Association of daily sitting time and leisure-time physical activity with body fat among U.S.adults

Background:Prolonged sitting and reduced physical activity lead to low energy expenditures.However,little is known about the joint impact of daily sitting time and physical activity on body fat distribution.We investigated the independent and joint associations of daily sitting time and physical activity with body fat among adults.Methods:This was a cross-sectional analysis of U.S.nationally representative data from the National Health and Nutrition Examination Survey2011-2018 among adults aged 20 years or older.Daily sitting time and leisure-time physical activity(LTPA)were self-reported using the Global Physical Activity Questionnaire.Body fat(total and trunk fat percentage)was determined via dual X-ray absorptiometry.Results:Among 10,808 adults,about 54.6%spent 6 h/day or more sitting;more than one-half reported no LTPA(inactive)or less than 150 min/week LTPA(insufficiently active)with only 43.3%reported 150 min/week or more LTPA(active)in the past week.After fully adjusting for sociodemographic data,lifestyle behaviors,and chronic conditions,prolonged sitting time and low levels of LTPA were associated with higher total and trunk fat percentages in both sexes.When stratifying by LTPA,the association between daily sitting time and body fat appeared to be stronger in those who were inactive/insuufficiently active.In the joint analyses,inactive/insuufficiently active adults who reported sitting more than 8 h/day had the highest total(female:3.99%(95%confidence interval(95%CI):3.09%-4.88%);male:3.79%(95%CI:2.75%-4.82%))and trunk body fat percentages(female:4.21%(95%CI:3.09%-5.32%);male:4.07%(95%CI:2.95%-5.19%))when compared with those who were active and sitting less than 4 h/day.Conclusion:Prolonged daily sitting time was associated with increased body fat among U.S.adults.The higher body fat associated with 6 h/day sitting may not be offset by achieving recommended levels of physical activity.

Glyphosate as a direct or indirect activator of pro-inflammatory signaling and cognitive impairment

Glyphosate-based herbicides are widely used around the world, making it likely that most humans have significant exposure. Because of habitual exposure, there are concerns about toxicity including neurotoxicity that could result in neurological, psychiatric, or cognitive impairment. We recently found that a single injection of glyphosate inhibits long-term potentiation, a cellular model of learning and memory, in rat hippocampal slices dissected 1 day after injection, indicating that glyphosate-based herbicides can alter cognitive function. Glyphosate-based herbicides could adversely affect cognitive function either indirectly and/or directly. Indirectly, glyphosate could affect gut microbiota, and if dysbiosis results in endotoxemia(leaky gut), infiltrated bacterial by-products such as lipopolysaccharides could activate pro-inflammatory cascades. Glyphosate can also directly trigger pro-inflammatory cascades. Indeed, we observed that acute glyphosate exposure inhibits long-term potentiation in rat hippocampal slices. Interestingly, direct inhibition of long-term potentiation by glyphosate appears to be similar to that of lipopolysaccharides. There are several possible measures to control dysbiosis and neuroinflammation caused by glyphosate. Dietary intake of polyphenols, such as quercetin, which overcome the inhibitory effect of glyphosate on long-term potentiation, could be one effective strategy. The aim of this narrative review is to discuss possible mechanisms underlying neurotoxicity following glyphosate exposure as a means to identify potential treatments.

New insights into astrocyte diversity from the lens of transcriptional regulation and their implications for neurodegenerative disease treatments

Astrocytes are a major glial cell type in the central nervous system,and they provide trophic and metabolic support to neurons.In addition to these roles,they play crucial roles in modulating synaptic functions,development,and pruning(Brandebura et al.,2023).Astrocytes become reactive(activated)by undergoing morphological,molecular,and functional alterations in response to neuropathology such as in injuries and neurodegenerative diseases(NDs)(Escartin et al.,2021).

Psychiatric comorbidities in children with conduct disorder:a descriptive analysis of real-world data

To the editor:Two recent advisories from the US surgeon general have underscored the unprecedented public health crisis in youth mental health and emphasised the need for“timely data collection and research to identify and respond to youth mental health needs more rapidly”.1 Increased rates of suicidal behaviour,depression and anxiety symptoms and substance use.

Patient care during interfacility transport:a narrative review of managing diverse disease states

BACKGROUND:When critically ill patients require specialized treatment that exceeds the capability of the index hospitals,patients are frequently transferred to a tertiary or quaternary hospital for a higher level of care.Therefore,appropriate and efficient care for patients during the process of transport between two hospitals(interfacility transfer)is an essential part of patient care.While medical adverse events may occur during the interfacility transfer process,there have not been evidence-based guidelines regarding the equipment or the practice for patient care during transport.METHODS:We conducted searches from the PubMed,Cumulative Index of Nursing and Allied Health(CINAHL),and Scopus databases up to June 2022.Two reviewers independently screened the titles and abstracts for eligibility.Studies that were not in the English language and did not involve critically ill patients were excluded.RESULTS:The search identified 75 articles,and we included 48 studies for our narrative review.Most studies were observational studies.CONCLUSION:The review provided the current evidence-based management of diverse disease states during the interfacility transfer process,such as proning positioning for respiratory failure,extracorporeal membrane oxygenation(ECMO),obstetric emergencies,and hypertensive emergencies(aortic dissection and spontaneous intracranial hemorrhage).

Ability of lactulose breath test results to accurately identify colorectal polyps through the measurement of small intestine bacterial overgrowth

BACKGROUND While colorectal polyps are not cancerous,some types of polyps,known as adenomas,can develop into colorectal cancer over time.Polyps can often be found and removed by colonoscopy;however,this is an invasive and expensive test.Thus,there is a need for new methods of screening patients at high risk of developing polyps.AIM To identify a potential association between colorectal polyps and small intestine bacteria overgrowth(SIBO)or other relevant factors in a patient cohort with lactulose breath test(LBT)results.METHODS A total of 382 patients who had received an LBT were classified into polyp and non-polyp groups that were confirmed by colonoscopy and pathology.SIBO was diagnosed by measuring LBTderived hydrogen(H)and methane(M)levels according to 2017 North American Consensus recommendations.Logistic regression was used to assess the ability of LBT to predict colorectal polyps.Intestinal barrier function damage(IBFD)was determined by blood assays.RESULTS H and M levels revealed that the prevalence of SIBO was significantly higher in the polyp group than in the non-polyp group(41%vs 23%,P<0.01;71%vs 59%,P<0.05,respectively).Within 90 min of lactulose ingestion,the peak H values in the adenomatous and inflammatory/hyperplastic polyp patients were significantly higher than those in the non-polyp group(P<0.01,and P=0.03,respectively).In 227 patients with SIBO defined by combining H and M values,the rate of IBFD determined by blood lipopolysaccharide levels was significantly higher among patients with polyps than those without(15%vs 5%,P<0.05).In regression analysis with age and gender adjustment,colorectal polyps were most accurately predicted with models using M peak values or combined H and M values limited by North American Consensus recommendations for SIBO.These models had a sensitivity of≥0.67,a specificity of≥0.64,and an accuracy of≥0.66.CONCLUSION The current study made key associations among colorectal polyps,SIBO,and IBFD and demonstrated that LBT has moderate potential as an alternative noninvasive screening tool for colorectal polyps.

Mechanism of Niacin Induced Hot Flushes and Suppression of Cholesterol

Niacin or nicotinic acid is a form of B3 vitamin prescribed at higher concentrations for the suppression of cholesterol levels. Supplemental doses may cause very little or no side effects. However, higher concentrations of niacin cause hot flushes for most people. Here we propose a biochemical mechanism of niacin induced hot flushes. Orally taken prescription doses of niacin are converted to NAD with the liberation of excess pyrophosphate which in turn releases energy in the form of heat (hot flushes through capsaicin receptor) by the action of pyrophosphatases. The excess pyrophosphate may suppress cholesterol biosynthesis through feedback mechanism. The pathways of NAD and cholesterol biosynthesis were discussed with refence to the production and function of pyrophosphate.

Direct cost variance analysis of peroral endoscopic myotomy vs heller myotomy for management of achalasia:A tertiary referral center experience

BACKGROUND Laparoscopic Heller myotomy(LHM)has been the traditional surgical treatment for achalasia.Recently,peroral endoscopic myotomy(POEM)has demonstrated similar clinical outcomes with shorter procedure times.Studies comparing the direct cost-effectiveness of POEM vs LHM are limited.AIM To compare costs of POEM vs LHM.METHODS Haider SA et al.Comparing costs:POEM vs Heller myotomy WJGE https://www.wjgnet.com 594 October 16,2023 Volume 15 Issue 10 This retrospective chart review aimed to compare the outcomes and cost of clinical care between patients who underwent POEM and LHM procedures for achalasia.The study was conducted at a tertiary academic center from January 2019 to December 2020.Clinical outcomes,including post-operative Eckardt scores and adverse events,were assessed and compared between the two groups.Direct cost variance analysis was utilized to evaluate the cost of clinical care incurred by patients undergoing POEM in the year preceding the procedure,during the index admission,and one year post-procedure,in comparison to patients undergoing LHM.RESULTS Of 30 patients were included(15 POEM and 15 LHM)in the study.Patients in the POEM group had a mean Eckardt score of 0.5±0.5 post-procedure,which was no different from patients in the LHM group(0.7±0.6,P=0.17)indicating comparative efficacy.However,the total costs of the admission for the procedure in the LHM group were on average$1827 more expensive than in the POEM group(P<0.01).Total healthcare costs one year prior to index procedure were$7777 higher in the LHM group,but not statistically different(P=0.34).The patients in the LHM group one year after the index procedure had accrued$19730.24 larger total cost,although this was not statistically different from POEM group(P=0.68).CONCLUSION Despite similar clinical outcomes,the cost of the index procedure admission for POEM was significantly lower than for LHM.The difference was primarily related to shorter time increments utilized in the operating room during the index procedure,and shorter length of hospital stay following POEM.

活动期糖尿病夏科神经性骨关节病诊疗指南——《国际糖尿病足工作组:糖尿病相关的足病预防与管理指南(2023)》的一部分

国际糖尿病足工作组(IWGDF)自1999年以来发布了糖尿病足病预防和治疗的循证指南。这是IWGDF发布的第一部关于糖尿病患者活动期夏科神经性骨关节病诊断和治疗的指南。我们遵循GRADE方法,以人群-评估-比较-结局(PACO)和人群-干预-比较-结局(PICO)的格式设计临床问题,系统检索医学文献,并提出有依据的推荐。这些推荐是基于我们系统综述的证据,如无证据则参考专家意见,并考虑到与干预相关的受益和危害、患者偏好、可行性和适用性以及成本的权衡。我们在本章节介绍了2023年糖尿病患者活动期夏科神经性骨关节病的诊断和治疗指南,并提出了未来的关键研究方向。

Endoplasmic reticulum stress,autophagy,neuroinflammation,and sigma 1 receptors as contributors to depression and its treatment

The etiological factors contributing to depression and other neuropsychiatric disorders are largely undefined. Endoplasmic reticulum stress pathways and autophagy are well-defined mechanisms that play critical functions in recognizing and resolving cellular stress and are possible targets for the pathophysiology and treatment of psychiatric and neurologic illnesses. An increasing number of studies indicate the involvement of endoplasmic reticulum stress and autophagy in the control of neuroinflammation, a contributing factor to multiple neuropsychiatric illnesses. Initial inflammatory triggers induce endoplasmic reticulum stress, leading to neuroinflammatory responses. Subsequently, induction of autophagy by neurosteroids and other signaling pathways that converge on autophagy induction are thought to participate in resolving neuroinflammation. The aim of this review is to summarize our current understanding of the molecular mechanisms governing the induction of endoplasmic reticulum stress, autophagy, and neuroinflammation in the central nervous system. Studies focused on innate immune factors, including neurosteroids with anti-inflammatory roles will be reviewed. In the context of depression, animal models that led to our current understanding of molecular mechanisms underlying depression will be highlighted, including the roles of sigma 1 receptors and pharmacological agents that dampen endoplasmic reticulum stress and associated neuroinflammation.

Approach to traumatic cardiac arrest in the emergency department: a narrative literature review for emergency providers

BACKGROUND:Traumatic cardiac arrest(TCA)is a major contributor to mortality and morbidity in all age groups and poses a significant burden on the healthcare system.Although there have been advances in treatment modalities,survival rates for TCA patients remain low.This narrative literature review critically examines the indications and eff ectiveness of current therapeutic approaches in treating TCA.METHODS:We performed a literature search in the PubMed and Scopus databases for studies published before December 31,2022.The search was refi ned by combining search terms,examining relevant study references,and restricting publications to the English language.Following the search,943 articles were retrieved,and two independent reviewers conducted a screening process.RESULTS:A review of various studies on pre-and intra-arrest prognostic factors showed that survival rates were higher when patients had an initial shockable rhythm.There were conflicting results regarding other prognostic factors,such as witnessed arrest,bystander cardiopulmonary resuscitation(CPR),and the use of prehospital or in-hospital epinephrine.Emergency thoracotomy was found to result in more favorable outcomes in cases of penetrating trauma than in those with blunt trauma.Resuscitative endovascular balloon occlusion of the aorta(REBOA)provides an advantage to emergency thoracotomy in terms of occupational safety for the operator as an alternative in managing hemorrhagic shock.When implemented in the setting of aortic occlusion,emergency thoracotomy and REBOA resulted in comparable mortality rates.Veno-venous extracorporeal life support(V-V ECLS)and veno-arterial extracorporeal life support(V-A ECLS)are viable options for treating respiratory failure and cardiogenic shock,respectively.In the context of traumatic injuries,V-V ECLS has been associated with higher rates of survival to discharge than V-A ECLS.CONCLUSION:TCA remains a signifi cant challenge for emergency medical services due to its high morbidity and mortality rates.Pre-and intra-arrest prognostic factors can help identify patients who are likely to benefit from aggressive and resource-intensive resuscitation measures.Further research is needed to enhance guidelines for the clinical use of established and emerging therapeutic approaches that can help optimize treatment effi cacy and ameliorate survival outcomes.

DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Congenital Heart Diseases

Aims:Multiple genes and environmental factors are known to be involved in congenital heart disease(CHD),but epigenetic variation has received little attention.Monozygotic(MZ)twins with CHD provide a unique model for exploring this phenomenon.In order to investigate the potential role of Deoxyribonucleic Acid(DNA)methyla-tion in CHD pathogenesis,the present study examined DNA methylation variation in MZ twins discordant for CHD,especially ventricular septal defect(VSD).Methods and Results:Using genome-wide DNA methylation profiles,we identified 4004 differentially methylated regions(DMRs)in 18 MZ twin pairs discordant for CHD,and 2826 genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed a list of CHD-associated pathways.To further investigate the role of DNA methylation in VSD,data from 7 pairs of MZ twins with VSD were analyzed.We identified 1614 DMRs corresponding to 1443 genes associated with arrhythmogenic right ventricular cardiomyopathy,cyclic guanosine monopho-sphate-protein kinase G(cGMP-PKG)signaling pathway by KEGG analysis,and cell-cell adhesion,calcium ion transmembrane transport by GO analysis.A proportion of DMR-associated genes were involved in calcium signaling pathways.The methylation changes of calcium signaling genes might be related to VSD pathogenesis.Conclusion:CHD is associated with differential DNA methylation in MZ twins.CHD may be etiologically linked to DNA methylation,and methylation of calcium signaling genes may be involved in the development of VSD.

Role of liver biopsy in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD), defined as abnormal accumulation(> 5%) of hepatic triglyceride without excess alcohol intake, is the most common form of chronic liver disease in adults and children in the United States. NAFLD encompasses a spectrum of histologic findings including uncomplicated steatosis, steatosis with inflammation and steatohepatitis [nonalcoholic steatohepatitis(NASH)]; the latter can advance to cirrhosis and hepatocellular carcinoma. NASH is currently accepted as the hepatic manifestation of the set of cardiovascular risk factors collectively known as metabolic syndrome. In 1999 a system for histologic grading and staging for NASH was proposed; this was revised by the NASH Clinical Research Network in 2005 for the entire spectrum of lesions in NAFLD, including the lesions and patterns of pediatric NAFLD, and for application in clinical research trials. Diagnosis remains distinct from grade and stage. A recent European proposal separates steatosis from activity to derive a numeric diagnosis of NASH. Even though there have been promising advancements in non-invasive testing, these tests are not yet detailed enough to replace the full range of findings provided by liver biopsy evaluation. Limitations of biopsy are acknowledged, but liver biopsy remains the "gold standard" for diagnosis and determination of amounts of necroinflammatory activity, and location of fibrosis, as well as remodeling of the parenchyma in NASH. This review focuses on the specific histologic lesions of NAFLD and NASH, grading and staging, differential diagnoses to be considered, and the continuing role of the liver biopsy in this important liver disease.

The utility of point-of-care ultrasound in the assessment of volume status in acute and critically ill patients

BACKGROUND:Volume resuscitation has only been demonstrated to be effective in approximately fifty percent of patients.The remaining patients do not respond to volume resuscitation and may even develop adverse outcomes(such as acute pulmonary edema necessitating endotracheal intubation).We believe that point-of-care ultrasound is an excellent modality by which to adequately predict which patients may benefi t from volume resuscitation.DATA RESOURCES:We performed a search using PubMed,Scopus,and MEDLINE.The following search terms were used:fluid responsiveness,ultrasound,non-invasive,hemodynamic,fluid challenge,and passive leg raise.Preference was given to clinical trials and review articles that were most relevant to the topic of assessing a patient’s cardiovascular ability to respond to intravenous fl uid administration using ultrasound.RESULTS:Point-of-care ultrasound can be easily employed to measure the diameter and collapsibility of various large vessels including the inferior vena cava,common carotid artery,subclavian vein,internal jugular vein,and femoral vein.Such parameters are closely related to dynamic measures of fluid responsiveness and can be used by providers to help guide fluid resuscitation in critically ill patients.CONCLUSION:Ultrasound in combination with passive leg raise is a non-invasive,costand time-effective modality that can be employed to assess volume status and response to fluid resuscitation.Traditionally sonographic studies have focused on the evaluation of large veins such as the inferior vena cava,and internal jugular vein.A number of recently published studies also demonstrate the usefulness of evaluating large arteries to predict volume status.

Relationship of functional gastrointestinal disorders and psychiatric disorders: Implications for treatment

这篇文章重游在象急躁的肠症候群( IBS )那样的精神病理学和功能的胃肠的混乱之间的连接，讨论抗抑郁剂的合理使用以及非药理学来临到 IBS 的管理，并且从知识的现在的状态基于一个学科交差的观点为 IBS 的处理建议指南。精神病学的混乱上的相关出版文学，特别躯体化混乱在 IBS 的上下文，并且为管理的文学提供方向被考察，并且新方向在文学从调查结果被提供。IBS 是有为它的临床的演讲负责的各种各样的潜在的机制的异构的症候群。IBS 与在另外的机关系统的精神病学的问题， unexplained 症状，和功能的症候群典型地是复杂的。没有表明的原因，大多数 IBS 病人有多重抱怨，并且这些症状能包含除肠以外的系统，例如骨头和关节(fibromyalgia，颞下颌关节症候群) ，心(非心脏的胸痛) ，脉管(绝经后的症候群) ，并且大脑(焦虑，消沉) 。大多数 IBS 病人没有精神病学的病伴随他们的 somatoform (当医药混乱不在时的物理症状) 的精神分析形式(当精神病学的混乱不在时的心理抱怨) 的本身，而是一个范围症状抱怨。作为精神病学的病人把 IBS 病人标记不是正确的(除了有真躯体化的那些更困难的病人混乱) 。治疗的一个模式是不大可能的普遍有效或解决大多数症状。心理疗法或认知行为的治疗的技术能允许 IBS 病人与他们的病更乐意地处理。特定的事件压抑或焦虑混乱能为那些条件作为适当被管理。设计改进焦虑或消沉的药不为在 IBS 的精神病学的抱怨是一致地有用的，因为听起来类似于在精神病学的混乱看见的那些的精神分析形式症状不能与 IBS 在病人有一样的意义。

Histopathology of nonalcoholic fatty liver disease

Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease(NAFLD) are measured.Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD,i.e.nonalcoholic steatohepatitis(NASH) and fibrosis.Included in the lesions of NAFLD are steatosis,lobular and portal inflammation,hepatocyte injury in the forms of ballooning and apoptosis,and fibrosis.However,patterns of these lesions are as distinguishing as the lesions themselves.Liver injury in adults and children due to NAFLD may have different histological patterns.In this review,the rationale for liver biopsy,as well as the histopathological lesions,the microscopically observable patterns of injury,and the differential diagnoses of NAFLD and NASH are discussed.

Pancreatic regenerating protein (regⅠ) and regⅠreceptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis

AIM: Pancreatic regenerating protein (regⅠ) stimulates pancreatic regeneration after pancreatectomy and is mitogenic to ductal andβ-cells. This suggests that regⅠand its receptor may play a role in recovery after pancreatic injury. We hypothesized that regⅠand its receptor are induced in acute pancreatitis. METHODS: Acute pancreatitis was induced in male Wistar rats by retrograde injection of 3% sodium taurocholate into the pancreatic duct. Pancreata and serum were collected 12, 24, and 36 hours after injection and from normal controls (4 rats/group). RegⅠreceptor mRNA, serum regⅠprotein, and tissue regⅠprotein levels were determined by Northern analysis, enzyme-linked immunosorbent assay (ELISA), and Western analysis, respectively. Immunohistochemistry was used to localize changes in regⅠand its receptor. RESULTS: Serum amylase levels and histology confirmed necrotizing pancreatitis in taurocholate treated rats. There was no statistically significant change in serum regⅠconcentrations from controls. However, Western blot demonstrated increased tissue levels of regⅠat 24 and 36 h. This increase was localized primarily to the acinar cells and the ductal cells by immunohistochemistry. Northern blot demonstrated a significant increase in regⅠreceptor mRNA expression with pancreatitis. Immunohistochemistry localized this increase to the ductal cells, islets, and acinar cells. CONCLUSION: Acute pancreatitis results in increased tissue regⅠprotein levels localized to the acinar and ductal cells, and a parallel threefold induction of regⅠreceptor in the ductal cells, islets, and acinar cells. These changes suggest that induction of reg I and its receptor may be important for recovery from acute pancreatitis.

Inhibitory Effects of Rap1GAP Overexpression on Proliferation and Migration of Endothelial Cells via ERK and Akt Pathways

Rapl is expressed in human umbilical vein endothelial cells （HUVECs）. Rapl-GTPase activating protein （RaplGAP）, with its specific target, Rapl, has been shown to be important in the regulation of many physiological and certain pathological processes. In this study, we investigated the effect of RaplGAP expression on endothelial cell function, or, more specifically, proliferation and migration of endothelial cells. HUVECs were transfected with pcDNA3.1 （empty vector）, pcDNA3.1 containing Flag-tagged-RaplGAP or Myc-tagged-RaplN17. The proliferation, migration and tube formation were examined and compared among the 3 groups. Expression of Rapl, RaplGAP, extracellular signal-regulated kinase （ERK）, phospho-ERK, Akt, phosphor-Akt was detected by Western blotting. The results showed that the proliferation, migration and tube formation were significantly reduced in RaplGAP- and RaplN17-transfected HUVECs as compared with empty vector-transfected control. These changes were coincident with increased expression of Rap 1GAP and decreased expression of activated Rap l, phospho-ERK and -Akt. After treatment of Rap l GAP-transfected HUVECs with a stimulator of Rapl guanine-nucleotide-exchange factor （RaplGEF） 8CPT-2＇OMe-cAMP, it was found that Rapl activity was decreased as compared with empty vector-transfected control. Pretreatment of HU- VECs with an ERK inhibitor PD98059 or a PI3K inhibitor LY294002 prior to stimulation not only blocked 8CPT-2＇OMe-cAMP-induced phosphorylation of ERK and Akt, but also significantly reduced cell proliferation and migration. Finally, we examined the effect of vascular endothelial growth factor （VEGF） on HUVECs overexpressing RaplGAP. VEGF-stimulated Rapl activity, phosphorylation of ERK and Akt, cyclin D1 expression and cell proliferation were repressed in HUVECs overexpressing RaplGAP as compared to empty vector-transfected Control. Taken together, our findings demonstrate that RaplGAP/Rapl and their downstream effectors regulate proliferation and migration of HUVECs via ERK and Akt pathways.

The use of 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia(BPH)is characterized by an enlarged prostate,lower urinary tract symptoms(LUTS),and a decreased urinary flow rate.Common in older men,BPH is a progressive disease that can eventually lead to complications including acute urinary retention(AUR)and the need for BPH-related surgery.Both normal and abnormal prostate growth is driven by the androgen dihydrotestosterone(DHT),which is formed from testosterone under the influence of 5-alpha reductase.Thus,5-alpha reductase inhibitors(5-ARIs)effectively reduce the serum and intraprostatic concentration of DHT,causing an involution of prostate tissue.Two 5-ARIs are currently available for the treatment of BPHdfinasteride and dutasteride.Both have been demonstrated to decrease prostate volume,improve LUTS and urinary flow rates,which ultimately reduces the risk of AUR and BPH-related surgery.Therefore,either alone or in combination with other BPH medications,5-ARIs are a mainstay of BPH management.

Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9

RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.