BMPRⅡ^(+)neural precursor cells isolated and characterized from organotypic neurospheres:an in vitro model of human fetal spinal cord development

Roof plate secretion of bone morphogenetic proteins(BMPs)directs the cellular fate of sensory neurons during spinal cord development,including the formation of the ascending sensory columns,though their biology is not well understood.Type-ⅡBMP receptor(BMPRⅡ),the cognate receptor,is expressed by neural precursor cells during embryogenesis;however,an in vitro method of enriching BMPRⅡ^(+)human neural precursor cells(hNPCs)from the fetal spinal cord is absent.Immunofluorescence was undertaken on intact second-trimester human fetal spinal cord using antibodies to BMPRⅡand leukemia inhibitory factor(LIF).Regions of highest BMPRⅡ^(+)immunofluorescence localized to sensory columns.Parenchymal and meningeal-associated BMPRⅡ^(+)vascular cells were identified in both intact fetal spinal cord and cortex by co-positivity with vascular lineage markers,CD34/CD39.LIF immunostaining identified a population of somas concentrated in dorsal and ventral horn interneurons,mirroring the expression of LIF receptor/CD118.A combination of LIF supplementation and high-density culture maintained culture growth beyond 10 passages,while synergistically increasing the proportion of neurospheres with a stratified,cytoarchitecture.These neurospheres were characterized by BMPRⅡ^(+)/MAP2ab^(+/–)/βⅢ-tubulin^(+)/nestin^(–)/vimentin^(–)/GFAP^(–)/NeuN^(–)surface hNPCs surrounding a heterogeneous core ofβⅢ-tubulin^(+)/nestin^(+)/vimentin^(+)/GFAP^(+)/MAP2ab^(–)/NeuN^(–)multipotent precursors.Dissociated cultures from tripotential neurospheres contained neuronal(βⅢ-tubulin^(+)),astrocytic(GFAP+),and oligodendrocytic(O4+)lineage cells.Fluorescence-activated cell sorting-sorted BMPRⅡ^(+)hNPCs were MAP2ab^(+/–)/βⅢ-tubulin^(+)/GFAP^(–)/O4^(–)in culture.This is the first isolation of BMPRⅡ^(+)hNPCs identified and characterized in human fetal spinal cords.Our data show that LIF combines synergistically with high-density reaggregate cultures to support the organotypic reorganization of neurospheres,characterized by surface BMPRⅡ^(+)hNPCs.Our study has provided a new methodology for an in vitro model capable of amplifying human fetal spinal cord cell numbers for>10 passages.Investigations of the role BMPRⅡplays in spinal cord development have primarily relied upon mouse and rat models,with interpolations to human development being derived through inference.Because of significant species differences between murine biology and human,including anatomical dissimilarities in central nervous system(CNS)structure,the findings made in murine models cannot be presumed to apply to human spinal cord development.For these reasons,our human in vitro model offers a novel tool to better understand neurodevelopmental pathways,including BMP signaling,as well as spinal cord injury research and testing drug therapies.

From intestinal stem cells to inflammatory bowel diseases

The pathogenesis of both entities of inflammatory bowel disease (IBD), namely Crohn's disease (CD) and ulcerative colitis (UC), is still complex and under investigation. The importance of the microbial flora in developing IBD is beyond debate. In the last few years, the focus has changed from adaptive towards innate immunity. Crohn's ileitis is associated with a deficiency of the antimicrobial shield, as shown by a reduced expression and secretion of the Paneth cell defensin HD5 and HD6, which is related to a Paneth cell differentiation defect mediated by a diminished expression of the Wnt transcription factor TCF4. In UC, the protective mucus layer, acting as a physical and chemical barrier between the gut epithelium and the luminal microbes, is thin- ner and in part denuded as compared to controls. This could be caused by a missing induction of the goblet cell differentiation factors Hath1 and KLF4 leading to immature goblet cells. This defective Paneth and goblet cell differentiation in Crohn's ileitis and UC may enablethe luminal microbes to invade the mucosa and trigger the inflammation. The exact molecular mechanisms behind ileal CD and also UC must be further clarified, but these observations could give rise to new therapeutic strategies based on a stimulation of the protective innate immune system.

Serum soluble ST2 is a promising prognostic biomarker in HBV-related acute-on-chronic liver failure

BACKGROUND： The IL-33/ST2 axis is involved in the pathogenesis of many diseases such as autoimmune diseases, cancer,and heart failure. However, studies of the IL-33/ST2 pathway in HBV-related acute-on-chronic liver failure（HBV-ACLF） are lacking. The present study aimed to determine the prognostic role of serum IL-33/soluble ST2（s ST2） in HBV-ACLF.METHODS： Serum levels of IL-33 and sS T2 in healthy controls（HC, n=18）, chronic hepatitis B（CHB, n=27） and HBV-ACLF（n=51） patients at the 1st and 4th week after enrollment were detected using ELISA, and clinical data were collected. The follow-up of HBV-ACLF patients lasted for 6 months at least.RESULTS： There was no significant difference of serum IL-33 level among HC, CHB and HBV-ACLF patients at week 1.However, serum s ST2 level differed significantly among the three groups： highest in the HBV-ACLF group, moderate in the CHB group and lowest in the HC group. There was a reverse correlation between serum s ST2 level and the survival of HBV-ACLF patients. The level of serum s ST2 in HBV-ACLF survivors was significantly declined from week 1 to week 4 following the treatment, whereas that in HBV-ACLF nonsurvivors remained at a high level during the same period. Furthermore, serum sS T2 level was significantly correlated with laboratory parameters and the most updated prognostic scores（CLIF-C OF score, CLIF-C ACLF score and ACLF grades）. Thereceiver operating characteristics curves demonstrated that serum sS T2 level was a good diagnostic marker for predicting the 6-month mortality in HBV-ACLF patients, comparable to the most updated prognostic scores. Serum sS T2 cut-off points for predicting prognosis in HBV-ACLF patients were 76 ng/mL at week 1 or 53 ng/mL at week 4, respectively. HBV-ACLF patients with serum sS T2 level above the cut-off point often had a worse prognosis than those below the cut-off point.CONCLUSION： Serum s ST2 may act as a promising biomarker to assess severity and predict prognosis of patients with HBV-ACLF and help for the early identification and optimal treatment of HBV-ACLF patients at high risk of mortality.

Crohn’s disease-Defect in innate defence

Crohn’s disease may prinicipally involve the whole gastrointestinal tract. Most commonly, the inflammation occurs in the small intestine and/or in the colon with stable disease location over the years. The pathogenesis of both disease phenotypes is complex, the likely primary defect lies in the innate rather than adaptive immunity, particularly in the chemical antimicrobial barrier of the mucosa. Crohn’s ileitis is associated with a reduced expression of the Wnt signalling pathway transcription factor T-cell factor 4 (TCF4), which is regulating Paneth cell differentiation. As a result, the alpha-defensins and principal Paneth cell products HD5 and HD6 are deficiently expressed in ileal disease, independent of current inflammation. In contrast, Crohn’s colitis is typically associated with an impaired induction of the beta-defensins HBD2 and HBD3 caused by fewer gene copy numbers in the gene locus of the beta-defensins on chromosome 8. This ileal and colonic defect in innate defence mediated by a deficiency of the protective alpha- and beta- defensins may enable the luminal microbes to invade the mucosa and trigger the inflammation. A better understanding of the exact molecular mechanisms behind ileal and colonic Crohn’s disease may give rise to new therapeutic strategies based on a stimulation of the protective innate immune system.

Bacterial infection triggers and complicates acute-on-chronic liver failure in patients with hepatitis B virus-decompensated cirrhosis: A retrospective cohort study

BACKGROUND Reports on bacterial infection(BI)in decompensated cirrhosis(DC)is mainly from alcoholic cirrhosis.The role of BI as a trigger or complication of acute-onchronic liver failure(ACLF)in patients with hepatitis B virus decompensated cirrhosis(HBV-DC)remains to be investigated.AIM To investigate the impact of BI on the outcomes of the patients with HBV-DC admitted into the hospital with or without ACLF.METHODS This retrospective study included patients with HBV-DC admitted to two tertiary centers in China.In-hospital overall survival,90-d transplant-free survival,5-year post-discharge survival,and cumulative incidence of ACLF were evaluated.Risk factors for death were analyzed considering liver transplantation as a competing event.RESULTS A total of 1281 hospitalized HBV-DC patients were included;284 had ACLF at admission.The overall prevalence of BI was 28.1%.The patients with BI had a significantly lower in-hospital survival and transplant-free 90-d survival than those without,in both the patients admitted with and without ACLF.The presence of BI significantly increased the risk of developing ACLF[subdistribution hazard ratio(sHR)=2.52,95%CI:1.75-3.61,P<0.001]in the patients without ACLF.In the patients discharged alive,those who had an episode of BI had a significantly lower 5-year transplant-free survival.BI was an independent risk factor for death in the patients admitted without ACLF(sHR=3.28,95%CI:1.93-5.57),while in ACLF admissions,the presence of pneumonia,but not other type of BI,independently increased the risk of death(sHR=1.87,95%CI:1.24-2.82).CONCLUSION BI triggers ACLF in patients with HBV-DC and significantly impairs short-term survival.HBV-DC patients should be monitored carefully for the development of BI,especially pneumonia,to avoid an adverse outcome.

Brains, bacteria and behaviors: the role of interferon-gamma in the pathogenesis of pneumococcal meningitis

of bacterial meningitis that occurs following brain infection by the Gram-positive cocci Streptococcus pneumoniae.Not only does it cause acute mortality,but pneumococcal meningitis also accounts for the highest proportion of survivors living with neurological sequelae,including behavioral disorders,cognitive deficits,hearing loss,motor impairment and epilepsy.More than 90 distinct pneumococcal serotypes have been identified worldwide based on their capsular compositions and serological responses.Serotype replacement continually poses great challenge to costly vaccination programs in developed countries(Koelman et al.,2020),this has therefore emphasized the need to develop new treatment strategies in addition to improving vaccine coverage.

Infant male circumcision: An evidence-based policy statement

Here we review the international evidence for benefits and risks of infant male circumcision (MC) and use this to develop an evidence-based policy statement for a developed nation setting, focusing on Australia. Evidence from good quality studies that include meta-analyses and randomized controlled trials showed that MC provides strong protection against: urinary tract infections and, in infancy, renal parenchymal disease;phimosis;paraphimosis;balanoposthitis;foreskin tearing;some heterosexually transmitted infections including HPV, HSV-2, trichomonas, HIV, and genital ulcer disease;thrush;inferior hygiene;penile cancer and possibly prostate cancer. In women, circumcision of the male partner protects against HPV, HSV-2, cervical cancer, bacterial vaginosis, and possibly Chlamydia. MC has no adverse effect on sexual function, sensitivity, penile sensation or satisfaction and may enhance the male sexual experience. Adverse effects are uncommon (<1%), and virtually all are minor and easily treated. For maximum benefits, safety, convenience and cost savings, MC should be performed in infancy and with local anesthesia. A risk-benefit analysis shows benefits exceed risks by a large margin. Over their lifetime up to half of uncircumcised males will suffer a medical condition as a result of retaining their foreskin. The ethics of infant MC and childhood vaccination are comparable. Our analysis finds MC is beneficial, safe and cost-effective, and should optimally be performed in infancy. In the interests of public health and individual wellbeing, adequate parental education, and steps to facilitate access and affordability should be encouraged in developed countries.

The role of granulocyte macrophage-colony-stimulating factor in acute intestinal inflammation

An imbalance of mucosal proand anti-inflammatory cytokincs is crucial in the pathogenesis of inflammatory bowel disease （IBD）. GM-CSF influences the development of hemopoietic cells. The precise role of GM-CSF in IBD remains to be elucidated. GM-CSF gene knockout （GM-CSF^-/-） and wild-type （Wt） mice were challenged with 2.5% dextran sulfate sodium （DSS） for 7 days. The ensued clinical and pathological changes, macrophage infiltration, colonic cytokine production, and bacterial counts were examined. DSS-treated GM-CSF^-/- mice developed more severe acute colitis than DSS-treated Wt mice, reflected by a greater body weight loss, more rectal bleeding, and aggravated histopathological changes. More infiltrating macrophages were observed in GM-CSF^-/-, compared with Wt mice following DSS challenge, correlating with monocyte chemoattractant protein-1 （MCP-1） production. The levels of colonic IL-17 and TNF-α were increased significantly in GM-CSF^-/- mice, but not in Wt mice, following DSS administration. The level of IL-6 was increased by 1.5- and 2-fold in the colon of GM-CSF^-/- and Wt mice, respectively, following DSS challenge. No significant changes in IL-4 and IFN-γ were detected in Wt and GM-CSF^-/- mice following DSS treatment. The bacteria recovery from colon was increased about 15- and 5-fold, respectively, in Wt mice and GM-CSF^-/- mice following DSS challenge. These results suggest that GM-CSF^-/- mice are more susceptible to acute DSS-induced colitis, possibly because of an impaired gut innate immune response as a result of diminished GM-CSF.

Remote photobiomodulation: an emerging strategy for neuroprotection

Photobiomodulation (PBM)- the irradiation of cells or tissues with low-intensity red to near-infrared light - is emerging as an effective means of enhancing cell and tissue resilience and repair. As reviewed elsewhere (Gordon et al., 2019), the intracellular effects of PBM appear to be primarily mediated by cytochrome C oxidase, a key enzyme in the mitochondrial respiratory chain and a primary photoacceptor of red to near-infrared light. Absorption of light by cytochrome C oxidase alters its redox state, resulting in increased ATP production, the liberation of nitric oxide and a transient burst in reactive oxygen species.

The Ionic Composition of Nasal Fluid and Its Function

The aim of the experiments reported here is to increase our understanding of the function of the nasal fluid. It is generally accepted that the nasal fluid assists in the humidification of the inspired air. It also assists in the capture of inspired particles such as pollen, preventing them getting lodged in the lungs. It is also known to contain antibacterial substances which keep the nose, nasopharynx and respiratory passages relatively free of infection. There are other features of the nasal fluid that are not understood. In cold weather, is it the fluid that collects in the nostrils pure water or nasal fluid? Why does nasal fluid have an exceptionally high potassium concentration? Does nasal fluid secreted during the common cold have the same composition as at other times? My objectives are to try to answer these questions. My method is to collect my nasal fluid in several different ways and have the ionic composition of each determined accurately. My findings are that nasal fluid is similar in composition however it is secreted. In cold weather, if expiration is via the nose, the nasal fluid is diluted by condensed water. The high concentration of potassium in the nasal fluid is not a way of controlling the level of potassium in the body but I suggest that it may assist in maintaining the antibacterial property of the nasal fluid.

P2X7 receptor signaling during adult hippocampal neurogenesis

Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus.Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories.Regulation of hippocampal neurogenesis is complex and multifaceted,and numerous signaling pathways converge to modulate cell proliferation,apoptosis,and clearance of cellular debris,as well as synaptic integration of newborn immature neurons.The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored.P2X7 receptors are exceptionally versatile:in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation.P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication,and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form,which induce apoptotic cell death through cytosolic ion dysregulation.Lastly,as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis,as well as during some disease states.Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine.This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus,and neural stem and progenitor cells.

The Occurrence of Migraine Auras and Possible Triggers

Our aim is to determine the cause(s) of migraine auras. Our understanding of how migraines and migraine auras originate is very imperfect. An important observation is that migraines occur more frequently in women at reproductive age than in men at a similar age. This suggests that gonadal hormones may be relevant triggers. The occurrence of classical (typical auras without headache) auras in one author (WB) has been recorded. Every aura in six years (85) has been noted, studied and analysed statistically. The auras occur predominantly in Spring and Autumn, especially in the longer reproductive season of Spring. This association is supported statistically. The results support the idea of gonadal hormones as relevant triggers, the strongest candidate being estrogen. Basic mechanisms underlying the auras are discussed, especially the phenomenon of cortical spreading depression. We also propose that both auras and migraines depend upon previous injury to the head or to the brain, giving rise to a condition of “deafferentation hypersensitivity”.

Early infant male circumcision:Systematic review,risk-benefit analysis,and progress in policy

AIM To determine whether recent evidence-based United States polices on male circumcision(MC) apply to comparable Anglophone countries,Australia and New Zealand.METHODS Articles in 2005 through 2015 were retrieved from PubM ed using the keyword "circumcision" together with 36 relevant subtopics.A further PubM ed search was performed for articles published in 2016.Searches of the EMBASE and Cochrane databases did not yield additional citable articles.Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further.The most relevant andrepresentative of the topic were included.Bibliographies were examined to retrieve further key references.Randomized controlled trials,recent high quality systematic reviews or meta-analyses(level 1++ or 1+ evidence) were prioritized for inclusion.A risk-benefit analysis of articles rated for quality was performed.For efficiency and reliability,recent randomized controlled trials,metaanalyses,high quality systematic reviews and large welldesigned studies were used if available.Internet searches were conducted for other relevant information,including policies and Australian data on claims under Medicare for MC.RESULTS Evidence-based policy statements by the American Academy of Pediatrics(AAP) and the Centers for Disease Control and Prevention(CDC) support infant and later age male circumcision(MC) as a desirable public health measure.Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria.Together,these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects,phimosis that causes difficult and painful erections and "ballooning" during urination,inflammatory skin conditions,inferior penile hygiene,candidiasis,various sexually transmissible infections in both sexes,genital ulcers,and penile,prostate and cervical cancer.Our risk-benefit analysis showed that benefits exceeded procedural risks,which are predominantly minor,by up to 200 to 1.We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime.Wide-ranging evidence from surveys,physiological measurements,and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function,sensitivity or pleasure.United States studies showed that early infant MC is cost saving.The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews.CONCLUSION Affirmative MC policies are needed in Australia and New Zealand.Routine provision of accurate,unbiased education,and access in public hospitals,will maximize health and financial benefits.

Targeting the body to protect the brain:inducing neuroprotection with remotely-applied near infrared light

The incidence of intractable age-related neurodegenerative conditions such as Alzheimer＇s and Parkinson＇s diseases and age-related macular degeneration is projected to increase substantially over the coming decades with the ageing of the global population. While the burden of disease associ- ated with other chronic conditions has decreased in recent times due to improved diagnosis and treatment, current therapies for neurodegenerative diseases still fall short in that they are only effective in treating signs and symptoms - they do little to slow or prevent disease progress. Thus, there is an urgent need for treatments that address disease progression.

Neuroprotective properties of dietary saffron：more than just a chemical scavenger？

There is increasing evidence that consumption of saffron,a spice derived from the flower of the Crocus savitus plant,has various therapeutic effects,including protection of the central nervous system.

Why do we yawn?

The biomedical hypothesis proposed here is that the immediate trigger for a yawn is a restricted collapse of a few alveoli in the lungs. The extent of this alveolar collapse may be too small for it to be detected by current X-ray technology, but this technology is continually improving and may soon be good enough to test the hypothesis. In support of the hypothesis, it is shown that yawning can be inhibited by deep breaths of air, nitrogen or carbogen, thus showing that yawning is not triggered by lack of oxygen or by excess carbon dioxide, leaving alveolar collapse as the most likely possibility. A more extensive form of alveolar collapse is termed atelectasis and this involves a serious state of hypoxia which, if deepened or prolonged, can be fatal. Therefore, if the hypothesis is correct, yawning may prevent the development of atelectasis and save lives. This paper is not concerned with other indirect ways in which yawning may be induced, nor with the mechanism and neural circuitry of the yawn, nor with social aspects of yawning, only with the immediate trigger. My aim is to get better evidence for the hypothesis put forward here and also to study the behaviour of the pulmonary alveoli in normal respiration.

小胶质细胞比星形胶质细胞对干扰素α的反应更广泛而多样性

Ⅰ型干扰素(IFN-Ⅰ)对于中枢神经系统(CNS)产生有效的抗菌防御是至关重要的,但IFN-Ⅰ也会引起严重的神经疾病(即脑干扰素病),例如Aicardi-Goutières综合征。在CNS中,小胶质细胞和星形胶质细胞在宿主对感染和损伤的反应中具有重要作用,这2种细胞都对IFN-Ⅰ有反应。虽然IFN-Ⅰ信号传导途径在星形胶质细胞和小胶质细胞中是相同的,但这2种细胞对IFN-Ⅰ的应答差异是否存在、程度如何,仍然是未知的。在本研究中,我们探索了星形胶质细胞和小胶质细胞对IFN-Ⅰ,IFN-α的全局转录反应。我们发现在基础条件下,每种细胞类型都有一种独特的基因表达模式,反映了其发育起源和生物学功能。在IFN-α刺激后,星形胶质细胞和小胶质细胞也显示出共同的核心反应,其特征是检测和消除病原体所需的基因表达增加。与星形胶质细胞相比,小胶质细胞对IFN-α具有更广泛和多样的反应,同时有更多的基因表达上调(282 vs.141)和下调(81 vs.3)。在脑干扰素病小鼠模型中也记录了特定IFN-Ⅰ调控基因的进一步验证。本研究结果不仅发现星形胶质细胞和小胶质细胞对IFN-I的反应机制存在相同之处,也存在明显的不同。这些细胞在宿主防御和脑干扰素病发展中都起着独特的作用。

Expertise and Ideology in Statistical Evaluation of Circumcision for Protection against HIV Infection

Aim: To critically evaluate data and arguments by Van Howe defending his stance opposing male circumcision (MC), in particular his meta-regression analyses evaluating the ability of MC to reduce HIV infection risk in heterosexual populations within and outside Africa. Methods: We performed metaregression analysis of log odds of HIV infection between uncircumcised and circumcised men using a single covariate (MC prevalence) in the meta-regression model involving the metareg package in STATA 13 for 103 populations worldwide and for populations within Africa. The meta-regression of log odds and MC prevalence was fitted to a line, as were empirical Bayes estimates resulting from post-estimation. Results: Our critical evaluation of Van Howe’s arguments attempting to undermine the scientific evidence in support of the benefits of MC in protection of men against HIV during heterosexual intercourse, as well as other infections and conditions, together with his use of statistics to support his beliefs, revealed serious flaws, obfuscation and missing data. We therefore performed our own meta-regression analysis using a trivariate model. Doing so revealed that for MC prevalences of 50%, 75% and 100% for general populations within Africa, odds ratios for HIV risk in uncircumcised vs. circumcised men were 1.35, 1.58 and 1.85, respectively. Our meta-regression analysis of data for all countries yielded similar findings. For a general population outside Africa with 100% MC prevalence, OR was 1.5. Van Howe failed to acknowledge that since MC prevalence in US whites (91%) and blacks (76%) exceeds 75% his results support MC having a protective effect in those population groups. Conclusions: The protective effect of MC against HIV infection during heterosexual intercourse applies to populations both within and outside Africa. The debate engineered by MC opponents, and led by Van Howe, now appears to have run its course. The scientific evidence has prevailed.

Clinical, cellular, microscopic, and ultrastructural studies of a case of fibrogenesis imperfecta ossium

Fibrogenesis imperfecta ossium is a rare disorder of bone usually characterized by marked osteopenia and associated with variable osteoporosis and osteosclerosis, changing over time. Histological examination shows that newly formed collagen is abnormal, lacking birefringence when examined by polarized light. The case presented demonstrates these features and, in addition, a previously undocumented finding of a persistent marked reduction of the serum C3 and C4. Osteoblasts established in culture from a bone biopsy showed abnormal morphology on electron microscopy and increased proliferation when cultured with benzoylbenzoyl-ATP and 1,25-dihydroxyvitamin D, contrasting with findings in normal osteoblasts in culture. A gene microarray study showed marked upregulation of the messenger RNA(mRNA) for G-protein-coupled receptor 128(GPR 128), an orphan receptor of unknown function and also of osteoprotegerin in the patient's osteoblasts in culture. When normal osteoblasts were cultured with the patient's serum, there was marked upregulation of the mRNA for aquaporin 1. A single pathogenetic factor to account for the features of this disorder has not been defined, but the unique findings described here may facilitate more definitive investigation of the abnormal bone cell function.

Histological Outcome of Fuzheng Huayu plus Entecavir Combination Therapy in Chronic Hepatitis B Patients with Significant Liver Fibrosis

Publications>Journals>Journal of Clinical and Translational Hepatology>Article Full Text ORIGINAL ARTICLE OPEN ACCESS Histological Outcome of Fuzheng Huayu plus Entecavir Combination Therapy in Chronic Hepatitis B Patients with Significant Liver Fibrosis Hong-Lian Gui#,1,Chang-Qing Zhao#,2,Yan Wang3,Hong-Tu Gu2,Wei-Jing Wang1,4,Wei Cai1,Qing Guo1,Shi-San Bao5,Lie-Ming Xu*,2 and Qing Xie*,1 Author information Journal of Clinical and Translational Hepatology 2020;8(3):277-284DOI:10.14218/JCTH.2020.00004 Abstract Background and Aims:To evaluate the efficacy of Fuzheng Huayu(FZHY),a Chinese herbal formula,plus entecavir(ETV)in regression of liver fibrosis in chronic hepatitis B(CHB)patients with significant fibrosis/cirrhosis.Methods:The current study was a two-center,randomized,double-blind and placebo-controlled pilot study.Fifty-two currently untreated chronic hepatitis B patients with Ishak fibrosis score≥3 points were identified and 1:1 randomized into FZHY plus ETV combination and placebo plus ETV groups.The second liver biopsy was performed after 48-week treatment.Necroinflammatory improvement and regression of fibrosis were assessed.Fine changes in different collagen features in paired liver biopsies were evaluated by dual-photon microscopy for both groups.Results:Forty-nine patients completed the full course of treatment;forty-six of them underwent second liver biopsy(for which twenty-two were in the combination group and twenty-four were in the control group).Compared to those in the control group,patients in the combination group had significantly higher rate of fibrosis regression(82%vs.54%)(p<0.05).Furthermore,the necroinflammatory improvement was greater in the combination group than in the control group(59%vs.25%,p<0.05).Among the more than 80 collagen parameters in the dual-photon analysis,5 decreased significantly in the combination group compared to the control group(p<0.05).However,no significant improvement was detected in either biochemical,virologic or serologic responses between these two groups at week 48.Conclusions:The combination therapy of FZHY plus ETV for 48 weeks resulted in a higher rate of necroinflammatory improvement and fibrosis regression than ETV alone in chronic hepatitis B patients with significant fibrosis/cirrhosis.The clinical trial number is ChiCTR-TRC-11001377.