[Study on the relationship between serum vitamin D and the risk of type 2 diabetes in Harbin residents].

Objective: To analyze the relationship between serum vitamin D level and the risk of type 2 diabetes in Harbin residents. Methods: On April 2010, 24 communities in 7 districts of Harbin were selected as research sites using multi-stage stratified cluster random sampling method. A total of 9 734 residents aged 20-74 years was investigated using general questionnaire survey, dietary survey and biochemical indicators test and followed up from January 2015 to July 2016. A total of 4 721 subjects with serum vitamin D were included in the study. According to the quartile of baseline serum vitamin D, the subjects were divided into four groups, from Q1 to Q4 group. The multivariate logistic regression model was used to analyze the relationship between serum vitamin D and the risk of type 2 diabetes. A mediation analysis model was used to analyze the mediating role of insulin resistance in this risk relationship. Results: At the time of follow-up, 432 patients with type 2 diabetes were screened. The median (P(25), P(75)) age of the diabetic group and the non-diabetic group were 54 (49, 61) and 51 (43, 57) years, respectively, and males accounted for 40.5% (175 cases) and 35.5% (1 513 cases), respectively. The median (P(25), P(75)) serum vitamin D was 16.0 (13.5, 18.5) and 17.4 (14.3, 20.5) ng/ml, respectively. After relevant confounders and insulin resistance index (HOMA-IR) were adjusted, compared to the serum vitamin D level Q(1) group, the risk of diabetes was reduced by 40% in the Q(3) group with RR (95%CI) about 0.60 (0.44-0.82), while the risk of diabetes was reduced by 59% in Q(4) group with RR (95%CI) about 0.41 (0.29-0.57). Through mediation analysis, the Gutt index mediating effect representing peripheral insulin resistance was 53.8%, and the mediating effect of HOMA-IR representing hepatic insulin resistance was 6.6%. Conclusion: The risk of type 2 diabetes is low in Harbin residents with higher serum vitamin D level. Insulin resistance has a mediating effect on the relationship of vitamin D and the risk of type 2 diabetes.

[Association between dietary magnesium and the risk of type 2 diabetes in Harbin residents].

Objective: To investigate the relationship between the magnesium intake and patterns of diary and the risk of type 2 diabetes in Harbin residents. Methods: On April 2010, 24 communities in 7 districts of Harbin were selected as research sites using multi-stage stratified random cluster sampling method. A total of 9 734 residents aged 20-74 years was investigated using general questionnaire survey, dietary survey and biochemical indicators test. A total of 9 376 subjects were included in the study. Factor analysis was used to analyze dietary patterns. According to the quartile of dietary magnesium intake, the subjects were divided into four groups, from Q(1) to Q(4) group. The multivariate logistic regression model was used to analyze the relationship between dietary magnesium intake and the risk of type 2 diabetes within different dietary patterns. Results: A total of 998 subjects with type 2 diabetes were screened. The median age of the diabetic group and the non-diabetic group were 54.8 and 50.8, respectively, and the males accounted for 43.4% (2 896 cases) and 34.6% (433 cases), respectively. The magnesium intake median (P(25), P(75)) of two groups was 336.36 (257.31, 440.65) and 339.50 (264.51, 443.78) mg/d. Four dietary patterns were identified as western dietary mode, savvy dietary mode, traditional dietary mode, and staple food mode. In the western dietary model, the Q(4) group had a higher risk of type 2 diabetes than Q(1) group, with an OR (95%CI) value of 1.56 (1.06 to 2.32). However, in the savvy diet mode, compared with the Q(1) group, the risk of diabetes in the Q(4) group was lower, and the OR (95%CI) value was 0.61 (0.37 to 0.96). There was no statistically significant association between dietary magnesium intake and the risk of type 2 diabetes without considering dietary patterns (P>0.05). Conclusion: Dietary magnesium intake has a different relationship with the risk of type 2 diabetes within different dietary patterns.

Different associations between body composition and alcohol when assessed by exposure frequency or by quantitative estimates of consumption.

BACKGROUND: Alcohol intake is widely assumed to contribute to excess body fatness, especially among young men; however, the evidence is inconsistent. We have addressed this research question by investigating associations between reported alcohol consumption and body composition from large representative national surveys in a high alcohol-consuming country with a high obesity prevalence. METHODS: The present study comprised a secondary analysis of combined cross-sectional nationally representative Scottish Health Surveys (1995-2010). Reported alcohol-drinking frequency was divided into five groups: from 'nonfrequent drinking' (reference) to daily/'almost every day' among 35 837 representative adults [mean (SD) age: 42.7 (12.7) years (range 18-64 years)]. Quantitative alcohol consumption was categorised into seven groups: from '1-7 to ≥50 10 g units per week'. Regression models against measured body mass index (BMI) and waist circumference (WC) were adjusted for age, physical activity, income, smoking, deprivation category and economic status. RESULTS: Among alcohol-consuming men, heavier drinking (21-28 units per week) was associated with a higher BMI by +1.4 kg m-2 [95% confidence interval (CI) = 1.38-1.43] and higher WC by +3.4 cm (95% CI = 3.2-3.6) than drinking 1-7 units per week. However, those who reported daily drinking frequency were associated with a lower BMI by -2.45 kg m-2 (95% CI = -2.4 to -2.5) and lower WC by -3.7 cm (95% CI = -3.3 to -4.0) than those who reported less-frequent drinking. Similar associations were found for women. Most of these associations were restricted to subjects aged >30 years. Unexplained variances in BMI and WC are large. CONCLUSIONS: Quantitative alcohol consumption and frequency of consumption were positively and inversely associated, respectively, with both BMI and WC among alcohol-consuming adults. Surveys are needed that evaluate both the quantity and frequency of consumption. The lowest BMI and WC were associated with a 'Mediterranean' drinking style (i.e. relatively little, but more frequently).

Glucocorticoid treatment regimen and health outcomes in adults with congenital adrenal hyperplasia.

BACKGROUND: Adults with congenital adrenal hyperplasia (CAH) are treated with a wide variety of glucocorticoid treatment regimens. OBJECTIVE, DESIGN AND METHODS: To test whether drug dose and timing of glucocorticoid treatment regimen impacts on health outcomes. This was a cross-sectional study of 196 adult CAH patients in whom treatment and health outcomes were measured. Glucocorticoid dose was converted to prednisolone dose equivalent (PreDEq) using three published formulae. Associations between the type of glucocorticoid regimen and PreDEq with specific health outcome variables were tested using partial correlation and principal components analysis (PCA). RESULTS: Patients on dexamethasone had lower androgens and ACTH but greater insulin resistance compared with those receiving hydrocortisone or prednisolone. Dexamethasone dose and once daily administration were associated with insulin resistance. Partial correlation analysis adjusted for age and sex showed PreDEq weakly correlated (r < 0·2) with blood pressure and androstenedione. Mutation severity was associated with increased PreDEq (F(3,141)  = 4·4, P < 0·01). In PCA, 3 PCs were identified that explained 62% of the total variance (r(2) ) in observed variables. Regression analysis (age and sex adjusted) confirmed that PC2, reflecting disease control (androstenedione, 17-hydroxypregesterone and testosterone), and PC3, reflecting blood pressure and mutations (systolic and diastolic blood pressure and mutation severity), related directly to PreDEq (r(2)  = 23%, P < 0·001). CONCLUSIONS: In adults with congenital adrenal hyperplasia, dexamethasone use was associated with lower androgens but greater insulin resistance, and increasing glucocorticoid dose associated with increased blood pressure, poor disease control and mutation severity.

Clinical Characteristics and Mortality of Old and Very Old Patients Hospitalized for Hip Fracture or Acute Medical Conditions.

BACKGROUND: There is increasing interest in healthcare quality and economic implications for hip fracture patients of very old age. However, results are limited by access to comparable control groups. OBJECTIVES: We examined healthcare quality measures including mortality and length of stay (LOS) in hospital of adults aged 60-107 years undergoing hip operations, compared to an age-matched group admitted for acute general medical conditions. DESIGN: Monocentric cross-sectional study. SETTING: Ashford and St Peter's Hospitals NHS Foundation Trust, Surrey, United Kingdom. PARTICIPANTS: A total of 3972 consecutive admissions for hip operation from 1st April 2009 to 30th June 2019 (dataset-1) and 6979 for acute general medical conditions from 1st April 2019 to 29th February 2020 (dataset-2). Respective ages, mean (±standard deviation), were 83.5 years (±9.1) and 79.8 years (±9.8). MEASUREMENTS: Mortality and LOS were assessed with each group divided into five- year age bands and those ≥95 years. RESULTS: There were proportionally more (P <0.001) females admitted for hip operations (72.8%) than for acute general medical conditions (53.8%). Amongst patients admitted with general medical conditions, the frequency of the most serious recorded conditions - including congestive heart failure, stroke, and pneumonia - increased with age. Amongst patients undergoing hip operations, 5.7% died in hospital and 29.3% had a LOS ≥3 weeks. Corresponding values for acute general medical conditions were 10.4% and 11.8%. For those undergoing hip operations in all age categories, the risk of death was lower than for acute general medical group: sex-adjusted odds ratios ranged between 0.27 and 0.67, but the risk of LOS ≥3 weeks was greater: odds ratios ranged between 2.46 and 2.95. CONCLUSIONS: Compared to those admitted with acute general medical conditions, patients admitted for hip operations had a lower risk of death, but a longer hospital LOS. .

Thyroid hormones and male sexual function.

The role of thyroid hormones in the control of erectile functioning has been only superficially investigated. The aim of the present study was to investigate the association between thyroid and erectile function in two different cohorts of subjects. The first one derives from the European Male Ageing Study (EMAS study), a multicentre survey performed on a sample of 3369 community-dwelling men aged 40-79 years (mean 60 ± 11 years). The second cohort is a consecutive series of 3203 heterosexual male patients (mean age 51.8 ± 13.0 years) attending our Andrology and Sexual Medicine Outpatient Clinic for sexual dysfunction at the University of Florence (UNIFI study). In the EMAS study all subjects were tested for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Similarly, TSH levels were checked in all patients in the UNIFI study, while FT4 only when TSH resulted outside the reference range. Overt primary hyperthyroidism (reduced TSH and elevated FT4, according to the reference range) was found in 0.3 and 0.2% of EMAS and UNIFI study respectively. In both study cohorts, suppressed TSH levels were associated with erectile dysfunction (ED). Overt hyperthyroidism was associated with an increased risk of severe erectile dysfunction (ED, hazard ratio = 14 and 16 in the EMAS and UNIFI study, respectively; both p < 0.05), after adjusting for confounding factors. These associations were confirmed in nested case-control analyses, comparing subjects with overt hyperthyroidism to age, BMI, smoking status and testosterone-matched controls. Conversely, no association between primary hypothyroidism and ED was observed. In conclusion, erectile function should be evaluated in all individuals with hyperthyroidism. Conversely, assessment of thyroid function cannot be recommended as routine practice in all ED patients.

Obesity and weight management in the elderly.

Our population is ageing, and obesity is increasing in the elderly bringing massive and rapidly changing burdens of ill health related to increased body weights and fat as well as the main drivers of poor diet and inactivity. Overweight and obesity, and a static body mass index (BMI) commonly conceal sarcopenia (gain in body fat but loss of muscle mass and functional capacity) in older people, aggravated by inactivity. A systematic computerized literature search using an iterative manipulation process of the keywords: obesity, elderly, weight loss. The following databases were accessed on 20 October 2010: Medline, Cochrane Collaboration, Ovid and Scholar Google. A large number of clinical consequences of overweight and obesity are particularly problematic for elderly individuals, including type 2 diabetes mellitus, arthritis, urinary incontinence and depression. The observation that the BMI value associated with the lowest relative mortality is slightly higher in older than in younger adults has often been misinterpreted that obesity is not as harmful in the elderly. BMI may be a less appropriate index in the elderly. All the medical consequences of obesity are multi-factorial but all are alleviated by modest, achievable weight loss (5-10 kg) with an evidence-based maintenance strategy. Since sarcopenic obesity is common in the elderly, a combination of exercise and modest calorie restriction appears to be the optimal method of reducing fat mass and preserving muscle mass. Reduction in polypharmacy is a valuable target for weight management. Age is not an obstacle to weight management interventions using moderate calorie restriction and exercise, and the currently licensed drug orlistat appears to have no age-related hazards. Overall balance of clinical outcomes has not been evaluated. In older people the risks from bariatric surgery outweigh benefits. Obesity, and specifically sarcopenic obesity, should also be prevented not only from younger age, but also during major life transitions including retirement, to improve better health outcomes and quality of life in later years, with a focus on those in 'obese families', where the main increases in obesity are located. Randomized controlled trials to determine health benefits and risks from long-term weight management in obese elderly are necessary.

Influence of age and sex steroids on bone density and geometry in middle-aged and elderly European men.

SUMMARY: The influence of age and sex steroids on bone density and geometry of the radius was examined in two European Caucasian populations. Age-related change in bone density and geometry was observed. In older men, bioavailable oestradiol may play a role in the maintenance of cortical and trabecular bone mineral density (BMD). INTRODUCTION: To examine the effect of age and sex steroids on bone density and geometry of the radius in two European Caucasian populations. METHODS: European Caucasian men aged 40-79 years were recruited from population registers in two centres: Manchester (UK) and Leuven (Belgium), for participation in the European Male Ageing Study. Total testosterone (T) and oestradiol (E(2)) were measured by mass spectrometry and the free and bioavailable fractions calculated. Peripheral quantitative computed tomography was used to scan the radius at distal (4%) and midshaft (50%) sites. RESULTS: Three hundred thirty-nine men from Manchester and 389 from Leuven, mean ages 60.2 and 60.0 years, respectively, participated. At the 50% radius site, there was a significant decrease with age in cortical BMD, bone mineral content (BMC), cortical thickness, and muscle area, whilst medullary area increased. At the 4% radius site, trabecular and total volumetric BMD declined with age. Increasing bioavailable E(2) (bioE(2)) was associated with increased cortical BMD (50% radius site) and trabecular BMD (4% radius site) in Leuven, but not Manchester, men. This effect was predominantly in those aged 60 years and over. In older Leuven men, bioavailable testosterone (Bio T) was linked with increased cortical BMC, muscle area and SSI (50% radius site) and total area (4% radius site). CONCLUSIONS: There is age-related change in bone density and geometry at the midshaft radius in middle-aged and elderly European men. In older men bioE(2) may maintain cortical and trabecular BMD. BioT may influence bone health through associations with muscle mass and bone area.

Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study.

Metabolic syndrome (MetS) is associated with cardiovascular disease in the general population and is also a potential cardiovascular risk factor in survivors of haematopoietic cell transplantation (HCT). We report an EBMT cross-sectional, multi-centre, non-interventional study of 453 adult HCT patients surviving a minimum of 2 years post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. The overall prevalence of MetS was 37.5% rising to 53% in patients >50 years of age at follow-up. There were no differences in rates of MetS between autologous and allogeneic HCT survivors, nor any association with graft-versus-host disease (GvHD) or current immunosuppressant therapy. Notably, there was a significantly higher occurrence of cardiovascular events (CVE, defined as cerebrovascular accident, coronary heart disease or peripheral vascular disease) in those with MetS than in those without MetS (26.7% versus 9%, p < 0.001, OR 3.69, 95% CI 2.09-6.54, p < 0.001), and, as expected, MetS and CVE were age-related. Unexpectedly, CVE were associated with occurrence of second malignancy. Screening for and management of MetS should be integrated within routine HCT long-term follow-up care for both allogeneic and autologous HCT survivors. Further research is warranted, including randomised controlled trials of interventional strategies and mechanistic studies of cardiovascular risk in HCT survivors.

What is the optimal therapy for young males with hypogonadotropic hypogonadism?

Hypogonadotropic hypogonadism (HH), consequent to congenital or acquired disorders of the hypothalamic-pituitary axis, presents as absent/delayed/arrested sexual maturation and infertility. Optimal management includes: (a) confirmation of the diagnosis and prognosis, (b) timing and choice of therapeutic intervention and (c) consideration of future fertility prospects. Therapy is usually initiated with testosterone to induce development of secondary sexual characteristics, taking the patient (often diagnosed late) through puberty. Monitoring of the impact of the condition on long-term health and psychosocial function is necessary. Treatment is likely to be life-long, requiring regular monitoring for its optimization and avoidance of adverse responses. Induction of spermatogenesis requires either pulsatile gonadotropin releasing hormone (GnRH) or gonadotropin administration. Gonadotropins can be self-administered subcutaneously and are not inferior to the more costly GnRH. 'Reversible genetic hypogonadotropic hypogonadism' is a recently described entity which has implications for the long-term management of patients with HH.

Gonadal sex steroid status and bone health in middle-aged and elderly European men.

SUMMARY: The influence of sex steroids on calcaneal quantitative ultrasound (QUS) parameters was assessed in a population sample of middle-aged and elderly European men. Higher free and total E(2) though not testosterone, were independently associated with higher QUS parameters. INTRODUCTION: The aim of this study was to investigate the association between QUS parameters and sex steroids in middle-aged and elderly European men. METHODS: Three thousand one hundred forty-one men aged between 40 and 79 years were recruited from eight European centres for participation in a study of male ageing: the European Male Ageing Study. Subjects were invited by letter to attend for an interviewer-administered questionnaire, blood sample and QUS of the calcaneus (Hologic-SAHARA). Blood was assessed for sex steroids including oestradiol (E(2)), testosterone (T), free and bio-available E(2) and T and sex hormone binding globulin (SHBG). RESULTS: Serum total T was not associated with any of the QUS parameters. Free T and both free and total E(2) were positively related to all QUS readings, while SHBG concentrations were negatively associated. These relationships were observed in both older and younger (<60 years) men. In a multivariate model, after adjustment for age, centre, height, weight, physical activity levels and smoking, free E(2) and SHBG, though not free T, remained independently associated with the QUS parameters. After further adjustment for IGF-1, however, the association with SHBG became non-significant. CONCLUSION: Higher free and total E(2) are associated with bone health not only among the elderly but also middle-aged European men.

Investigating the determinants of international differences in the prevalence of chronic widespread pain: evidence from the European Male Ageing Study.

OBJECTIVES: To determine whether among middle-aged and elderly men there is evidence of international differences in the prevalence of chronic widespread pain (CWP) and whether any such differences could be explained by psychological, psychosocial factors or differences in physical health status. METHODS: The European Male Ageing Study (EMAS) sampled from population registers in cities (centres) of eight European countries. Each centre recruited an age-stratified sample of men aged 40-79 years. Information on pain was collected by questionnaire and subjects were classified according to whether they satisfied the American College of Rheumatology definition of CWP. Information was collected on social status, mental health, recent life events and co-morbidities. RESULTS: Across all centres 3963 subjects completed a study questionnaire, with participation rates ranging from 24% in Hungary to 72% in Estonia. There were significant differences in prevalence: between 5% and 7% in centres in Italy, England, Belgium and Sweden, 9-15% in centres in Spain, Poland and Hungary and 15% in Estonia. There were strong relationships between poor mental health, adverse recent life events, co-morbidities and CWP. Adjustment for these factors explained between half and all of the excess risk in the eastern European centres: the excess risk in Poland was explained (odds ratio (OR) 1.1, 95% CI 0.9 to 1.2) but there remained excess risk in Hungary (OR 1.6, 95% CI 1.4 to 1.8) and Estonia (OR 2.6, 95% CI 2.2 to 2.9). CONCLUSIONS: This study is the first directly to compare the occurrence of CWP internationally. There is an excess prevalence in countries of eastern Europe and this excess is associated with adverse psychosocial factors as well as poorer psychological and physical health.

Benzofuran derivatives and the thyroid.

Amiodarone and dronedarone are two clinically important benzofuran derivatives. Amiodarone has been used widely for treating resistant tachyarrhythmias in the past three decades. However amiodarone and its main metabolically active metabolite desethylamiodarone can adversely affect many organs, including the thyroid gland. Amiodarone-induced thyroid disorders are common and often present as a management challenge for endocrinologists. The pathogenesis of amiodarone-induced thyroid dysfunction is complex but the inherent effects of the drug itself as well as its high iodine content appear to play a central role. The non-iodinated dronedarone also exhibits anti-arrhythmic properties but appears to be less toxic to the thyroid. This review describes the biochemistry of benzofuran derivatives, including their pharmacology and the physiology necessary for understanding the cellular mechanisms involved in their actions. The known effects of these compounds on thyroid action are described. Recommendations for management of amiodarone-induced hypothyroidism and thyrotoxicosis are suggested. Dronedarone appears to be an alternative but less-effective anti-arrhythmic agent and it does not have adverse effects on thyroid function. It may have a future role as an alternative agent in patients being considered for amiodarone therapy especially those at high risk of developing thyroid dysfunction but not in severe heart failure.

Associations of BMI, waist circumference, body fat, and skeletal muscle with type 2 diabetes in adults.

AIMS: Type 2 diabetes (T2D) is known to be associated with high BMI and waist circumference (WC). These measures do not discriminate well between skeletal muscle (SM) and body fat (BF), which may have opposite influences. METHODS: We conducted a secondary analysis of population-based data from 58,128 aged 18-85 yrs from Scottish Health Surveys (2003, 2008-2011) and Health Surveys for England (2003-2006, 2008-2013), excluding pregnant women and insulin-treated diabetes. Logistic regression was used to assess associations of known T2D, and of screened HbA1c > 48 mmol/mol (> 6.5%), with sex-specific quintiles of BMI, WC, and BF% and SM% estimated by validated anthropometric equations, adjusted for age, sex, smoking, ethnicity, country, and survey year. RESULTS: As expected, ORs for having known T2D rose with quintiles of BMI (1, 1.5, 2.3, 3.1, and 6.5) and WC (1, 1.8, 2.5, 3.5, and 8.7). Compared to the lowest BF% quintile, OR for having T2D in highest BF% quintile was 11.1 (95% CI = 8.4-14.6). Compared to the highest SM% quintile, OR for having T2D in lowest SM% quintile was 2.0 (1.7-2.4). Of 72 adults with T2D/HbA1c > 6.5% in the lowest quintile of BF%, 27 (37.5%) were in quintile 1 of SM%. Similar patterns of OR were observed for having HbA1c > 6.5% in those without known T2D. CONCLUSIONS: Estimated BF% associates strongly with T2D. Low SM% also has a significant association, suggesting a neglected aspect of aetiology within T2D. These two simple measures with biological relevance, available from data collected in most health surveys, may be more useful than the purely statistical terms BMI.

Efficacy of moxibustion after rolling correction in dairy cows with abomasal displacement.

This study was performed to assess the efficacy of moxibustion after rolling correction in dairy cows with abomasal displacement (AD). The experimental group comprised 86 Holstein cows with left displacement of the abomasum (LDA) and right displacement of the abomasum (RDA), with a mean age of 3.8 with AD during a 2-year period. The cows were rolled for correction of AD. After the rolling procedure, moxibustion was conducted on six acupoints once a day during the course of treatment. After repositioning the abomasums, the bilateral points of BL-20, BL-21 and BL-26 were then stimulated. During the follow-up of 1 week, 67 (93.1%) of 72 LDA and 12 (85.7%) of 14 RDA cows were released as cured after moxibustion. In conclusion, moxibustion effectively treats AD following rolling correction in dairy cows.

Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation.

Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated ApcΔ716 Trp53LSL•R270H villin-CreER compound mice, in which mutant p53R270H was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids. Mutant Trp53R270H, but not Trp53-null mutation accelerated submucosal invasion with generation of desmoplastic microenvironment. The nuclear accumulation of p53 was evident in ApcΔ716 Trp53R270H/R270H homozygous tumors like human CRC. Although p53 was distributed to the cytoplasm in ApcΔ716 Trp53+/R270H heterozygous tumors, it accumulated in the nuclei at the invasion front, suggesting a regulation mechanism for p53 localization by the microenvironment. Importantly, mutant p53 induced drastic morphological changes in the tumor organoids to complex glandular structures, which was associated with the acquisition of invasiveness. Consistently, the branching scores of human CRC that carry TP53 mutations at codon 273 significantly increased in comparison with those of TP53 wild-type tumors. Moreover, allografted ApcΔ716 Trp53R270H/R270H organoid tumors showed a malignant histology with an increased number of myofibroblasts in the stroma. These results indicate that nuclear-accumulated mutant p53R270H induces malignant progression of intestinal tumors through complex tumor gland formation and acquisition of invasiveness. Furthermore, RNA sequencing analyses revealed global gene upregulation by mutant p53R270H, which was associated with the activation of inflammatory and innate immune pathways. Accordingly, it is possible that mutant p53R270H induces CRC progression, not only by a cell intrinsic mechanism, but also by the generation or activation of the microenvironment, which may synergistically contribute to the acceleration of submucosal invasion. Therefore, the present study indicates that nuclear-accumulated mutant p53R270H is a potential therapeutic target for the treatment of advanced CRCs.

Impairment of health and quality of life using new US federal guidelines for the identification of obesity.

BACKGROUND: Estimating total burdens of disease associated with overweight and obesity has been hampered by a lack of consistent published data using standardized body mass index (BMI or Quetelet index [calculated as weight in kilograms divided by the square of the height in meters: weight (kg)/[height x (m)2]]) diagnostic criteria, and by poorly standardized reference populations. SUBJECTS AND METHODS: Symptoms of respiratory insufficiency, low back pain, non-insulin-dependent diabetes mellitus, cardiovascular risk factors, and physical functioning using SF-36 questionnaire were determined in a cross-sectional representative survey of 5887 men and 7018 women aged 20 to 59 years from the Netherlands and analyzed using BMI criteria of the National Institutes of Health and the World Health Organization guidelines. RESULTS: The prevalences of cardiovascular risks were higher in men than women, but the other health outcomes were more frequent in women. Virtually all health outcomes considered were significantly influenced by BMI. A BMI of 25 to 30 kg/m2 had a generally greater impact on odds ratios for health outcomes in women than in men. People with BMI below 25 kg/m2 were considered the reference group, with low prevalence of symptoms of obesity-related diseases and good quality of life. Between 25 to 30 kg/m2, the prevalences of these were all increased, and above 30 kg/m2 greatly increased. After adjustments for age and lifestyle factors, odds ratios (95% confidence intervals [95% CI]) in those with a BMI of 30 kg/m2 or higher were 3.5 (95% CI, 2.8-4.4) in men and 3.3 (95% CI, 2.8-3.9) in women for shortness of breath when walking upstairs, 4.6 (95% CI, 2.4-8.8) in men and 5.4 (95% CI, 2.8-10.5) in women for non-insulin-dependent diabetes mellitus, 5.5 (95% CI, 4.5-6.6) in men and 2.9 (95% CI, 2.4-3.4) in women for having at least 1 major cardiovascular risk factor. Both men and women with BMI of 30 kg/m2 or higher were twice as likely to have difficulties in performing a range of basic daily physical activities. Compared with women with BMI lower than 25 kg/m2, those with BMI of 30 kg/m2 or higher were 1.5 times more likely to have symptoms of intervertebral disk herniation. Significantly more overweight women had problems associated with low back pain, including hindrance to their daily business, absence from work, and medical consultation. CONCLUSIONS: Health risks for a range of problems are presented using the standard BMI cutoff points. Overweight and obesity are associated with increased risks of chronic diseases, secondary symptoms, and impairment of quality of life.

Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes.

OBJECTIVE: To examine the effects of a thiazolidinedione (600 mg troglitazone) insulin-sensitizing treatment on total body fat measured by underwater weighing, on intra- and extra-abdominal fat mass using magnetic resonance imaging (MRI), and on anthropometric measures. RESEARCH DESIGN AND METHODS: Type 2 diabetic outpatients were studied in a double-blind randomized trial carried out at Glasgow Royal Infirmary, Scotland. RESULTS: Groups who received troglitazone (8 men, 3 women) and placebo (8 men, 2 women) were well matched for age, BMI, total body fat percentage by underwater weighing, and intra-abdominal fat (kilograms) by MRI. After 12 weeks, body weight changes in the troglitazone group (mean +0.66 kg [95% CI -0.71 to 2.04], P = 0.31) and the placebo group (mean +0.25 kg [-0.64 to 1.13], P = 0.55) were not statistically different. Changes in total body fat with troglitazone (mean +1.02% body wt [-1.13 to 3.17], P = 0.32) and placebo (mean -0.54% body wt [-1.68 to 0.59], P = 0.31) were not significantly different. There was, however, a decrease in intra-abdominal fat mass in the troglitazone-treated group (mean -0.47 kg [-0.79 to -0.13], P = 0.01), and this was significantly different (P = 0.03) from placebo treatment (mean -0.41 kg [-0.77 to -0.05]). CONCLUSIONS: Treatment with the thiazolidinedione troglitazone in human patients with type 2 diabetes decreases intra-abdominal fat mass but does not affect total body fat or weight. This potentially valuable effect points to a differential action on insulin sensitivity in different adipose tissue depots.

Contributions of maternal and paternal adiposity and smoking to adult offspring adiposity and cardiovascular risk: the Midspan Family Study.

OBJECTIVE: Obesity has some genetic basis but requires interaction with environmental factors for phenotypic expression. We examined contributions of gender-specific parental adiposity and smoking to adiposity and related cardiovascular risk in adult offspring. DESIGN: Cross-sectional general population survey. SETTING: Scotland. PARTICIPANTS: 1456 of the 1477 first generation families in the Midspan Family Study: 2912 parents (aged 45-64 years surveyed between 1972 and 1976) who had 1025 sons and 1283 daughters, aged 30-59 years surveyed in 1996. MAIN MEASURES: Offspring body mass index (BMI), waist circumference (WC), cardiometabolic risk (lipids, blood pressure and glucose) and cardiovascular disease as outcome measures, and parental BMI and smoking as determinants. All analyses adjusted for age, socioeconomic status and family clustering and offspring birth weight. RESULTS: Regression coefficients for BMI associations between father-son (0.30) and mother-daughter (0.33) were greater than father-daughter (0.23) or mother-son (0.22). Regression coefficient for the non-genetic, shared-environment or assortative-mating relationship between BMIs of fathers and mothers was 0.19. Heritability estimates for BMI were greatest among women with mothers who had BMI either <25 or ≥30 kg/m(2). Compared with offspring without obese parents, offspring with two obese parents had adjusted OR of 10.25 (95% CI 6.56 to 13.93) for having WC ≥102 cm for men, ≥88 cm women, 2.46 (95% CI 1.33 to 4.57) for metabolic syndrome and 3.03 (95% CI 1.55 to 5.91) for angina and/or myocardial infarct (p<0.001). Neither parental adiposity nor smoking history determined adjusted offspring individual cardiometabolic risk factors, diabetes or stroke. Maternal, but not paternal, smoking had significant effects on WC in sons (OR=1.50; 95% CI 1.13 to 2.01) and daughters (OR=1.42; 95% CI 1.10 to 1.84) and metabolic syndrome OR=1.68; 95% CI 1.17 to 2.40) in sons. CONCLUSIONS: There are modest genetic/epigenetic influences on the environmental factors behind adverse adiposity. Maternal smoking appears a specific hazard on obesity and metabolic syndrome. A possible epigenetic mechanism linking maternal smoking to obesity and metabolic syndrome in offspring is proposed. Individuals with family histories of obesity should be targeted from an early age to prevent obesity and complications.

Associations of obesity with socioeconomic and lifestyle factors in middle-aged and elderly men: European Male Aging Study (EMAS).

BACKGROUND: Social and lifestyle influences on age-related changes in body morphology are complex because lifestyle and physiological response to social stress can affect body fat differently. OBJECTIVE: In this study, we examined the associations of socioeconomic status (SES) and lifestyle factors with BMI and waist circumference (WC) in middle-aged and elderly European men. DESIGN AND SETTING: A cross-sectional study of 3319 men aged 40-79 years recruited from eight European centres. OUTCOMES: We estimated relative risk ratios (RRRs) of overweight/obesity associated with unfavourable SES and lifestyles. RESULTS: The prevalence of BMI ≥ 30 kg/m(2) or WC ≥ 102 cm rose linearly with age, except in the eighth decade when high BMI, but not high WC, declined. Among men aged 40-59 years, compared with non-smokers or most active men, centre and BMI-adjusted RRRs for having a WC between 94 and 101.9 cm increased by 1.6-fold in current smokers, 2.7-fold in least active men and maximal at 2.8-fold in least active men who smoked. Similar patterns but greater RRRs were observed for men with WC ≥ 102 cm, notably 8.4-fold greater in least active men who smoked. Compared with men in employment, those who were not in employment had increased risk of having a high WC by 1.4-fold in the 40-65 years group and by 1.3-fold in the 40-75 years group. These relationships were weaker among elderly men. CONCLUSION: Unfavourable SES and lifestyles associate with increased risk of obesity, especially in middle-aged men. The combination of inactivity and smoking was the strongest predictor of high WC, providing a focus for health promotion and prevention at an early age.