Search

BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D(3) would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D(3) (2000 IU per day), n–3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D(3), as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D(3) supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.)

Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/ LUMA). The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes, and up- or downstream regulators. Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) were applied for genetic correlation, functional enrichment, and coexpression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans. We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, whereas levels of Tmem43 highly positively correlated with plasma high-density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild-type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, hypertrophic cardiomyopathy, dilated cardiomyopathy, nonalcoholic fatty liver disease, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6, and Uqcrc2 were significantly altered in Tmem43S358L mice versus Tmem43WT controls. Our study defined the importance of Tmem43 for cardiac- and metabolism-related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.

The mortgage sector plays a pivotal role in the financial services industry, and the U.S. economy in general, with the Federal Reserve, St. Louis, reporting Households and Nonprofit Organizations for One-to-Four-Family Residential Mortgages Liability Level at $10.8T in Q3 2020. It has been in the interest of banks to know which factors are the most influential predicting mortgage default, and the implementation of survival models can utilize data from defaulted obligors as well as non-default obligors who are still making payments as of the sampling period cutoff date. Besides the Cox proportional hazard model and the accelerated failure time model, this paper investigates two machine learning-based models, a random survival forest model, and a Cox proportional hazard neural network model DeepSurv. We compare the accuracy of covariate selection for the Cox model, AFT model, random survival forest model, and DeepSurv model, and this investigation is the first research using machine learning based survival models for mortgage default prediction. The result shows that Random survival forest can achieve the most accurate, and stable, covariate selection, while DeepSurv can achieve the highest accuracy of default prediction, and finally, the covariates selected by the models can be meaningful for mortgage programs throughout the banking industry.

This study evaluated whether zoledronic acid (ZA) inhibited the progression of abdominal aortic calcification (AAC) over 3 years in 502 postmenopausal women with osteoporosis. AAC progressed in a similar proportion of participants in the ZA (29%) and placebo (31%) groups, suggesting no effect of ZA on AAC progression. Bisphosphonate use is associated with reduced risk of all-cause mortality and cardiovascular events. The underlying mechanisms are uncertain but may include effects on vascular calcification. This study aimed to evaluate the effect of zoledronic acid (ZA) on abdominal aortic calcification (AAC) in postmenopausal women with osteoporosis. This was a post hoc analysis of the HORIZON Pivotal Fracture Trial that included 502 postmenopausal women (mean age 72.5 years) with osteoporosis (234 received ZA and 268 placebo). AAC scores (range, 0–8) were assessed from paired spine X-rays at baseline and after 3 years. Progression of AAC was defined as any increase in AAC score. The association between change in hip and femoral neck bone mineral density and change in AAC score was also assessed. At baseline, 292 (58.2%) participants had AAC (i.e., AAC score > 0), with AAC scores similar in the two intervention groups (median [interquartile range], 1 [0 to 2] for both; p = 0.98). Over 3 years, AAC progressed in a similar proportion of participants in both groups (ZA 29% and placebo 31%; p = 0.64). Change in bone mineral density and change in AAC score were not correlated. Once-yearly zoledronic acid did not affect progression of AAC over 3 years in postmenopausal women with osteoporosis. ClinicalTrials.gov identifier: NCT00049829

The discovery of apolipoprotein A5 (APOA5) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome-wide association studies have consistently identified APOA5 as a regulator of plasma TG levels, which is further supported by studies in transgenic and knockout mouse models. The present review describes recent concepts pertaining to the roles of APOA5 in TG metabolism as related to the vascular compartment, liver, adipose tissue and the gut. Recent evidence indicates that APOA5 may also affect postprandial TG metabolism through influencing chylomicron formation and transport by the intestine into the intestinal lymph. While substantial evidence supports the notion that APOA5 plays both extracellular and intracellular roles in TG homeostasis, mysteries remain on how this low-abundance, liver-derived protein may modulate TG homeostasis, including via the gut. Given the strong correlation between elevated plasma TG and cardiometabolic diseases, there is great scientific and public interest in understanding the intriguing mysteries presented by APOA5.

Both osteoporosis and cardiovascular disease (CVD) increase in women after menopause. Estrogen deficiency is thought to be an underlying mechanism for both these conditions.Healthy menopausal women (n = 374, age 42-58 years) underwent cardiac CT scans over four years as participants in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, controlled trial to Women randomized to either oral conjugated equine estrogens (o-CEE, n = 104), transdermal 17β-estradiol (t-E2, n = 119) or placebo (n-115). CAC (Agatston units, AU), and BMD (mg/cmAt baseline 374 women, 40 participants with CAC0 had greater decrements in BMD than the 334 participants with CAC = 0 at baseline, The average change in BMD in o-CEE group with CAC was -9.6 ± 13.3 versus -3.1 ± 19.5 in those with zero CAC, p = 0.0018. With t-E2, BMD changed by -11.7 ± 26.2 in those with CAC versus +5.7 ± 26.2 in the zero CAC group, p ≤ 0. 0001. Similarly in the 66 participants that showed progression of CAC1, had more BMD loss, than those with stable CAC regardless of the treatment.Progression of bone loss is reduced among women treated with o-CEE or t-E2. Progression of CAC is associated with greater BMD loss, a relationship that is differentially modified by t-E2 and o-CEE.

Studies showed that the gastrointestinal (GI) tract is one of the most important pathways for SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19). As SARS-CoV-2 cellular entry depends on the ACE2 receptor and TMPRSS2 priming of the spike protein, it is important to understand the molecular mechanisms through which these two proteins and their cognate transcripts interact and influence the pathogenesis of COVID-19. In this study, we quantified the expression, associations, genetic modulators, and molecular pathways for Tmprss2 and Ace2 mRNA expressions in GI tissues using a systems genetics approach and the expanded family of highly diverse BXD mouse strains. The results showed that both Tmprss2 and Ace2 are highly expressed in GI tissues with significant covariation. We identified a significant expression quantitative trait locus on chromosome 7 that controls the expression of both Tmprss2 and Ace2. Dhx32 was found to be the strongest candidate in this interval. Co-expression network analysis demonstrated that both Tmprss2 and Ace2 were located at the same module that is significantly associated with other GI-related traits. Protein–protein interaction analysis indicated that hub genes in this module are linked to circadian rhythms. Collectively, our data suggested that genes with circadian rhythms of expression may have an impact on COVID-19 disease, with implications related to the timing and treatment of COVID-19.

Credit card fraudulent data is highly imbalanced, and it has presented an overwhelmingly large portion of nonfraudulent transactions and a small portion of fraudulent transactions. The measures used to judge the veracity of the detection algorithms become critical to the deployment of a model that accurately scores fraudulent transactions taking into account case imbalance, and the cost of identifying a case as genuine when, in fact, the case is a fraudulent transaction. In this paper, a new criterion to judge classification algorithms, which considers the cost of misclassification, is proposed, and several undersampling techniques are compared by this new criterion. At the same time, a weighted support vector machine (SVM) algorithm considering the financial cost of misclassification is introduced, proving to be more practical for credit card fraud detection than traditional methodologies. This weighted SVM uses transaction balances as weights for fraudulent transactions, and a uniformed weight for nonfraudulent transactions. The results show this strategy greatly improve performance of credit card fraud detection.

Desorption rate index (DRI) was presented to the Australian underground coal industry in 1995 as a means for determining outburst threshold limits for Australian coal seams. DRI is a measure of the gas volume released from a coal sample in the first 30 s of crushing during the Q3 stage of gas content testing, multiplied by the ratio between measured Q3 and QM. Relationships were identified between QM and DRI for both CO2 and CH4 rich coal samples collected from the Bulli Seam at West Cliff Colliery and that identified relationship was referred to as the Bulli Seam Benchmark. The outburst mining gas content threshold limit values specified for the Bulli Seam at that time, when applied to the QM-DRI Bulli Seam benchmark, was shown to closely align with a DRI value of 900 (DRI900), for both CO2 and CH4 rich seam gas conditions. The Australian coal industry adopted the DRI900 as the basis for determining outburst gas content TLV for Australian coal seams. Outburst mining experience in Australia has shown that gas content is not the only significant factor that impacts outburst risk, as all significant outburst events have been associated with abnormal geological conditions, such as faults and dykes. Therefore, assessing the potential application of additional outburst risk factors, to accurately define outburst risk zones, set safe mining threshold levels, and determine appropriate mining controls, warrants further investigation. Several Australian coal mines have implemented mining procedures enabling mining to continue in areas with gas content greater than the TLV determined using the DRI900 approach, without inducing an outburst. There is a broad lack of understanding among Australian coal mine operators as to the procedure and calculations used to determine DRI. Also, there has been growing concern regarding the accuracy and validity of the DRI900 method for determining outburst TLV. A comprehensive set of gas data has been collected from Australian coal seams, including the Bulli Seam, and this data has been used to investigate the DRI, Bulli Seam Benchmark, and the applicability of using DRI900 as the basis for assessing outburst risk and determining gas content TLV. The results are presented and discussed. Keywords: Outburst, Desorption rate, DRI, Threshold limit

Outburst of coal and gas represents a significant risk to the health and safety of mine personnel working in development and longwall production face areas. There have been over 878 outburst events recorded in twenty-two Australian underground coal mines. Most outburst incidents have been associated with abnormal geological conditions.Details of Australian outburst incidents and mining experience in conditions where gas content was above current threshold levels are presented and discussed. Mining experience suggests that for gas content below 9.0 m3/t, mining in carbon dioxide (CO2) rich seam gas conditions does not pose a greater risk of outburst than mining in CH4 rich seam gas conditions. Mining experience also suggests that where no abnormal geological structures are present that mining in areas with gas content greater than the current accepted threshold levels can be undertaken with no discernible increase in outburst risk. The current approach to determining gas content threshold limits in Australian mines has been effective in preventing injury from outburst, however operational experience suggests the current method is overly conservative and in some cases the threshold limits are low to the point that they provide no significant reduction in outburst risk. Other factors that affect outburst risk, such as gas pressure, coal toughness and stress and geological structures are presently not incorporated into outburst threshold limits adopted in Australian mines. These factors and the development of an outburst risk index applicable to Australian underground coal mining conditions are the subject of ongoing research. Keywords: Outburst, Desorption rate, DRI, Threshold limit

Ursodeoxycholic acid (UDCA) is commonly used to treat several liver disorders in adults and children, including primary sclerosing cholangitis (PSC) for which it is not U.S. Food and Drug Administration approved. UDCA treatment has an uncertain impact on disease outcomes and has been reported in high doses to be associated with worse outcome in adults with PSC. In this context, controlled withdrawal and reintroduction of UDCA in children with PSC were studied. Prior to study initiation, participants were required to have alanine aminotransferase (ALT) and gamma‐glutamyl transpeptidase (GGT) 100 IU/L (flare group). None developed elevated bilirubin. All flares responded to UDCA reinstitution. Serum GGT, interleukin‐8, and tumor necrosis factor α levels were higher in the flare group at baseline. Liver biochemistries increased in children with PSC during controlled UDCA withdrawal; one third increased above 100 IU/L and one third remained normal during UDCA withdrawal. Conclusion: The impact of prolonged UDCA use in childhood PSC and the significance of a biochemical flare are unclear. Further studies of the natural history and treatment of pediatric PSC and UDCA use are needed.

Background EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment-related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population. Case (methods/results) We present the case of a 12-year-old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre-emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched-unrelated donor bone marrow-derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis. Conclusion Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP-hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.

Australian coal mines currently use gas content to assess outburst risk. The gas content threshold values for each mine are indirectly determined from measurement of gas volume liberated from 150 g coal samples during Q3 residual gas content testing. It has been more than twenty years since this method, known as desorption rate index (DRI), was presented to the Australian coal industry, and in that time, there have been significant changes in mining conditions and the outburst threshold limits used at the benchmark Bulli seam mines. NSW Regulations list matters to be considered in developing control measures to manage the risk of gas outburst, and specifies that gas content, or DRI method, is used as the basis for determining outburst control zone. Whilst Queensland Regulations state that a coal or rock outburst is a high potential incident, there is no guidance provided to assist mine operators to define outburst prone conditions. A research project is planned at UOW to investigate the application of the DRI method and other potentially significant factors, such as gas pressure, coal toughness and permeability, which can be utilised by mine operators to assess outburst risk and determine appropriate outburst threshold limits and controls. Keywords: Outburst, Desorption rate, DRI, Threshold limit

Objectives: This study sought to delineate clinical phenotype and investigate pathophysiological mechanisms of arrhythmogenic right ventricular cardiomyopathy (ARVC5) in vivo.Background: Mutation p.S358L in TMEM43/LUMA causes ARVC5, a fully penetrant gender- and exercise-dependent disease. Exact pathophysiological mechanisms of ARVC5 remain incomplete and controversial. Methods: Knock-in Tmem43S358L mice were generated using conventional targeting. Assessment of cardiac and intestinal phenotypes, transcriptome and protein analysis were performed. Results: Onset of systolic dysfunction and rhythm asymmetry was apparent in 3-month-old homozygote mutants. Heterozygote 6-month-old mutants displayed systolic dysfunction as well. Biventricular myocardial fibro-fatty infiltration and subcellular abnormalities were found in both mutants, while acute stress caused ventricular tachycardia and death in homozygotes. Microarray revealed that WNT-b-catenin and PPARG signaling-associated genes were differentially expressed between LV and RV. Tmem43S358L mutants displayed significantly reduced PPARG activities and downregulation of PPARG-downstream metabolic genes in the heart. Expression of b-catenin were significantly reduced, while JUP was translocated into nuclei of mutant cardiomyocytes. Conversely in small intestine, b-catenin and PPARG-associated genes responsible for cholesterol, bile acid, and lipid transport were upregulated in Tmem43S358L mutants resulting in elevated lipids absorption, hyperlipidemia, and reciprocal fecal lipids reduction. These abnormalities were associated with elongated villi, fatty infiltrations, and gut epithelial proliferation markers in small intestine. Conclusions: We defined novel distinct effects of the TMEM43-S358L mutation on small intestine homeostasis in addition to cardiac damage. Tmem43-S358L perturbs PPARG and WNT-b-catenin signaling in the heart as well as in intestine, elevating lipids absorption from gut lumen whereby triggering ACM pathophysiology.

Lipids entering the gastrointestinal tract include dietary lipids (triacylglycerols, cholesteryl esters and phospholipids) and endogenous lipids from bile (phospholipids and cholesterol) and from shed intestinal epithelial cells (enterocytes). Here, we comprehensively review the digestion, uptake and intracellular re-synthesis of intestinal lipids as well as their packaging into pre-chylomicrons in the endoplasmic reticulum, their modification in the Golgi apparatus and the exocytosis of the chylomicrons into the lamina propria and subsequently to lymph. We also discuss other fates of intestinal lipids, including intestinal HDL and VLDL secretion, cytosolic lipid droplets and fatty acid oxidation. In addition, we highlight the applicability of these findings to human disease and the development of therapeutics targeting lipid metabolism. Finally, we explore the emerging role of the gut microbiota in modulating intestinal lipid metabolism and outline key questions for future research. The small intestine is a key site for the absorption of nutrients, including lipids. In this Review, the physiology and biochemistry of intestinal fat absorption during health and disease is discussed, including insights into enterocyte biology and clinical disorders of intestinal fat absorption.

Background: Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that augment glucose-stimulated insulin secretion, promote pancreatic β-cell proliferation, neogenesis and inhibit β-cell apoptosis. Thus, they are excellent therapeutic targets against type 2 diabetes. Using a lymph fistula rat model, we studied the secretion of incretins into lymph. In adult rats, we found that GIP and GLP-1 concentrations in the fasting lymph were 132 ± 19 pg/ml and 31 ± 8 pM, respectively. After intraduodenal lipid infusion, their concentrations rose to 441 ± 144 pg/ml and 154 ± 23 pM, respectively. Rationale: However, little is known about nutrient-stimulated secretion of GIP and GLP-1 in baby rats, whose gastrointestinal system and pancreatic β-cells are immature compared to adult rats. Methods: Using our well-established lymph fistula model with conscious baby rats, just weaned (21 day after birth) and weighing 50-65 g, we assessed the secretion of GIP and GLP-1 in lymph after an intraduodenal challenge of lipid meal. Results: Fasting GIP and GLP-1 levels were 295.4 ± 48.1 pg/ml and 59.6 ± 16.2 pM, respectively. After lipid infusion, GIP and GLP-1 levels increased to 1052 ± 90.1 pg/ml and 192.0 ± 19.7 pM respectively. Elevated incretin levels in baby rats (relative to adult animals) indicate possible involvement in the maturation of the enteroendocrine system and β-cells. This increase may be also important to ensure the adequate secretion of insulin to regulate blood glucose as the animals shift from a high-fat mother’s milk diet to a chow diet. Further studies are needed to determine the physiological role of the higher incretin levels in baby rats. Conclusions: Lymph fistula baby rats can serve as an excellent model to study regulation of gut hormones by nutrient absorption at their early developmental stage. This model can also be used to study the influence of mother’s milk on the secretion of gut hormones and their impact on glucose and lipid metabolism in the newborn. Disclosure J. Qu: None. Q. Yang: None. C. Ko: None. M. Liu: None. D.D. Black: Advisory Panel; Self; Intercept Pharmaceuticals, Inc. P. Tso: None. Funding National Institutes of Health (DK59630)

This study investigates the relationship between cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality among 514 hip fracture hospitalized older persons. Patients with early cognitive dysfunction or delirium experienced a 2-fold increased mortality risk. Early post-operative cognitive dysfunction and delirium are negative prognostic factors for mortality. Premorbid cognitive impairment and dementia in older individuals negatively affect functional recovery after hip fracture. Additionally, post-operative delirium is an established risk factor for negative outcomes among hip fracture patients. While the majority of hip fracture patients experience minor post-surgical cognitive dysfunction, the prognostic value of this phenomenon is unknown. Therefore, we investigated the relationship between minor cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality after index hip fracture. We enrolled 514 patients with hip fracture (77.4 % women), aged 65 years or older (mean age 83.1 ± 7.3 years), who underwent surgical hip fracture repair. Patients were assessed daily from the second to the fourth post-operative day and at 3, 6, and 12 months thereafter. All participants underwent comprehensive assessment, including detection of delirium by using the confusion assessment method and evaluation of cognitive function by using mini-mental state examination (MMSE; score range 0 to 30, with lower scores indicating poorer performance). In the absence of delirium, post-surgical cognitive dysfunction was defined as having low performance on MMSE. Vital status of 1 year after the index fracture and date of death were gathered from local registries. The observed 1-year mortality rate was 14.8 %. Men were more likely to die than women within 1 year of the index fracture (p

Thrombospondin-2 ( THBS 2) and Thrombospondin-4 ( THBS 4) play an important role in cancer development and progression. However, genetic evidence for their roles in gastric cancer (GC) is lacking. The aim of this study was to explore the association of THBS 2/ THBS 4 polymorphisms with risk and clinicopathological features of GC in a Southeast Chinese population. Eight tagging SNPs in THBS 2 and THBS 4 were genotyped in 761 GC cases and 739 controls from Chinese case–control sets using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. THBS 2/ THBS 4 mRNA expression was studied in 82 human GC tumors and in mouse stomach tissues by real-time PCR. We found that both THBS 2 and THBS 4 were abundantly expressed in mouse stomach. THBS 4 mRNA expression in human stomach was associated with tumor size ( P = 0.002) and tumor-node-metastasis (TNM) ( P = 0.010), and THBS2 mRNA expression was associated with the TNM ( P = 0.010). Patients with the rs77878919^AG genotype were more prone to developing diffuse-type GC. THBS 4 SNPs (rs77878919 and rs7736549) had a modest cumulative effect on the risk of poor prognosis (TNM), with that risk in the highest trend for patients carrying both these unfavorable genotypes. In addition, individuals carrying the THBS4 rs10474606 variant homozygous AA had a modest reduced GC risk. We conclude that THBS2 / THBS4 may be functional in playing important role in GC, which was supported by the evidence of the mRNA overexpression in GC and the modest associations of THBS2/THBS4 polymorphisms to GC. These findings might be useful for risk assessment and prognosis prediction of GC.

The aim of the present study was to determine the effects of feeding of a high-fat diet containing different types of lipids for four weeks on the cholesterol and triglyceride contents of different fat depots and on body temperature in rats. Four groups of adult rats were fed 10% fat, containing either beef tallow, safflower oil, or fish oil, respectively, as well as a normal rodent diet with 4% fat, for four weeks. The rats on normal rodent diet consumed significantly more food and water than the rats in the other three groups. Rectal temperature increased only after four-week feeding with safflower oil fat. Increased fat deposition and adipocyte size were observed in rats fed safflower oil and beef tallow. In all fat pads of safflower oil-fed rats, cholesterol content was significantly higher than the other three groups. Feeding of beef tallow increased triglyceride depot without increasing cholesterol content. The rats fed fish oil had significantly less triglyceride and cholesterol deposition in adipose tissues than the rats fed safflower oil or beef tallow. These results clearly demonstrated the differences in fat deposition, adipocyte size and number, triglyceride and cholesterol accumulation in fat cells are dependent on the dietary lipid composition.

Omega-3 long-chain polyunsaturated fatty acids (ω3PUFA) have been shown to be antiinflammatory in the attenuation of hepatocellular injury. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that inhibits the activation of nuclear factor κB, thereby repressing inflammation, and ωPUFA are PPARα ligands. The purpose of this study was to determine if ω3PUFA attenuate bile acid-induced apoptosis via PPARα.Human hepatocellular carcinoma (HepG2) cells were treated with chenodeoxycholic acid (CDCA) ± ω3PUFA. Activation of PPARα was evaluated, and expression of PPARα, farnesoid X receptor, liver X receptor alpha (LXRα), and retinoid X receptor mRNA was evaluated by reverse-transcriptase PCR.PPARα activation was increased in HepG2 cells treated with ω3PUFA, and decreased in the presence of CDCA when compared with untreated cells. PPARα mRNA was reduced by 67% with CDCA and restored to the level of control with ω3PUFA. LXRα mRNA increased twofold with CDCA treatment and was significantly reduced by ω3PUFA.Expression of PPARα, as well as LXRα mRNA levels, was reduced with CDCA treatment and restored with the addition of ω3PUFA. These results suggest that PPARα and LXRα may be mediators by which ω3PUFA attenuate bile acid-induced hepatocellular injury.

Aim Prematurity, prolonged parenteral nutrition (PN), and concurrent intestinal injury, are considered to be risk factors in the development and severity of PN-associated liver disease (PNALD). The aim of this study was to develop a preterm porcine model of PNALD. Methods

Background: Cancer Registries (CRs) remain the gold standard for providing official epidemiological estimations. However, due to CRs’ partial population coverage, hospitalization records might represent a valuable tool to provide additional information on cancer occurrence and expenditures at national/regional level for research purposes. The Epidemiology of Cancer in Italy (EPIKIT) study group has been built up, within the framework of the Civic Observers for Health and Environment: Initiative of Responsibility and Sustainability (COHEIRS) project under the auspices of the Europe for Citizens Program, to assess population health indicators. Objective: To assess the burden of all cancers in Italian children and adults. Methods: We analyzed National Hospitalization Records from 2001 to 2011. Based on social security numbers (anonymously treated), we have excluded from our analyses all re-hospitalizations of the same patients (n = 1,878,109) over the entire 11-year period in order to minimize the overlap between prevalent and incident cancer cases. To be more conservative, only data concerning the last five years (2007–2011) have been taken into account for final analyses. The absolute number of hospitalizations and standardized hospitalization rates (SHR) were computed for each Italian province by sex and age-groups (0–19 and 20–49). Results: The EPIKIT database included a total of 4,113,169 first hospital admissions due to main diagnoses of all tumors. The annual average number of hospital admissions due to cancer in Italy has been computed in 2362 and 43,141 hospitalizations in pediatric patients (0–19 years old) and adults (20–49 years old), respectively. Women accounted for the majority of cancer cases in adults aged 20–49. As expected, the big city of Rome presented the highest average annual number of pediatric cancers (n = 392, SHR = 9.9), followed by Naples (n = 378; SHR = 9.9) and Milan (n = 212; SHR = 7.3). However, when we look at SHR, minor cities (i.e., Imperia, Isernia and others) presented values >10 per 100,000, with only 10 or 20 cases per year. Similar figures are shown also for young adults aged 20–49. Conclusions: In addition to SHR, the absolute number of incident cancer cases represents a crucial piece of information for planning adequate healthcare services and assessing social alarm phenomena. Our findings call for specific risk assessment programs at local level (involving CRs) to search for causal relations with environmental exposures.

To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis).ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients.Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P.001). Kaplan-Meier estimated rates of nonvertebral fractures were PBO/ALN, 5.6% vs ABL-SC/ALN, 2.7%; risk reduction, 52% (hazard ratio [HR], 0.48; 95% CI, 0.26-0.89; log-rank P=.02). There was also a 58% risk reduction of major osteoporotic fractures (HR, 0.42; 95% CI, 0.21-0.85; log-rank P=.01) and a 45% risk reduction of clinical fractures (HR, 0.55; 95% CI, 0.33-0.92; log-rank P=.02) in the ABL-SC/ALN group vs the PBO/ALN group. At 25 months, bone mineral density percentage change from ACTIVE baseline for ABL-SC/ALN vs PBO/ALN was as follows: lumbar spine, 12.8%; total hip, 5.5%; femoral neck, 4.5% vs 3.5%, 1.4%, 0.5%, respectively (group differences at all sites P.001).Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis.clinicaltrials.gov Identifier: NCT01657162.