The SLC9A-C Mammalian Na+/H+ Exchanger Family: Molecules, Mechanisms, and Physiology.

Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. They belong to an ancient family of highly evolutionarily conserved proteins, and they play essential physiological roles in all phyla. In this review, we focus on the mammalian Na+/H+ exchangers (NHEs), the solute carrier (SLC) 9 family. This family of electroneutral transporters constitutes three branches: SLC9A, -B, and -C. Within these, each isoform exhibits distinct tissue expression profiles, regulation, and physiological roles. Some of these transporters are highly studied, with hundreds of original articles, and some are still only rudimentarily understood. In this review, we present and discuss the pioneering original work as well as the current state-of-the-art research on mammalian NHEs. We aim to provide the reader with a comprehensive view of core knowledge and recent insights into each family member, from gene organization over protein structure and regulation to physiological and pathophysiological roles. Particular attention is given to the integrated physiology of NHEs in the main organ systems. We provide several novel analyses and useful overviews, and we pinpoint main remaining enigmas, which we hope will inspire novel research on these highly versatile proteins.

Mid- to long-term functional outcome and return to sport after elbow dislocation in bouldering: a clinical retrospective cohort study.

INTRODUCTION: Traumatic elbow dislocations are among the most common injuries in sport climbing. They occur most frequently in bouldering (a climbing discipline with strong upward trend often performed indoors) due to the typical low-height backward fall into crashpads. There is still no data about the functional outcome and return to sport of this typical bouldering injury. MATERIALS AND METHODS: All Patients with elbow dislocations due to a bouldering associated fall between 2011 and 2020 were identified retrospectively in our level I trauma centre. Trauma mechanisms, injury types and therapies were obtained. Follow-up was performed with an online questionnaire including sports-related effects, return to sport and the Elbow Self-Assessment Score (ESAS). RESULTS: 30 patients with elbow dislocations after bouldering accidents were identified. In 22 (73.3%) patients the injury was a simple dislocation. The questionnaire was completed by 20 patients. The leading mechanism was a low-height fall into crashpads. Surgical procedures were performed in every second patient. 18 patients (90%) reported return to bouldering after 4.7 ± 2.1 months. 12 patients (66.7%) regained their pre-injury level. Mid-/Long-term follow-up (mean 105 ± 37.5 months) showed excellent results in ESAS score (97.2 ± 3.9 points). Persistent limited range of motion or instability was reported by only 3 patients (15%). CONCLUSION: Most athletes are able to return to bouldering but only two thirds regain their pre-injury performance level in this demanding upper-extremity sport. The unique low-height trauma mechanism may create a false sense of security. Specific awareness and safety features should be placed for climbing athletes to reduce elbow injuries.

Internet-Delivered, Therapist-Assisted Treatment for Anxiety and Depression in Patients with Cardiovascular Disease: Evidence-Base and Challenges.

PURPOSE OF REVIEW: This review focuses on the efficacy of internet-based psychological interventions for patients with cardiovascular disease (CVD) and comorbid anxiety and depression. Anxiety and depression comprise barriers for treatment adherence and are associated with poorer patient-reported and clinical outcomes, and greater health care costs. RECENT FINDINGS: Internet-based, therapist-assisted interventions targeting anxiety and depression can be as efficacious as face-to-face therapy and may have some advantages, as patients can do it from their own laptop/smartphone at home at a time of their convenience, which may facilitate a better integration in their lives. To enhance the field of internet-based therapy for patients with CVD, we need to involve patients in the development of interventions, focus on developing standards for adherence and assessment of fidelity, and assess and augment health literacy in patients to safeguard equality in health care.

Position specific physical performance and running intensity fluctuations in elite women's football.

The purpose of the present study was to investigate the physical performance of elite female football players during match play along with transient alterations in running performance following 1- and 5-min univariate peak periods. 54 elite female players from four top-level Norwegian teams were monitored for one season (n = 393 match observations), and physical performance data collected using STATSport GPS APEX. Results revealed significant differences in physical performance between the positions during full match play, particularly between wide and central players. Both full backs (FBs) and wide midfielders (WMs) covered more total distance (TD), high-speed running distance (HSRD), and sprint distance (SpD) than center backs (CBs) (p < 0.05-0.001), while WMs also covered more HSRD than both central midfielders (CMs) (p < 0.01) and forwards (FWs) (p < 0.05), and more acceleration -and deceleration distance (Accdist and Decdist ) than both CBs and CMs (p < 0.01-0.001). A similar pattern was observed for the peak period analysis, with FBs and WMs covering more SpD in peak 1 min than CBs and CM (p < 0.001) and more SpD in peak 5-min than CBs, CMs, and FWs (p < 0.001). Irrespective of the variable analyzed, greater distances were covered during the peak 5-min period than in the next-5 and mean 5-min periods (p < 0.001). Significant (p < 0.001), but small to trivial (Cohen's Dz : 0.07-0.20), decreases in distance covered were also observed for each variable following each univariate peak 5-min period. In conclusion, practitioners should account for differences in physical performance when developing training programs for female football players and be aware of transient reductions in physical performance following univariate peak 1- and 5-min periods. Specifically, the very high intensity in 1-min peak periods adds support to the principal of executing speed endurance activities during training to mirror and be prepared for the physical demands of match play.

The effect of vitamin MK-7 on bone mineral density and microarchitecture in postmenopausal women with osteopenia, a 3-year randomized, placebo-controlled clinical trial.

We conducted a randomized placebo-controlled double-blinded clinical trial of MK-7 or placebo daily for 3 years in postmenopausal women with osteopenia. BMD decreased at all sites without differences between the MK-7 and placebo-treated women. Changes in bone turnover markers and microstructure were similar between the two groups. INTRODUCTION: Vitamin K is a cofactor in the carboxylation of osteocalcin (OC) and carboxylated OC promotes mineralization of bone. Clinical studies suggest that vitamin K2 prevents bone loss. The aim of the study was to investigate the effect of vitamin K2 as an add-on to calcium and vitamin D supplementation on osteocalcin, bone mass, and microarchitecture in postmenopausal women. METHODS: We conducted a randomized placebo-controlled double-blinded clinical trial, including 142 postmenopausal women with osteopenia who received vitamin K2 (375 µg MK-7) or placebo daily for 3 years. Both groups received vitamin D3 (38 µg/day) and calcium (800 mg/day). We measured bone turnover markers in serum and bone mineral density and microarchitecture by DXA and HRpQCT. RESULTS: Undercarboxylated osteocalcin decreased in the MK-7-group (- 65.2 ± 23.5%) (mean ± SD) compared with the placebo group (- 0.03 ± 38.5%), p < 0.01 after 1 year. After 3 years, aBMD decreased at all sites without differences between the MK-7 and placebo-treated women (p > 0.09). aBMD decreased at the total hip by 1.5 ± 2.5% and 2.4 ± 2.7% in the MK-7 and the placebo groups, respectively, at the femoral neck by 1.5 ± 3.5% and 1.0 ± 5.0% in the MK-7 and the placebo groups, respectively, and at the lumbar spine by 1.8 ± 3.9% and 1.1 ± 3.1% in the MK-7 and the placebo groups, respectively. Changes in bone turnover markers were also similar between the two groups.We have previously reported improved microarchitecture with MK-7 after 1 year. However, changes in microstructure over 3 years were similar between the two groups, as assessed by both HRpQCT and DXA trabecular bone score. CONCLUSION: Treatment with MK-7 375 µg daily as an add-on to calcium and vitamin D increased carboxylation of osteocalcin. However, treatment of postmenopausal women with osteopenia for 3 years did not affect biochemical markers of bone turnover, bone mineral density, or bone microarchitecture. TRIAL REGISTRATION: The study was registered at Clinicaltrial.gov : NCT01922804 .

Oral 3-hydroxybutyrate ingestion decreases endogenous glucose production, lipolysis, and hormone-sensitive lipase phosphorylation in adipose tissue in men: a human randomized, controlled, crossover trial.

AIMS: To test whether oral administration of D/L-3-hydroxybutyrate as a sodium salt inhibits lipolysis and intracellular lipid signalling, in particular, hormone-sensitive lipase, and whether D/L-3-hydroxybutyrate alters endogenous glucose production. METHODS: We studied six young men in a randomized, controlled, crossover study after ingestion of Na-D/L-3-hydroxybutyrate (hyperketotic condition) or saline (placebo control). We quantified lipolysis and endogenous glucose production using [9,10-3 H]-palmitate and [3-3H]glucose tracers, and adipose tissue biopsies were collected to investigate key lipolytic enzymes. RESULTS: After ingestion, D/L-3-hydroxybutyrate increased by more than 2.5 mmol/l, free fatty acid concentrations decreased by >70%, and palmitate rate of appearance was halved. Protein kinase A phosphorylation of perilipin was reduced and hormone-sensitive lipase 660 phosphorylation in adipose tissue biopsies was 70-80% decreased in the hyperketotic condition and unchanged in the control. Compared to the control, endogenous glucose production was reduced by close to 20% (P<0.05) after 3-hydroxybutyrate ingestion. CONCLUSION: We conclude that oral D/L-Na-3-hydroxybutyrate increases D/L-3-hydroxybutyrate concentrations within half an hour, decreases free fatty acid concentrations, lowers lipolysis and endogenous glucose production, and dephosphorylates hormone-sensitive lipase. Collectively these phenomena may be viewed as an orchestrated feedback loop, controlling endogenous glucose production, lipolysis and ketogenesis. Such effects would be beneficial in insulin-resistant states. (www.clinicaltrials.gov ID number: NCT02917252).

Socio-economic inequalities in fragility fracture outcomes: a systematic review and meta-analysis of prognostic observational studies.

Individuals with low socio-economic status (SES) have a higher risk of dying following hip fracture compared with individuals with high SES. Evidence on social inequalities in non-hip fractures is lacking as well as evidence on the impact of SES on health-related quality of life post fracture. INTRODUCTION: Fragility fractures, especially of the hip, cause substantial excess mortality and impairment in health-related quality of life (HRQoL). This systematic review and meta-analysis aimed to investigate the association between socio-economic status (SES) and post-fracture mortality and HRQoL. METHODS: PubMed, EMBASE and CINAHL databases were searched from inception to the last week of November 2018 for studies reporting an association between SES and post-fracture mortality and/or HRQoL among people aged ≥ 50 years. Risk ratios (RRs) were meta-analyzed using a standard inverse-variance-weighted random effects model. Studies using individual-level and area-based SES measures were analyzed separately. RESULTS: A total of 24 studies from 15 different countries and involving more than one million patients with hip fractures were included. The overall risk of mortality within 1-year post-hip fracture in individuals with low SES was 24% higher than in individuals with high SES (RR 1.24, 95% CI 1.19 to 1.29) for individual-level SES measures, and 14% (RR 1.14, 95% CI 1.09 to 1.19) for area-based SES measures. The quality of the evidence for the outcome mortality was moderate. Using individual SES measures, we estimated the excess HRQoL loss to be 5% (95% CI - 1 to 10%) among hip fracture patients with low SES compared with high SES. CONCLUSIONS: We found a consistently increased risk of post-hip fracture mortality with low SES across SES measures and across countries with different political structures and different health and social care infrastructures. The impact of SES on post-fracture HRQoL remains uncertain due to sparse and low-quality evidence.

Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system.

BACKGROUND: A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). METHODS: After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). RESULTS: Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin-eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. CONCLUSIONS: These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Scoring magnetic resonance imaging (MRI) inflammation and structural lesions in sacroiliac joints of patients with axial spondyloarthritis: assessment of all MRI slices of the cartilaginous compartment versus standardized six or five slices.

Objectives: The Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint (SIJ) scoring system assesses six or five (6/5) semicoronal magnetic resonance imaging (MRI) slices for inflammation/structural lesions in patients with axial spondyloarthritis (axSpA). However, the cartilaginous SIJ compartment may be visible in a few additional slices. The objective was to investigate interreader reliability, sensitivity to change, and classification of MRI scans as positive or negative for various lesion types using an 'all slices' approach versus standard SPARCC scoring of 6/5 slices.Method: Fifty-three axSpA patients were treated with the tumour necrosis factor inhibitor golimumab and followed with serial MRI scans at weeks 0, 4, 16, and 52. The most anterior and posterior slices covering the cartilaginous compartment and the transitional slice were identified. Scores for inflammation, fat metaplasia, erosion, backfill, and ankylosis in the cartilaginous SIJ compartment were calculated for the 'all slices' approach and the 6/5 slices standard.Results: By the 'all slices' approach, three readers scored mean 7.2, 7.7, and 7.0 slices per MRI scan. Baseline and change scores for the various lesion types closely correlated between the two approaches (Pearson's rho ≥ 0.95). Inflammation score was median 13 (interquartile range 6-21, range 0-49) for 6/5 slices versus 14 (interquartile range 6-23, range 0-69) for all slices at baseline. Interreader reliability, sensitivity to change, and classification of MRI scans as positive or negative for various lesion types were similar.Conclusion: The standardized 6/5 slices approach showed no relevant differences from the 'all slices' approach and, therefore, is equally suited for monitoring purposes.

Hormone replacement therapy and the risk of melanoma in post-menopausal women.

STUDY QUESTION: Is hormone replacement therapy (HRT) associated with an increased risk of melanoma skin cancer or prognostic outcomes amongst post-menopausal women? SUMMARY ANSWER: Whilst we found evidence of an association with melanoma risk, the lack of dose-response and associations observed with recent use, localised disease and intravaginal oestrogens suggests this is a non-causal association. WHAT IS KNOWN ALREADY: Evidence on HRT and melanoma risk remains inconclusive, with studies providing conflicting results. Furthermore, evidence on melanoma survival is sparse, with only one previous study reporting protective associations with HRT use, likely attributable to immortal time bias. STUDY DESIGN, SIZE, DURATION: We conducted a nation-wide population-based case-control study and a retrospective cohort study utilising the Danish healthcare registries. Case-control analyses included 8279 women aged 45-85 with a first-ever diagnosis of malignant melanoma between 2000 and 2015, matched by age and calendar time to 165 580 population controls. A cohort of 6575 patients with a diagnosis of primary malignant melanoma between 2000 and 2013 and followed through 2015 was examined to determine if HRT use had an impact on melanoma survival outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on prescriptions dispensed since 1995, ever-use of HRT was defined as having filled at least one prescription for HRT prior to the index date. In total, 2629 cases (31.8%) and 47 026 controls (28.4%) used HRT. Conditional logistic regression was used to calculate odds ratios (ORs) for melanoma risk according to HRT use, compared with non-use, adjusting for potential confounders. For cohort analyses, Cox proportional hazards models was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for second melanoma incidence and all-cause mortality associated with HRT. MAIN RESULTS AND THE ROLE OF CHANCE: High use of HRT was associated with an OR of 1.21 (95% CI 1.13-1.29) for melanoma risk, with no evidence of a dose-response pattern. Results were most pronounced amongst recent high users (OR, 1.28; 95% CI 1.17-1.41), for localised disease (OR, 1.25; 95% CI 1.15-1.36) and for intravaginal oestrogen therapy (OR, 1.38; 95% CI 1.13-1.68). Compared with non-use, there was no evidence of an association for secondary melanoma for post-diagnostic new-use (fully adjusted HR, 1.56; 95% CI 0.64-3.80) or continuous HRT use (fully adjusted HR, 1.26; 95% CI 0.89-1.78). Similar associations were observed for all-cause mortality. LIMITATIONS, REASONS FOR CAUTION: Despite the large sample size and the use of robust population-based registries with almost complete coverage, we lacked information on some important confounders including sun exposure. WIDER IMPLICATIONS OF THE FINDINGS: Whilst we cannot rule out an association between HRT use and melanoma risk, the associations observed are also compatible with increased healthcare utilisation and thus increased melanoma detection amongst HRT users. No association between HRT use and melanoma survival outcomes was observed. This should provide some reassurance to patients and clinicians, particularly concerning the use of HRT in patients with a history of melanoma. STUDY FUNDING/COMPETING INTEREST(S): B.M.H. is funded by a Cancer Research UK Population Research Postdoctoral Fellowship. The funding source had no influence on the design or conduct of this study. A.P. reports participation in research projects funded by Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Servier, Novo Nordisk and LEO Pharma, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this article. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Fracture-induced changes in biomarkers CTX, PINP, OC, and BAP-a systematic review.

To assess the time from fracture until bone turnover markers (BTM), which are biochemical markers reflecting in vivo bone formation and resorptive activity, have returned to a stable level since BTM have been shown to be at least as good as bone mineral density in monitoring the effect of anti-resorptive treatment in osteoporosis. This study searched for articles in PUBMED, CINAHL, Medline, EM-BASE, and Cochrane, and identified 3486 unique articles. These articles were screened based on predefined inclusion and exclusion criteria. Seven articles addressing time to normalization of either CTX, PINP, osteocalcin, or bone-specific alkaline phosphatase after a recent fracture were identified and these were analyzed qualitatively. CTX appeared to return to baseline within 6 months. PINP appeared to return to baseline within 6 months and interestingly dip below baseline after a year. Osteocalcin was elevated throughout the first year after a fracture, with most changes in the first 6 months. Bone-specific alkaline phosphatase (BAP) was increased for up to a year, however with a discrepancy between used assays. Seven studies were identified, showing CTX and PINP to return to baseline within 6 months. OC was elevated for 12 months. BAP was increased for up to a year. However, none of these studies had fasting patients and a long follow-up period with regular measurements. The studies could indicate that the BTM CTX and PINP have returned to baseline within 6 months; however, further studies are needed assessing pre-analytical factors while having a long follow-up. Bone turnover markers appear as good as or better than bone mineral density in monitoring the effect of anti-resorptive medication in osteoporosis. This study tries to identify the time from fracture until BTM are back at baseline. Most studies did not however take pre-analytical variation into consideration. Further research is therefore needed.

Structural progression rate decreases over time on serial radiography and magnetic resonance imaging of sacroiliac joints and spine in a five-year follow-up study of patients with ankylosing spondylitis treated with tumour necrosis factor inhibitor.

OBJECTIVE: To investigate temporal changes in structural progression assessed by serial conventional radiography and magnetic resonance imaging (MRI) of the sacroiliac joints (SIJs) and spine in patients with ankylosing spondylitis (AS) treated with tumour necrosis factor (TNF) inhibitor for 5 years. METHOD: Forty-two patients were included and 33 patients were followed for 5 years in a prospective investigator-initiated study. Conventional radiographs were required four times and MRI seven times. The modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS); Spondyloarthritis Research Consortium of Canada (SPARCC) MRI SIJ and Spine Inflammation, and SPARCC MRI SIJ Structural Score (SSS) for Fat, Erosion, Backfill, and Ankylosis; and the Canada-Denmark MRI scores for Spine Inflammation, Fat, Erosion, and New Bone Formation (NBF) were applied. RESULTS: Compared with baseline, MRI Inflammation had decreased significantly at week 22 (spine)/week 46 (SIJ) and thereafter. MRI SIJ Fat (from week 22), SIJ Ankylosis, Spine NBF, and mSASSS had increased significantly at week 46 and thereafter. SIJ Erosion had decreased from year 2. The annual progression rate in mSASSS was significantly higher during weeks 0-46 compared to week 46 to year 3. In multivariate regression analyses, baseline SIJ Inflammation and Backfill were independent predictors of 5 year progression in SIJ Ankylosis. Spine Erosion predicted progression in Spine NBF. Longitudinally, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, MRI Spine Inflammation, Fat, and Erosion scores were significantly associated with mSASSS. SIJ Inflammation, Fat, Erosion, and Backfill scores were longitudinally associated with SIJ Ankylosis. Structural progression was not associated with body mass index, smoking, or Assessment of SpondyloArthritis international Society Non-Steroidal Anti-Inflammatory Drug Index. CONCLUSION: In a 5 year follow-up study of patients with AS treated with TNF inhibitor, structural progression decreased over time.

Prevalence of anxiety in patients with an implantable cardioverter defibrillator: measurement equivalence of the HADS-A and the STAI-S.

PURPOSE: The Hospital Anxiety and Depression Scale (HADS-A) and State-Trait Anxiety Inventory (STAI-S) are popular instruments for assessing anxiety and are considered interchangeable, although little is known about their equivalence. Hence, we examined whether the two instruments are (i) equivalent with respect to determining the prevalence of probable clinical anxiety levels and (ii) reflect variation on a common anxiety attribute. METHODS: Score and construct concordance were evaluated using equipercentile equating and bifactor modeling, respectively. Secondary data from the WEBCARE trial and the MIDAS study were used for the current study, where patients implanted with a first-time implantable cardioverter defibrillator completed both the HADS-A and the STAI-S within 10 days post implant. RESULTS: Data from 710 patients were included in the analyses. Results showed that the STAI-S produced a higher prevalence rate than the HADS-A (39% vs. 23%). A crosswalk table was generated with equivalent scores and cutoffs for the HADS-A and STAI-S, respectively. Bifactoring suggested that HADS-A and STAI-S largely tapped into the same generic anxiety attributes. CONCLUSIONS: STAI-S and HADS-A reflect a common anxiety attribute, but using the recommended cutoff scores on the respective measures show very different prevalence rates and would classify patients as anxious with the STAI-S who would not be identified as such with the HADS-A. Clinicians and researchers should be aware of the inequivalence when using these measures for screening and determining the prevalence of probable clinical anxiety levels.

Prevalence and predictors of weight loss maintenance: a retrospective population-based survey of European adults with overweight and obesity.

BACKGROUND: The prevalence of weight loss attempts has increased worldwide, although the extent to which sustained weight loss is achieved is unknown. There is insufficient research into weight loss maintenance (WLM) in individuals with overweight or obesity who have recently lost clinically significant amounts of weight (≥5%), particularly in the European general population. The present study aimed to determine the prevalence and retrospective predictors of WLM in population-based samples of European adults with overweight or obesity who had made a recently completed weight loss attempt. METHODS: Participants (N = 2000) in UK, Denmark and Portugal completed an online survey about loss and regain in their most recent completed weight loss attempt, features of their attempt (duration, self-weighing, lapses, strategies), as well as loss of control and binge eating. Multiple regression analysis was used to determine factors retrospectively associated with WLM in those who achieved clinically significant weight loss (n = 1272). RESULTS: Mean (SD) self-reported weight loss was 9% (8%) and mean (SD) regain was 96.3% (9%) of participants' start weight. Twenty-three percent of the total sample had maintained weight loss of ≥5% for at least 1 month. Controlling for weight loss and time since attempt, predictors of better WLM were avoidance of a temporary lapse, infrequent/absent loss of control and binge eating, and use of a greater number of dietary strategies for WLM (r2  = 0.338, P < 0.001). PRINCIPAL CONCLUSIONS: Factors associated with recent successful WLM indicate the importance of the continued use of dietary and other strategies for WLM, particularly in the face of a lapse, as well as the need to manage dysfunctional eating behaviours.

Chylomicronemia risk factors ranked by importance for the individual and community in 108 711 women and men.

BACKGROUND: Hypertriglyceridemia prevalence is increasing as more individuals become obese, and chylomicronemia risk factors for the individual and community have not been described previously. OBJECTIVE: To describe chylomicronemia risk factors in the general population for individuals and community. METHODS: A total of 108 711 individuals from the Copenhagen General Population Study were grouped as unlikely chylomicronemia (nonfasting triglycerides <2 mmol L-1 (177 mg dL-1 )), possible chylomicronemia (2-4.99 mmol L-1 (177-442 mg dL-1 )), probable chylomicronemia (5-9.99 mmol L-1 (443-885 mg dL-1 )) and definite chylomicronemia (≥10 mmol L-1 (≥ 886 mg dL-1 )). Relative risk (RR) from Poisson regression ranked dichotomized chylomicronemia risk factors for individuals, and population attributable fractions (PAF) for the community: type 2 diabetes, alcohol intake, obesity, fat intake, hypothyroidism, kidney function, education, sedentary lifestyle, menopause and hormone replacement (women). RESULTS: For women and men, chylomicronemia was unlikely in 81% and 64%, possible in 18% and 33%, probable in 1% and 3% and definite in 0.03% and 0.14%, respectively. For the individual, the three top-ranked risk factors for probable/definite versus unlikely chylomicronemia in women were type 2 diabetes (RR: 4.21; 95% confidence interval: 3.30-5.36), menopause (RR: 3.74; 2.62-5.36) and obesity (RR: 3.44; 2.81-4.21). Corresponding top-ranked risk factors in men were obesity (RR: 3.86; 3.46-4.30), type 2 diabetes (RR: 1.88; 1.61-2.19) and reduced kidney function (RR: 1.86; 1.48-2.34). For the community, top-ranked risk factors in women were menopause (PAF: 63%), obesity (PAF: 29%) and type 2 diabetes (PAF: 15%). Corresponding top-ranked risk factors in men were obesity (PAF: 29%), type 2 diabetes (PAF: 6.4%) and sedentary lifestyle (PAF: 6.0%). CONCLUSIONS: Obesity and type 2 diabetes were the most important modifiable chylomicronemia risk factors in women and men, both for the individual and community. This could influence chylomicronemia prevention and help design randomized trials aimed at reducing triglycerides.

Phenylbutazone induces equine glandular gastric disease without decreasing prostaglandin E2 concentrations.

In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n = 6; 4.4 mg/kg phenylbutazone PO in 20 ml molasses q 12 hr for 7 days) or placebo (n = 6; 20 ml molasses PO q 12 hr for 7 days) groups. Before treatment and 3 and 7 days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80°C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E2 concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone-treated horses developed grade ≥2 glandular disease. Prostaglandin concentrations increased over time (p = .0017), but there was no effect of treatment (p = .49). These findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration.

Circulating sCD36 levels in patients with non-alcoholic fatty liver disease and controls.

BACKGROUND AND OBJECTIVE: CD36 is implicated in fatty-acid uptake in multiple tissues, including hepatocytes and adipocytes. Circulating CD36 (sCD36) is increased in non-alcoholic fatty liver disease (NAFLD). We explored this association further by investigating correlations between sCD36 levels, intrahepatic lipid content and markers of obesity in NAFLD patients and controls. METHODS: In total, 111 NAFLD patients and 33 normal/overweight controls were included. Intrahepatic lipid content was measured by magnetic resonance spectroscopy; and subgroups of participants had a dual-energy X-ray absorptiometry (n=99), magnetic resonance imaging (n=94, subcutaneous and visceral adipose tissue) and liver biopsy (n=28 NAFLD patients) performed. Plasma sCD36 was assessed by enzyme-linked immunosorbent assay. RESULTS: NAFLD patients had elevated sCD36 levels compared with controls (0.68 (0.12-2.27) versus 0.43 (0.10-1.18), P<0.01). sCD36 correlated with intrahepatic lipid (rs=0.30), alanine transaminase (ALT) (r=0.31), homeostasis model assessment index-insulin resistance (r=0.24), high-density lipoprotein (r=-0.32) and triglyceride (r=0.44, all P<0.01). Intrahepatic lipid and plasma triglyceride were independent predictors of sCD36 levels in a multiple regression analysis. Further, sCD36 and body mass index were weakly correlated (r=0.17, P=0.04); yet, we found no correlations between sCD36 and other measures of fat distribution except an inverse relation to visceral adipose tissue (rs=-0.21, P<0.05). We observed a trend for correlation between sCD36 and hepatic CD36 mRNA expression (r=0.37, P=0.07). CONCLUSIONS: sCD36 levels increased with the level of intrahepatic lipid, insulin resistance and dyslipidemia. The weak association with markers of obesity and the association with hepatic CD36 mRNA expression suggest that excess sCD36 in NAFLD patients is derived from the hepatocytes, which may support that CD36 is involved in NAFLD development. An unhealthy and unbalanced CD36 expression in adipose and hepatic tissue may shift the fatty-acid load to the liver.

Chronic maternal inflammation or high-fat-feeding programs offspring obesity in a sex-dependent manner.

BACKGROUND/OBJECTIVES: The current world-wide obesity epidemic partially results from a vicious circle whereby maternal obesity during pregnancy predisposes the offspring for accelerated weight gain and development of metabolic syndrome. Here we investigate whether low-grade inflammation, characteristic of the obese state, provides a causal role for this disastrous fetal programming in mice. METHODS: We exposed pregnant and lactating C57BL/6JBom female mice to either high-fat diet (HFD), or continuous infusion of lipopolysaccharide (LPS), a potent trigger of innate immunity, and studied offspring phenotypes. RESULTS: Both maternal LPS or HFD treatments rendered the offspring hyperphagic and inept of coping with a HFD challenge during adulthood, increasing their adiposity and weight gain. The metabolic effects were more pronounced in female offspring, while exposed male offspring mounted a larger inflammatory response to HFD at adulthood. CONCLUSIONS: This supports our hypothesis and highlights the programming potential of inflammation in obese pregnancies.

Tumor microenvironment conditions alter Akt and Na+/H+ exchanger NHE1 expression in endothelial cells more than hypoxia alone: implications for endothelial cell function in cancer.

BACKGROUND: Chronic angiogenesis is a hallmark of most tumors and takes place in a hostile tumor microenvironment (TME) characterized by hypoxia, low nutrient and glucose levels, elevated lactate and low pH. Despite this, most studies addressing angiogenic signaling use hypoxia as a proxy for tumor conditions. Here, we compared the effects of hypoxia and TME conditions on regulation of the Na+/H+ exchanger NHE1, Ser/Thr kinases Akt1-3, and downstream effectors in endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVEC) and Ea.hy926 endothelial cells were exposed to simulated TME (1% hypoxia, low serum, glucose, pH, high lactate) or 1% hypoxia for 24 or 48 h, with or without NHE1 inhibition or siRNA-mediated knockdown. mRNA and protein levels of NHE1, Akt1-3, and downstream effectors were assessed by qPCR and Western blotting, vascular endothelial growth factor (VEGF) release by ELISA, and motility by scratch assay. RESULTS: Within 24 h, HIF-1α level and VEGF mRNA level were increased robustly by TME and modestly by hypoxia alone. The NHE1 mRNA level was decreased by both hypoxia and TME, and NHE1 protein was reduced by TME in Ea.hy926 cells. Akt1-3 mRNA was detected in HUVEC and Ea.hy926 cells, Akt1 most abundantly. Akt1 protein expression was reduced by TME yet unaffected by hypoxia, while Akt phosphorylation was increased by TME. The Akt loss was partly reversed by MCF-7 human breast cancer cell conditioned medium, suggesting that in vivo, the cancer cell secretome may compensate for adverse effects of TME on endothelial cells. TME, yet not hypoxia, reduced p70S6 kinase activity and ribosomal protein S6 phosphorylation and increased eIF2α phosphorylation, consistent with inhibition of protein translation. Finally, TME reduced Retinoblastoma protein phosphorylation and induced poly-ADP-ribose polymerase (PARP) cleavage consistent with inhibition of proliferation and induction of apoptosis. NHE1 knockdown, mimicking the effect of TME on NHE1 expression, reduced Ea.hy926 migration. TME effects on HIF-1α, VEGF, Akt, translation, proliferation or apoptosis markers were unaffected by NHE1 knockdown/inhibition. CONCLUSIONS: NHE1 and Akt are downregulated by TME conditions, more potently than by hypoxia alone. This inhibits endothelial cell migration and growth in a manner likely modulated by the cancer cell secretome.

Maternal systemic or cord blood inflammation is associated with birth anthropometry in a Tanzanian prospective cohort.

OBJECTIVES: HIV infection is associated with chronic systemic inflammation, with or without antiretroviral therapy. Consequences for foetal growth are not understood, particularly in settings where multiple maternal infections and malnutrition are common. The study was designed to examine maternal systemic circulating and umbilical cord blood cytokine concentrations in relation to birth anthropometry in a Tanzanian prospective cohort. METHODS: A 9-plex panel of maternal plasma cytokines in HIV-positive (n = 44) and HIV-negative (n = 70) mothers and the same cytokines in umbilical cord blood collected at delivery was assayed. Linear regression modelled associations between maternal or cord blood cytokines and birth anthropometry. RESULTS: Health indicators (haemoglobin, mid-upper-arm circumference, body mass index) in HIV-positive mothers without considerable immunosuppression did not differ from HIV-negative women. Despite this, HIV-exposed infants had lower birthweight and length. Subgroup analyses indicated that HIV management using HAART was associated with lower plasma TNF-α, as were longer durations of any antiretroviral therapy (≥2 months). Greater maternal plasma TNF-α was associated with earlier delivery (-1.7 weeks, P = 0.039) and lower birthweights (-287 g; P = 0.020), while greater umbilical cord TNF-α (-1.43 cm; P = 0.036) and IL-12p70 (-2.4 cm; P = 0.008) were associated with shorter birth length. Birthweight was inversely associated with cord IL-12p70 (-723 g; P = 0.001) and IFN-γ (-482 g, P = 0.007). Maternal cytokines during pregnancy did not correlate with umbilical cord cytokines at delivery. CONCLUSIONS: Systemic inflammation identified in maternal plasma or umbilical cord blood was associated with poorer birth anthropometrics in HIV-exposed and HIV-unexposed infants. Controlling maternal and/or foetal systemic inflammation may improve birth anthropometry.