the HF offspring. Accordingly, the H1N and H5N offspring increased expression of key adipogenesis and fat trafficking genes compared to the NF group, which was totally reversed in H9N offspring, respectively. F4/80 positive cells indicated decreased number of adipose tissue macrophage in H9N offspring than NF offspring. However, there was increased ATM infiltration in H1N and H5N, compared to the HF offspring. Consistently, the H9N offspring also had the least amount of crown like structures among all groups. Additionally, the H1N offspring had the highest expression of Tnf-α and Il-6 among all groups, while the H9N offspring expressed the similar level as the NF offspring, indicating enhanced adipose tissue inflammation in H1N offspring, which was completely reversed in H9N offspring. This result was echoed by significant upregulation of Jnk and Nf-κB in H1N group, but not H5N or H9N. In conclusion, our study showed that a long-term, but not a short-term transition from HFD to NFD before pregnancy is efficient to block the adipocyte hypertrophy and adipose tissue inflammation induced by maternal HFD

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A long-term maternal diet transition from high-fat diet to normal fat diet during pre-pregnancy avoids adipose tissue inflammation in next generation.

Recent studies have suggested that maternal high-fat (HF) diet caused inflammation changes in adipose tissue; however, it remains unclear if maternal diet intervention before pregnancy rescues such effects in offspring. To address this question, female mice were continued on a normal-fat (NF group), or a HF diet (HF group) or transitioned from a HF diet to a NF diet at 1 (H1N group), 5 (H5N group) or 9 weeks (H9N group) prior to pregnancy. Among the three intervention groups, the H9N offspring displayed less and steady body weight gain, and maintained glucose tolerance, whereas the H1N and H5N offspring showed exacerbate these phenotypes. The H1N and H5N, but not the H9N offspring, displayed adipocyte hypertrophy associated with increased expression of genes involved in fat deposition. The H1N and H5N, but not the H9N adipose tissue, displayed increased macrophage infiltration with enhanced expression of inflammatory cytokine genes. In addition, overactivation of the NF-κB and the JNK signaling were observed in the H1N adipose tissue. Overall, our study showed that a long-term but not a short- or medium-term diet intervention before pregnancy released offspring adipose tissue inflammation induced by maternal HF diet, which adds details in our understanding how the maternal environment either promotes or discourages onset of disease in offspring. Clinically, this study is of great value for providing evidence in the design of clinical trials to evaluate the urgently required intervention strategies to minimize the intergenerational cycle of obesity

“The quarry proposed by St Marys Cement Inc. for a location near Carlisle, Ontario should not be permitted” : Proponents’ Brief

This paper presents a set of arguments claiming that construction of the quarry near Flamborough, Ontario proposed St. Mary’s Cement Inc. should not be permitted. First, the quarry would violate local citizens’ property rights, compromise community health and safety, and incur excessive economic costs. Precautionary measures are insufficient, such that the quarry is expected to irreparably damage drinking water and quality of life. Second, the area proposed for aggregate extraction is mostly undeveloped, containing unique, valuable natural features and ecological linkages. Despite regulation and monitoring according to the provincial Aggregate Resources Act, rehabilitation of the site after aggregate extraction would be inadequate in returning the land to its former condition. This will result in habitat fragmentation and loss of high quality farmland. Furthermore, the construction of the quarry is not permitted under current City of Hamilton zoning regulations; the City of Hamilton, along with the city’s Public Health Services, filed an official objection against construction. Finally, a GIS study has selected a more suitable alternative site for aggregate extraction near Carlisle, which meets the geographic, topographic, and mineral needs of St. Mary’s Cement Group without disturbing habitat or nearby communities

Effect of synthetic agonists of toll-like receptor 9 on canine lymphocyte proliferation and cytokine production in vitro.

Synthetic agonists of TLR9 containing novel DNA structures and R'pG (wherein R=1-(2'-deoxy-beta-d-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine) motifs, referred to as immune modulatory oligonucleotides (IMOs), have been shown to stimulate T(H)-1-type-immune responses and potently reverse allergen-induced T(H)-2 responses to T(H)-1 responses in vitro and in vivo in mice. In order to investigate the immunomodulatory potential of IMOs in dogs, canine peripheral blood mononuclear cells (PBMC) from healthy dogs were stimulated with three different IMOs and a control IMO, alone or in combination with concanavalin A (ConA). Lipopolysaccharide (LPS) was used as a positive control for B lymphocyte activation. Carboxyfluorescein diacetate succinimidyl ester and phenotype staining was used to tag proliferating T and B lymphocytes (CD5(+) and CD21(+)) by flow cytometry. Real-time PCR and ELISA were processed to assay cytokine production of IFN-gamma, IL-10, TGF-beta, IL-6 and IL-10. Like LPS, IMOs alone induced neither proliferation of CD5(+) T cells nor CD21(+) B cells, but both LPS and IMO had the capacity to co-stimulate ConA and induced proliferation of B cells. In combination with ConA, one of the IMOs (IMO1) also induced proliferation of T cells. IMO1 also significantly enhanced the expression of IFN-gamma on the mRNA and protein level in canine PBMC, whereas expression of IL-10, TGF-beta and IL-4 mRNAs was not induced by any of the IMOs. These results indicate that in canine PBMC from healthy dogs, IMO1 was able to induce a T(H)-1 immune response including T- and B-cell proliferation