Smokeless tobacco consumption and its association with risk factors of chronic kidney disease in rural and peri-urban Bangladesh.

INTRODUCTION: Compared to smoking, which has major consequences in chronic kidney disease (CKD) initiation and progression, smokeless tobacco (SLT) consumption is considered to have fewer health consequences. We investigated the prevalence of SLT consumption and its association with risk factors of CKD in a rural and peri-urban Bangladeshi population. METHODS: Using random sampling we recruited 872 adults in 2020, from the Mirzapur Demographic Surveillance System of Bangladesh, who had resided in the area for at least five years. Interviews using a semi-structured questionnaire, physical examination and anthropometric measurements were done, followed by blood and urine testing. The blood and urine tests were repeated in selected participants after three months as per the CKD Epidemiology Collaboration equation. RESULTS: The prevalence of SLT consumption was 29%. Being aged ≥46 years (OR=7.10; 95% CI: 4.79-10.94), female (OR=1.64; 95% CI: 1.21-2.22), housewife (OR=1.82; 95% CI: 1.35-2.45), farmer (OR=1.71; 95% CI: 1.06-2.76), widow (OR=3.40; 95% CI: 2.24-5.17), and having no formal schooling (OR=4.91; 95% CI: 3.59-6.72), family income of <$100/month (OR=1.66; 95% CI: 1.13-2.43), sleeping duration <7 hours per day (OR=2.33; 95% CI: 1.70-3.19), were associated with a significantly higher odds of SLT consumption. However, being aged 31-45 years (OR=0.25; 95% CI: 0.16-0.38) had significantly lower odds of being an SLT consumer. Among the diseases investigated, undernutrition (OR=1.63; 95% CI: 1.15-2.33), hypertension (OR=1.52; 95% CI: 1.13-2.05), anemia (OR=1.94; 95% CI: 1.39-2.71) and CKD (OR=1.62; 95% CI: 1.15-2.27) were significantly associated with SLT consumption. In the multivariable analysis, being aged 31-45 years (AOR=3.06; 95% CI: 1.91-4.90), ≥46 years (AOR=15.69; 95% CI: 4.64-53.09) and having no formal schooling (AOR=2.47; 95% CI: 1.72-3.55) were found to have a significant association with being an SLT consumer. CONCLUSIONS: SLT consumption is associated with most of the established risk factors of CKD within the studied population.

Omega-3 fatty acid-rich fish oil supplementation prevents rosiglitazone-induced osteopenia in aging C57BL/6 mice and in vitro studies.

Rosiglitazone is an effective insulin-sensitizer, however associated with bone loss mainly due to increased bone resorption and bone marrow adiposity. We investigated the effect of the co-administration of fish oil rich in omega-3 fatty acids (FAs) on rosiglitazone-induced bone loss in C57BL/6 mice and the mechanisms underlying potential preventive effect. Mice fed the iso-caloric diet supplemented with fish oil exhibited significantly higher levels of bone density in different regions compared to the other groups. In the same cohort of mice, reduced activity of COX-2, enhanced activity of alkaline phosphatase, lower levels of cathepsin k, PPAR-γ, and pro-inflammatory cytokines, and a higher level of anti-inflammatory cytokines were observed. Moreover, fish oil restored rosiglitazone-induced down-regulation of osteoblast differentiation and up-regulation of adipocyte differentiation in C3H10T1/2 cells and inhibited the up-regulation of osteoclast differentiation of RANKL-treated RAW264.7 cells. We finally tested our hypothesis on human Mesenchymal Stromal Cells differentiated to osteocytes and adipocytes confirming the beneficial effect of docosahexaenoic acid (DHA) omega-3 FA during treatment with rosiglitazone, through the down-regulation of adipogenic genes, such as adipsin and FABP4 along the PPARγ/FABP4 axis, and reducing the capability of osteocytes to switch toward adipogenesis. Fish oil may prevent rosiglitazone-induced bone loss by inhibiting inflammation, osteoclastogenesis, and adipogenesis and by enhancing osteogenesis in the bone microenvironment.

Population health and regional variations of disease burden in Japan, 1990-2015: a systematic subnational analysis for the Global Burden of Disease Study 2015.

BACKGROUND: Japan has entered the era of super-ageing and advanced health transition, which is increasingly putting pressure on the sustainability of its health system. The level and pace of this health transition might vary across regions within Japan and concern is growing about increasing regional variations in disease burden. The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) provides a comprehensive, comparable framework. We used data from GBD 2015 with the aim to quantify the burden of disease and injuries, and to attribute risk factors in Japan at a subnational, prefecture-level. METHODS: We used data from GBD 2015 for 315 causes and 79 risk factors of death, disease, and injury incidence and prevalence to measure the burden of diseases and injuries in Japan and in the 47 Japanese prefectures from 1990 to 2015. We extracted data from GBD 2015 to assess mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), life expectancy, and healthy life expectancy (HALE) in Japan and its 47 prefectures. We split extracted data by prefecture and applied GBD methods to generate estimates of burden, and attributable burden due to known risk factors. We examined the prefecture-level relationships of common health system inputs (eg, health expenditure and workforces) to the GBD outputs in 2015 to address underlying determinants of regional health variations. FINDINGS: Life expectancy at birth in Japan increased by 4·2 years from 79·0 years (95% uncertainty interval [UI] 79·0 to 79·0) to 83·2 years (83·1 to 83·2) between 1990 and 2015. However, the gaps between prefectures with the lowest and highest life expectancies and HALE have widened, from 2·5 to 3·1 years and from 2·3 to 2·7 years, respectively, from 1990 to 2015. Although overall age-standardised death rates decreased by 29·0% (28·7 to 29·3) from 1990 to 2015, the rates of mortality decline in this period substantially varied across the prefectures, ranging from -32·4% (-34·8 to -30·0) to -22·0% (-20·4 to -20·1). During the same time period, the rate of age-standardised DALYs was reduced overall by 19·8% (17·9 to 22·0). The reduction in rates of age-standardised YLDs was very small by 3·5% (2·6 to 4·3). The pace of reduction in mortality and DALYs in many leading causes has largely levelled off since 2005. Known risk factors accounted for 34·5% (32·4 to 36·9) of DALYs; the two leading behavioural risk factors were unhealthy diets and tobacco smoking in 2015. The common health system inputs were not associated with age-standardised death and DALY rates in 2015. INTERPRETATION: Japan has been successful overall in reducing mortality and disability from most major diseases. However, progress has slowed down and health variations between prefectures is growing. In view of the limited association between the prefecture-level health system inputs and health outcomes, the potential sources of regional variations, including subnational health system performance, urgently need assessment. FUNDING: Bill & Melinda Gates Foundation, Japan Ministry of Education, Science, Sports and Culture, Japan Ministry of Health, Labour and Welfare, AXA CR Fixed Income Fund and AXA Research Fund.

Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs.

Advanced age is associated with chronic low-grade inflammation (i.e. inflamm-aging) and poor macrophage function that includes a weak pro-inflammatory cytokine response to bacteria and diminished phagocytosis (i.e. age-dependent macrophage dysfunction [ADMD]). One reason for this is that ADMD is associated with poor NFκB and MAPK activation following Toll-like receptor stimulation. Herein, we tested the hypothesis that inflamm-aging induces production of A20, a cytosolic and homeostatic suppressor of the NFκB and MAPK signaling cascades that deubiquitinates (i.e. inactivates) the common upstream signaling molecule TRAF6, and this is responsible for ADMD. Western blots and immunohistochemistry comparing tissues from young, mature, and aged C57BL/6 mice indicated that A20 was strongly elevated in the lungs of aged mice but not in other tissues. Elevated A20 was also detected in alveolar macrophages (AM) from aged mice. In contrast CYLD, a second deubiquitinase that also negatively regulates the NFκB pathway was decreased with aging. Following co-incubation of AM with the bacteria Streptococcus pneumoniae, TRAF6 polyubiquitination was diminished in AM isolated from aged versus young mice. A20 production was inducible in the J774A.1 macrophage cell line and C57BL/6AM by overnight incubation with TNFα but not IL-6. Retrovirus-induced expression of A20 in J774A.1 cells resulted in their diminished production of IL-6 following exposure to S. pneumoniae but had no effect on levels of phagocytosis. Overnight incubation of AM from young mice with TNFα also resulted in a dampened IL-6 response to S. pneumoniae. Finally, dietary supplementation of aged mice with anti-inflammatory n-3 polyunsaturated fatty acids in the form of fish oil lowered lung A20 levels and enhanced resistance, including a 100-fold reduction in bacterial titers in the lungs, to experimental challenge with S. pneumoniae. We conclude that elevated A20 due to TNFα partially explains the ADMD phenotype and that ADMD is potentially reversible.

t10c12-CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity.

Conjugated linoleic acid (CLA) has been shown to positively influence calcium and bone metabolism. Earlier, we showed that CLA (equal mixture of c9t11-CLA and t10c12-CLA) could protect age-associated bone loss by modulating inflammatory markers and osteoclastogenesis. Since, c9t11-CLA and t10c12-CLA isomers differentially regulate functional parameters and gene expression in different cell types, we examined the efficacy of individual CLA isomers against age-associated bone loss using 12 months old C57BL/6 female mice fed for 6 months with 10% corn oil (CO), 9.5% CO + 0.5% c9t11-CLA, 9.5% CO + 0.5% t10c12-CLA or 9.5% CO + 0.25% c9t11-CLA + 0.25% t10c12-CLA. Mice fed a t10c12-CLA diet maintained a significantly higher bone mineral density (BMD) in femoral, tibial and lumbar regions than those fed CO and c9t11-CLA diets as measured by dual-energy-X-ray absorptiometry (DXA). The increased BMD was accompanied by a decreased production of osteoclastogenic factors, that is, RANKL, TRAP5b, TNF-alpha and IL-6 in serum. Moreover, a significant reduction of high fat diet-induced bone marrow adiposity was observed in t10c12-CLA fed mice as compared to that of CO and c9t11-CLA fed mice, as measured by Oil-Red-O staining of bone marrow sections. In addition, a significant reduction of osteoclast differentiation and bone resorbing pit formation was observed in t10c12-CLA treated RAW 264.7 cell culture stimulated with RANKL as compared to that of c9t11-CLA and linoleic acid treated cultures. In conclusion, these findings suggest that t10c12-CLA is the most potent CLA isomer and it exerts its anti-osteoporotic effect by modulating osteoclastogenesis and bone marrow adiposity.

Combination of conjugated linoleic acid with fish oil prevents age-associated bone marrow adiposity in C57Bl/6J mice.

The inverse relationship between fat in bone marrow and bone mass in the skeleton of aging subjects is well known. However, there is no precise therapy for the treatment of bone marrow adiposity. We investigated the ability of conjugated linoleic acid (CLA) and fish oil (FO), alone or in combination, to modulate bone loss using 12 months old C57Bl/6J mice fed 10% corn oil diet as control or supplemented with 0.5% CLA or 5% FO or 0.5% CLA+5% FO for 6 months. We found, CLA-fed mice exhibited reduced body weight, body fat mass (BFM) and enhanced hind leg lean mass (HLLM) and bone mineral density (BMD) in different regions measured by dual energy x-ray absorptiometry (DXA); however, associated with fatty liver and increased insulin resistance; whereas, FO fed mice exhibited enhanced BMD, improved insulin sensitivity, with no changes in BFM and HLLM. Interestingly, CLA+FO fed mice exhibited reduced body weight, BFM, peroxisome proliferator-activated receptor gamma and cathepsin K expression in bone marrow with enhanced BMD and HLLM. Moreover, CLA+FO supplementation reduced liver hypertrophy and improved insulin sensitivity with remarkable attenuation of bone marrow adiposity, inflammation and oxidative stress in aging mice. Therefore, CLA with FO combination might be a novel dietary supplement to reduce fat mass and improve BMD.

High fat diet-induced animal model of age-associated obesity and osteoporosis.

Osteoporosis and obesity remain a major public health concern through its associated fragility and fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require unique surgical skills and expensive set up. The challenging aspect of these age-associated diseases is that no single animal model exactly mimics the progression of these human-specific chronic conditions. Accordingly, to develop a simple and novel model of post menopausal bone loss with obesity, we fed either a high fat diet containing 10% corn oil (CO) or standard rodent lab chow (LC) to 12-month-old female C57Bl/6J mice for 6 months. As a result, CO fed mice exhibited increased body weight, total body fat mass, abdominal fat mass and reduced bone mineral density (BMD) in different skeletal sites measured by dual energy X-ray absorptiometry. We also observed that decreased BMD with age in CO fed obese mice was accompanied by increased bone marrow adiposity, up-regulation of peroxisome proliferator-activated receptor γ, cathepsin k and increased proinflammatory cytokines (interleukin 6 and tumor necrosis factor α) in bone marrow and splenocytes, when compared to that of LC fed mice. Therefore, this appears to be a simple, novel and convenient age-associated model of post menopausal bone loss, in conjunction with obesity, which can be used in pre-clinical drug discovery to screen new therapeutic drugs or dietary interventions for the treatment of obesity and osteoporosis in the human population.