Impact of microplastics and nanoplastics on liver health:Current understanding and future research directions

With continuous population and economic growth in the 21st century,plastic pollution is a major global issue.However,the health concern of microplastics/nanoplastics(MPs/NPs)decomposed from plastic wastes has drawn public attention only in the recent decade.This article summarizes recent works dedicated to understanding the impact of MPs/NPs on the liver-the largest digestive organ,which is one of the primary routes that MPs/NPs enter human bodies.The interrelated mechanisms including oxidative stress,hepatocyte energy re-distribution,cell death and autophagy,as well as immune responses and inflammation,were also featured.In addition,the disturbance of microbiome and gut-liver axis,and the association with clinical diseases such as metabolic dysfunction-associated fatty liver disease,steatohepatitis,liver fibrosis,and cirrhosis were briefly discussed.Finally,we discussed potential directions in regard to this trending topic,highlighted current challenges in research,and proposed possible solutions.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes:A new horizon

Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

Public health importance of light intensity physical activity

1.Light intensity physical activity(PA)benefits health PA guidelines worldwide recommend that adults accumulate 150 min of moderate intensity or 75 min of vigorous intensity PA(moderate-to-vigorous PA(MVPA))weekly to achieve health benefits.1-3 Absent from these guidelines are recommendations for light intensity PA(LPA,e.g.,walking at a leisurely pace of 3 km/h or less,equivalent to 1.5-2.9 metabolic equivalents).

The Role of Adipose Tissue-derived Exosomes in Chronic Metabolic Disorders

Excessive fat deposition in obese subjects promotes the occurrence of metabolic diseases,such as type 2 diabetes mellitus(T2DM),cardiovascular diseases,and non-alcoholic fatty liver disease(NAFLD).Adipose tissue is not only the main form of energy storage but also an endocrine organ that not only secretes adipocytokines but also releases many extracellular vesicles(EVs)that play a role in the regulation of whole-body metabolism.Exosomes are a subtype of EVs,and accumulating evidence indicates that adipose tissue exosomes(AT Exos)mediate crosstalk between adipose tissue and multiple organs by being transferred to targeted cells or tissues through paracrine or endocrine mechanisms.However,the roles of AT Exos in crosstalk with metabolic organs remain to be fully elucidated.In this review,we summarize the latest research progress on the role of AT Exos in the regulation of metabolic disorders.Moreover,we discuss the potential role of AT Exos as biomarkers in metabolic diseases and their clinical application.

Diagnostic challenges from conflicting results of tests and imaging

Accurate diagnosis is the foundation of clinical care but accurate diagnosis is not easily reached in some cases.In rare instances,even a sophisticated multidisciplinary team at an academic medical center cannot reliably reach an accurate diagnosis after extensive testing and imaging,and has to wait until histological diagnosis or even autopsy results are available.The underlying reason of challenging diagnoses is mostly conflicting data from history,tests,and imaging that point to different diagnoses.In this issue of World Journal of Clinical Cases,Huffaker et al reported such a challenging case of a tricuspid mass in a patient with Li-Fraumeni syndrome.The case by Huffaker et al powerfully illustrates the occasional diagnostic challenges inherent in our current diagnostic approach and the current technology.Clinicians should realize that in rare situations,agnosticism in diagnosis is unavoidable but a treatment has to be initiated so long as the principle of primum non nocere is upheld.

Occupational physical activity, all-cause, cardiovascular disease, and cancer mortality in 349,248 adults: Prospective and longitudinal analyses of the MJ Cohort

Background:Evidence on the health benefits of occupational physical activity(OPA)is inconclusive.We examined the associations of baseline OPA and OPA changes with all-cause,cardiovascular disease(CVD),and cancer mortality and survival times.Methods:This study included prospective and longitudinal data from the MJ Cohort,comprising adults over 18 years recruited in 1998-2016,349,248 adults(177,314 women)with baseline OPA,of whom 105,715(52,503 women)had 2 OPA measures at 6.3±4.2 years(mean±SD)apart.Exposures were baseline OPA,OPA changes,and baseline leisure-time physical activity.Results:Over a mean mortality follow-up of 16.2±5.5 years for men and 16.4±5.4 years for women,11,696 deaths(2033 of CVD and 4631 of cancer causes)in men and 8980 deaths(1475 of CVD and 3689 of cancer causes)in women occurred.Combined moderately heavy/heavy baseline OPA was beneficially associated with all-cause mortality in men(multivariable-adjusted hazard ratio(HR)=0.93,95%confidence interval(95%CI):0.89-0.98 compared to light OPA)and women(HR=0.86,95%CI:0.79-0.93).Over a mean mortality follow-up of 12.5±4.6 years for men and 12.6±4.6 years for women,OPA decreases in men were detrimentally associated(HR=1.16,95%CI:1.01-1.33)with all-cause mortality,while OPA increases in women were beneficially(HR=0.83,95%CI:0.70-0.97)associated with the same outcome.Baseline or changes in OPA showed no associations with CVD or cancer mortality.Conclusion:Higher baseline OPA was beneficially associated with all-cause mortality risk in both men and women.Our longitudinal OPA analyses partly confirmed the prospective findings,with some discordance between sex groups.

Diabetic cardiomyopathy:Importance of direct evidence to support the roles of NOD-like receptor protein 3 inflammasome and pyroptosis

Recently,the roles of pyroptosis,a form of cell death induced by activated NODlike receptor protein 3(NLRP3)inflammasome,in the pathogenesis of diabetic cardiomyopathy(DCM)have been extensively investigated.However,most studies have focused mainly on whether diabetes increases the NLRP3 inflammasome and associated pyroptosis in the heart of type 1 or type 2 diabetic rodent models,and whether various medications and natural products prevent the development of DCM,associated with decreased levels of cardiac NLRP3 inflammasome and pyroptosis.The direct link of NLRP3 inflammasome and associated pyroptosis to the pathogenesis of DCM remains unclear based on the limited evidence derived from the available studies,with the approaches of NLRP3 gene silencing or pharmaceutical application of NLRP3 specific inhibitors.We thus emphasize the requirement for more systematic studies that are designed to provide direct evidence to support the link,given that several studies have provided both direct and indirect evidence under specific conditions.This editorial emphasizes that the current investigation should be circumspect in its conclusion,i.e.,not overemphasizing its role in the pathogenesis of DCM with the fact of only significantly increased expression or activation of NLRP3 inflammasome and pyroptosis in the heart of diabetic rodent models.Only clear-cut evidence-based causative roles of NLRP3 inflammasome and pyroptosis in the pathogenesis of DCM can help to develop effective and safe medications for the clinical management of DCM,targeting these biomarkers.

Associations of accelerometry-measured and self-reported physical activity and sedentary behavior with skeletal muscle energetics:The Study of Muscle,Mobility and Aging(SOMMA)

Background:Skeletal muscle energetics decline with age,and physical activity(PA)has been shown to offset these declines in older adults.Yet,many studies reporting these effects were based on self-reported PA or structured exercise interventions.Therefore,we examined the associations of accelerometry-measured and self-reported PA and sedentary behavior(SB)with skeletal muscle energetics and explored the extent to which PA and sedentary behavior would attenuate the associations of age with muscle energetics.Methods:As part of the Study of Muscle,Mobility and Aging,enrolled older adults(n=879),810(age=76.4±5.0 years old,mean±SD;58%women)had maximal muscle oxidative capacity measured ex vivo via high-resolution re spirometry of permeabilized myofibers(maximal oxidative phosphorylation(maxOXPHOS))and in vivo by ^(31)phosphorus magnetic resonance spectroscopy(maximal adenosine triphosphate(ATP_(max))).Accelerometry-measured sedentary behavior,light activity,and moderate-to-vigorous PA(MVPA)were assessed using a wrist-worn ActiGraph GT9X over 7 days.Self-reported sedentary behavior,MVPA,and all PA were assessed with the Community Healthy Activities Model Program for Seniors(CHAMPS)questionnaire.Linear regression models with progressive covariate adjustments evaluated the associations of sedentary behavior and PA with muscle energetics,as well as the attenuation of the age/muscle energetics association by MVP A and sedentary behavior.As a sensitivity analysis,we also examined activPAL-measured daily step count and time spent in sedentary behavior and their associations with muscle energetics.Results:Every 30 min/day more of ActiGraph-measured MVPA was associated with 0.65 pmol/(s×mg)higher maxOXPHOS and 0.012 mM/s higher ATP_(max)after adjusting for age,site/technician,and sex(p<0.05).Light activity was not associated with maxOXPHOS or ATP_(max).Meanwhile,every 30 min/day spent in ActiGraph-measured sedentary behavior was associated with 0.39 pmol/s×mg lower maxOXPHOS and0.006 mM/s lower ATP_(max)(p<0.05).Only associations with ATP_(max)held after further adjusting for socioeconomic status,body mass index,lifestyle factors,and multimorbidity.CHAMPS MVPA and all PA yielded similar associations with maxOXPHOS and ATP_(max)(p<0.05),but sedentary behavior did not.Higher activPAL step count was associated with higher maxOXHPOS and AT_(Pmax)(p<0.05),but time spent in sedentary behavior was not.Additionally,age was significantly associated with muscle energetics for men only(p<0.05);adjusting for time spent in ActiGraph-measured MVPA attenuated the age association with ATP_(max)by 58%in men.Conclusion:More time spent in accelerometry-measured or self-reported daily PA,especially MVPA,was associated with higher skeletal muscle energetics.Interventions aimed specifically at increasing higher intensity activity might offer potential therapeutic interventions to slow age-related decline in muscle energetics.Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.

Effect of smoking on the risk of gastrointestinal cancer after cholecystectomy: A national population-based cohort study

BACKGROUND The role of smoking in the incidence of colorectal cancer(CRC)or gastric cancer(GC)in populations undergoing cholecystectomy has not been investigated.AIM To evaluate the effect of smoking on CRC or GC development in cholecystectomy patients.METHODS A total of 174874 patients who underwent cholecystectomy between January 1,2010 and December 31,2017 were identified using the Korean National Health Insurance Service claims database.These patients were matched 1:1 with mem-bers of a healthy population according to age and sex.CRC or GC risk after cholecystectomy and the association between smoking and CRC or GC risk in cholecystectomy patients were evaluated using adjusted hazard ratios(HRs)and 95%CIs.RESULTS The risks of CRC(adjusted HR:1.15;95%CI:1.06-1.25;P=0.0013)and GC(adjusted HR:1.11;95%CI:1.01-1.22;P=0.0027)were significantly higher in cholecystectomy patients.In the population who underwent cholecystectomy,both CRC and GC risk were higher in those who had smoked compared to those who had never smoked.For both cancers,the risk tended to increase in the order of non-smokers,ex-smokers,and current smokers.In addition,a positive correlation was observed between the amount of smoking and the risks of both CRC and GC.CONCLUSION Careful follow-up and screening should be performed,focusing on the increased risk of gastrointestinal cancer in the cholecystectomy group,particularly considering the individual smoking habits.

TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine

Dear Editor, DNA methylation, which often occurs at the 5-carbon position of cytosine （5mC） located in CpG dinucleotide, is a key epigenetic hallmark and serves as a major epigenetic mechanism for establishing X-inactivation, parental imprinting and silencing retrotransposable elements during early embryogenesis in mammals. Accumulative evidence also suggests that DNA methylation plays key roles in transcriptional regulation [1].

Risk of cardiovascular,cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)has emerged as a public health problem of epidemic proportions worldwide.Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease(CHD),abnormalities of cardiac function and structure(e.g.,left ventricular dysfunction and hypertrophy,and heart failure),valvular heart disease(e.g.,aortic valve sclerosis)and arrhythmias(e.g.,atrial fibrillation).Experimental evidence suggests that NAFLD itself,especially in its more severe forms,exacerbates systemic/hepatic insulin resistance,causes atherogenic dyslipidemia,and releases a variety of pro-inflammatory,pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications.Collectively,these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications.The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular,cardiac and arrhythmic complications,to briefly examine the putative biological mechanisms underlying this association,and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications.

Impact of diabetes mellitus on risk of cardiovascular disease and all-cause mortality: Evidence on health outcomes and antidiabetic treatment in United States adults

AIMTo examine the epidemic of diabetes mellitus (DM) and its impact on mortality from all-cause and cardiovascular disease (CVD), and to test the effect of antidiabetic therapy on the mortality in United States adults. METHODS The analysis included a randomized population sample of 272149 subjects ages ≥ 18 years who participated in the National Health Interview Surveys (NHIS) in2000-2009. Chronic conditions (hypertension, DM and CVD) were classified by participants’ self-reports of physician diagnosis. NHIS-Mortality Linked Files, and NHIS-Medical Expenditure Panel Survey Linkage Fileson prescribed medicines for patients with DM were used to test the research questions. χ 2, Poisson and Cox’s regression models were applied in data analysis.RESULTS Of all participants, 22305 (8.2%) had DM. The prevalence of DM significantly increased from 2000 to 2009 in all age groups (P < 0.001). Within an average 7.39 (SD= 3) years of follow-up, male DM patients had 1.56 times higher risk of death from all-cause (HR = 1.56, 95%CI:1.49-1.64), 1.72 times higher from heart disease [1.72 (1.53-1.93)], 1.48 times higher from cerebrovascular disease [1.48 (1.18-1.85)], and 1.67 times higher from CVD [1.67 (1.51-1.86)] than subjects without DM,respectively. Similar results were observed in females. In males, 10% of DM patients did not use any antidiabetic medications, 38.1% used antidiabetic monotherapy, and 51.9% used ≥ 2 antidiabetic medications. These corresponding values were 10.3%, 40.4% and 49.4% in females. A significant protective effect of metformin monotherapy or combination therapy (except for insulin) on all-cause mortality and a protective but non-significant effect on CVD mortality were observed. CONCLUSION This is the first study using data from multiple linkage files to confirm a significant increased prevalence of DM in the last decade in the United States. Patients with DM have significantly higher risk of death from all-cause and CVD than those without DM. Antidiabetic mediations,specifically for metformin use, show a protective effect against all-cause and CVD mortalities.

Lean diabetes mellitus:An emerging entity in the era of obesity

Much has been published on the characteristics of type 2 diabetes mellitus and its association with the epidemic of obesity.But relatively little is known about the incidence of lean diabetes,progression of disease and fate of the patients with low-normal body mass index(< 25).Studies in developing countries have shown that the clinical characteristics of these patients include history of childhood malnutrition,poor socioeconomic status,relatively early age of onset and absence of ketosis on withdrawal of insulin.In the United States,recent studies showed that the lean,normal weight diabetes is not rare especially among minority populations.They showed that these patients are mainly males,have higher prevalence of insulin use indicating rapid beta cell failure.They might have increased total,cardiovascular and non cardiovascular mortality when compared to obese diabetic patients.In this review,the epidemiologic and clinical features of lean diabetes are presented.The potential causal mechanisms of this emerging diabetes type that may include genetic,autoimmune,acquired and behavioral factors are discussed.The need for studies to further elucidate the causation as well as specific prevention and treatment of lean diabetes is emphasized.

Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome

Polycystic ovary syndrome(PCOS) is the most common endocrine disorder in reproductive-aged women. Women with PCOS frequently have metabolic complications including insulin resistance(IR), early diabetes, hypertension and dyslipidemia. Recent studies have demonstrated an association between PCOS and another metabolic complication: nonalcoholic fatty liver disease(NAFLD). NAFLD occurs as a result of abnormal lipid handling by the liver, which sensitizes the liver to injury and inflammation. It can progress to nonalcoholic steatohepatitis(NASH), which is characterized by hepatocyte injury and apoptosis. With time and further inflammation, NASH can progress to cirrhosis. Thus, given the young age at which NAFLD may occur in PCOS, these women may be at significant risk for progressive hepatic injury over the course of their lives. Many potential links between PCOS and NAFLD have been proposed, most notably IR and hyperandrogenemia. Further studies are needed to clarify the association between PCOS and NAFLD. In the interim, clinicians should be aware of this connection and consider screening for NAFLD in PCOS patients who have other metabolic risk factors. The optimal method of screening is unknown. However, measuring alanine aminotransferase and/or obtaining ultrasound on high-risk patients can be considered. First line treatment consists of lifestyle interventions and weight loss, with possible pharmacologic interventions in some cases.

Increased liver markers are associated with higher risk of type 2 diabetes

AIM: To investigate the association between liver markers and the risk of type 2 diabetes(T2DM) and impaired fasting glucose(IFG).METHODS: A total of 8863 participants(3408 men and 5455 women) over 30 years of age were analyzed from the fifth Korean National Health and Nutrition Examination Survey(2010-2011). The associations of serum liver markers such as aspartate aminotransferase(AST), alanine aminotransferase(ALT), AST/ALT, and gamma-glutamyltransferase(GGT) with T2 DM and IFG were analyzed using logistic regression models. Participants were divided into sex-specific quartiles on the basis of liver markers.RESULTS: The prevalence of T2 DM and IFG were 11.3% and 18.3%. Increasing quartiles of ALT and GGT were positively and AST/ALT were negatively correlated with T2 DM and IFG. Analysis of the liver marker combinations showed that if any two or more markers were in the highest risk quartile, the risks of both T2 DM and IFG increased significantly. The risk was greatest when the highest ALT and GGT and lowest AST/ALT quartile were combined, with the riskof T2 DM at 3.21(95%CI: 1.829-5.622, P < 0.001) in men and 4.60(95%CI: 3.217-6.582, P < 0.001) in women. Men and women with the highest AST and ALT and lowest AST/ALT quartile had a 1.99 and 2.40 times increased risk of IFG.CONCLUSION: Higher levels of GGT and ALT and lower AST/ALT within the physiological range are independent, additive risk factors of T2 DM and IFG.

Increased prevalence of symptoms of gastroesophageal reflux diseases in type 2 diabetics with neuropathy

AIM： To analyze the prevalence of gastroesophageal reflux disease （GERD） related symptoms in patients with diabetes mellitus （DM） and to find out the relationship between diabetic neuropathy and the prevalence of GERD symptoms. METHODS： In this prospective questionnaire study, 150 consecutive type 2 diabetic patients attending the endocrine clinic were enrolled. A junior physician helped the patients to understand the questions. Patients were asked about the presence of five most frequent symptoms of GERD that included heartburn （at least 1/wk）, regurgitation, chest pain, hoarseness of voice and chronic cough. Patients with past medical history of angina, COPD, asthma, cough due to ACEI or preexisting GERD prior to onset of diabetes and apparent psychiatric disorders were excluded from the survey. We further divided the patients into two groups based on presence or absence of peripheral neuropathy. Out of 150 patients, 46 had neuropathy, whereas 104 patients did not have neuropathy. Data are expressed as mean ± SD, and number of patients in each category and percentage of total patients in that group. Normal distributions between groups were compared with Student t test and the prevalence rates between groups were compared with Chi-square tests for significance. RESULTS： The average duration of diabetes were 12 ± 9.2 years and the average HbAlc level of this group was 7.7% ± 2.0%. The mean weight and BMI were 198 ± 54 Ibs. and 32 ± 7.2 kg/m^2. Forty percent （61/150） patients reported having at least one of the symptoms of GERD and thirty percent （45/150） reported having heartburn at least once a week. The prevalence of GERD symptoms is higher in patients with neuropathy than patients without neuropathy （58.7% vs 32.7%, P 〈 0.01）. The prevalence of heartburn, chest pain and chronic cough are also higher in patients with neuropathy than in patients without neuropathy （43.5% vs 24%; 10.9% vs 4.8% and 17.8% vs 6.7% respectively, P 〈 0.05）. CONCLUSION： The prevalence of GERD symptoms in type 2 DM is higher than in the general population. Our data suggest that DM neuropathy may be an important associated factor for developing GERD symptoms.

Prevention of macrovascular complications in patients with type 2 diabetes mellitus: Review of cardiovascular safety and efficacy of newer diabetes medications

Lack of conclusive beneficial effects of strict glycemic control on macrovascular complications has been very frustrating for clinicians involved in care of patients with diabetes mellitus (DM). Highly publicized controversy surrounding cardiovascular (CV) safety of rosiglitazone resulted in major changes in United States Food and Drug Administration policy in 2008 regarding approval process of new antidiabetic medications, which has resulted in revolutionary data from several large CV outcome trials over the last few years. All drugs in glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitor classes have shown to be CV safe with heterogeneous results on CV efficacy. Given twofold higher CV disease mortality in patients with DM than without DM, GLP-1 RAs and SGLT-2-inhibitors are important additions to clinician’s armamentarium and should be second line-therapy particularly in patients with T2DM and established atherosclerotic CV disease or high risks for CV disease. Abundance of data and heterogeneity in CV outcome trials results can make it difficult for clinicians, particularly primary care physicians, to stay updated with all the recent evidence. The scope of this comprehensive review will focus on all major CV outcome studies evaluating CV safety and efficacy of GLP-1 RAs and SGLT-2 inhibitors.

Alterations of seminal and hormonal parameters:An extrahepatic manifestation of HCV infection?

AIM： To evaluate the possible influences of HCV infection and relative antiviral treatment on seminal parameters and reproductive hormonal serum levels. METHODS： Ten male patients with HCV-related chronic hepatitis and 16 healthy male volunteers were studied. In all subjects seminal parameters （nemaspermic concentration, progressive motility, morphology） and hormonal levels were determined. Seminal parameters and inhibin B, follicle-stimulating hormone, luteinizing hormone, total and free testosterone, estradiol, prolactine in patients were measured after six and twelve months of antiviral combined （interferon ± ribavirin） treatment. RESULTS： Patients before treatment showed a significantly lower nemaspermic motility and morphology as well as lower inhibin B and free testosterone levels than controls. Inhibin B levels in cases were improved six and 12 mo after treatment in five responders （161.9 ± 52.8 pg/mL versus 101.7 ± 47.0 pg/mL and 143.4 ± 46.1 pg/ mL versus 95.4 ± 55.6 pg/mL, respectively）. Hormonal pattern of patients did not significantly change after treatment, with the exception of estradiol levels with an initial reduction and an overall subsequent increment （19.7 ± 6.4 pg/mL versus 13.6 ± 5.0 pg/mL versus 17.3 ± 5.7 pg/mL）. However in 1-year responders a significant increment of free testosterone （14.2 ± 2.54 pg/mL versus 17.1 ± 2.58 pg/mL） occurred. An impairment of nemaspermic morphology occurred, while other seminal parameters did not change significantly during antiviral treatment. CONCLUSION： Patients with HCV infection show worse spermatic parameters than controls, suggesting a possible negative influence of virus on spermatogenesis, with further mild impairment during antiviral treatment. However therapy could improve the spermatic function, as suggested by the increased inhibin B levels and improved hormonal pattern in responders. Further studies are needed to confirm these preliminary intriguing results.

Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters

Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level （25-hydroxy-vitamin D, or 250HD） and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal （total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone） and semen parameters, adjusted （n= 147） for age, body mass index （BMI）, season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined apriori. The mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m-2. The mean 250HD was 34.1± 15.06 ng m1-1. BMI showed a negative association with 250HD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with ‘250HD ≥ 50 ng ml-1＇ when compared to men with‘20 ng ml-1 ≤ 250H D〈 50 ng ml-1,. Total sperm count and total progressive motile sperm count were lower in men with ‘250HD〈20 ng ml-1＇ when compared to men with‘20 ng ml-1≤250HD〈50 ng ml-1＇. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 250HD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor （TR） a and ~, of which TRa seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance.