Two-sample Mendelian randomization analysis of causal relationship between eczema and autoimmune diseases

Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.

DYNAMIC ANALYSIS OF A TYPE OF FINANCIAL RISK CONTAGION MODEL INVOLVING IMMUNITY PERIOD AND SELF-RESCUE

In this paper,we study the dynamics of a Susceptible-Exposed-Infectious-Recovered(SEIR)nancial risk contagion model with time delay.Using stability theory and Hopf bifurcation theory,equilibria stability and Hopf bifurcation are analyzed in detail.Based on the epidemic model,we improve it by taking prior prevention and self-rescue into consideration,conclude pre-ventive intensity and self-rescue capabilities e ect the number of infections.At the same time,the analytical conditions for Hopf bifurcation are obtained,and the relevant results are veri ed by numerical simulations.

The Distribution of Repetitive DNAs Along Chromosomes in Plants Revealed by Self-genomic in situ Hybridization

The distribution of repetitive DNAs along chromosomes is one of the crucial elements for understanding the organization and the evolution of plant genomes. Using a modified genomic in situ hybridization （GISH） procedure, fluorescence in situ hybridization （FISH） with genomic DNA to their own chromosomes （called self-genomic in situ hybridization, self-GISH） was carried out in six selected plant species with different genome size and amount of repetitive DNA. Nonuniform distribution of the fluorescent labeled probe DNA was observed on the chromosomes of all the species that were tested. The signal patterns varied among species and were related to the genome size. The chromosomes of the small Arabidopsis genome were labeled almost only in the pericentromeric regions and the nucleolus organizer regions （NORs）. The signals in the relatively small genomes, rice, sorghum, and Brassica oleracea var. capitata L., were dispersed along the chromosome lengths, with a predominant distribution in the pericentromeric or proximal regions and some heterochromatic arms. All chromosomes of the large genomes, maize and barley, were densely labeled with strongly labeled regions and weakly labeled or unlabeled regions being arranged alternatively throughout the lengths. In addition, enhanced signal bands were shown in all pericentromeres and the NORs in B. oleracea var. capitata, and in all pericentromeric regions and certain intercalary sites in barley. The enhanced signal band pattern in barley was found consistent with the N-banding pattern of this species. The GISH with self-genomic DNA was compared with FISH with Cot-1 DNA in rice, and their signal patterns are found to be basically consistent. Our results showed that the self-GISH signals actually reflected the hybridization of genomic repetitive DNAs to the chromosomes, thus the self-GISH technique would be useful for revealing the distribution of the regions where repetitive DNAs concentrate along chromosomes and some chromatin differentiation associated with repetitive DNAs in plants.

Immunologic pathogenesis of multiple sclerosis

Multiple sclerosis （MS） is an autoimmune disease. The etiology and pathogenesis of MS remain unclear. At present, there are substantial evidences to support the hypothesis that genetics plays a crucial role. The people who have genetic predisposing genes easily develop immune-mediated disorder, probably in conjunction with environmental factors. The aim of this review is to describe recent observations regarding the immunologic pathogenesis of MS.

Preparation of Recombinant Islet Cell Autoantigen 69 kD Fusion Protein

To get recombinant antigen (Is/et Cell Autoantigen 69)ICA69 which was expressed in Escherichia coli strains (E.coli) by means of the gene engineering technique so that it can be used for early diagnosis of and screening in type Ⅰ diabetes mellitus, the cDNA fragment of human ICA69 was amplified by PCR, and then cloned into pSPORT 1 vector. After DNA sequencing, it was inserted into pGEX-2T between the sites of EcoR Ⅰ and Sma Ⅰ, then recombinant plasmid p2T-ICA69 was constructed and introduced into E.coli. The GST-ICA69 fusion protein was expressed by the induction of IPTG. The recombinant ICA69 proteins were used to detect the antibodies against hICA69 in 100 healthy subjects and type Ⅰ diabetic serum by the use of indirect ELISA. The sequence analysis showed that the amplified fragments contained 1449 bp, encoded 483 amino acids, and had been correctly inserted into pGEX-2T vector. The recombinant proteins expressed in the prokaryotic cells had immunogenicity and could be used to detect antibodies against ICA69 in type Ⅰ diabetic serum. Finally it can be concluded in this paper that the expression products obtained by the method of gene engineering are recombinant ICA69 antigen and may be used to improve the forecast rate and the diagnostic rate of type Ⅰ diabetes in combination with other tests.

Autoimmune liver serology:Current diagnostic and clinical challenges

Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseas-es(AiLD),namely autoimmune hepatitis types 1 and 2(AIH-1 and 2),primary biliary cirrhosis(PBC),and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody(ANA) and smooth muscle antibody(SMA).AIH-2 is specified by antibody to liver kidney microsomal antigen type-1(anti-LKM1) and anti-liver cytosol type 1(anti-LC1).SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies(AMA) react-ing with enzymes of the 2-oxo-acid dehydrogenase complexes(chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis(PSC) mostly affecting adult men wherein the only(and non-specific) reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody(p-ANCA),also termed peri-nuclear anti-neutrophil nuclear antibodies(p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis(ASC) with serological features resembling those of type 1 AIH.Liver diagnostic serol-ogy is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement(or even compete with) tradi-tional immunofluorescence procedures.We survey for the first time global trends in quality assurance impact-ing as it does on(1) manufacturers/purveyors of kits and reagents,(2) diagnostic service laboratories that fulfill clinicians' requirements,and(3) the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.

IgG4-related sclerosing disease

Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.

Overlap syndromes among autoimmune liver diseases

The three major immune disorders of the liver are autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC) and primary sclerosing cholangitis(PSC).Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis(AMA-negative PBC) overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.

Diagnostic criteria for autoimmune pancreatitis in Japan

Autoimmune pancreatitis （AIP） is a particular type of pancreatitis of presumed autoimmune etiology. Currently, AIP should be diagnosed based on combination of clinical, serological, morphological, and histopathological features. When diagnosing AIP, it is most important to differentiate it from pancreatic cancer. Diagnostic criteria for AIP, proposed by the Japan Pancreas Society in 2002 first in the world, were revised in 2006. The criteria are based on the minimum consensus of AIP and aim to avoid misdiagnosing pancreatic cancer as far as possible, but not for screening AIR The criteria consist of the following radiological, serological, and histopathological items： （1） radiological imaging showing narrowing of the main pancreatic duct and enlargement of the pancreas, which are characteristic of the disease; （2） laboratory data showing abnormally elevated levels of serum y-globulin, IgG or IgG4, or the presence of autoantibodies; （3） histopathological examination of the pancreas demonstrating marked fibrosis and prominent infiltration of lymphocytes and plasma cells, which is called lymphoplasmacytic sclerosing pancreatitis （LPSP）. For a diagnosis of AIP, criterion 1 must be present, together with criterion 2 and/ or criterion 3. However, it is necessary to exclude malignant diseases such as pancreatic or biliary cancer.

MRCP and MRI findings in 9 patients with autoimmune pancreatitis

AIM： To evaluate magnetic resonance cholangiopancreatography （HRCP） findings in conjunction with magnetic resonance （MR） images in autoimmune pancreatitis （AIP） patients. METHODS： Nine patients with AIP underwent HRI, HRCP, endoscopic retrograde cholangiopancreatography （ERCP）, computed tomography, and ultrasonography. The HRCP and MR images taken before and after steroid therapy were reviewed and compared with other imaging modalities. The HRCP findings of the AIP cases were compared to those of 10 cases with carcinoma of the head of the pancreas.RESULTS： On MRCP, the narrowed portion of the main pancreatic duct noted on ERCP was not visualized, while the non-involved segments of the main pancreatic duct were visualized. The degree of upstream dilatation of the proximal main pancreatic duct was milder than that seen in cases of pancreatic carcinoma. Stenosis or obstruction of the lower bile duct was detected in 8 patients. MR images showed enlargement of the pancreas with decreased signal intensity on T1- weighted MR images, increased signal intensity on T2- weighted MR images, and, in 3 patients, a hypointense capsule-like rim. After steroid therapy, the previously not visualized portion of the main pancreatic duct was seen, along with improvement of the bile duct stenosis. Pancreatic enlargement decreased, and the abnormal signal intensity on both T1- and T2-weighted MR images became isointense.CONCLUSION： MRCP cannot differentiate irregular narrowing of the main pancreatic duct seen with AIP from stenosis of the main pancreatic duct seen with pancreatic carcinoma. However, MRCP findings in conjunction with MR imaging of pancreatic enlargement that shows abnormal signal intensity on T1- and T2- weighted MR images are useful in supporting a diagnosis of AIP.

Diagnostic criteria for autoimmune chronic pancreatitis revisited

Autoimmune chronic pancreatitis （AIP） is increasingly being recognized worldwidely, as knowledge of this entity builds up. Above all, AIP is a very attractive disease to clinicians in terms of its dramatic response to the oral steroid therapy in contrast to ordinary chronic pancreatitis. Although many characteristic findings of AIP have been described, definite diagnostic criteria have not been fully established. In the year 2002, the Japan Pancreas Society published the diagnostic criteria of AIP and many clinicians around the world use these criteria for the diagnosis of AIP. The diagnostic criteria proposed by the Japan Pancreas Society, however, are not completely satisfactory and some groups use their own criteria in reporting AIP. This review discusses several potential limitations of current diagnostic criteria for this increasingly recognized condition. The manuscript is organized to emphasize the need for convening a consensus to develop improved diagnostic criteria.

Budesonide induces complete remission in autoimmune hepatitis

AIM： Prednisone and azathioprine represent the standard treatment for autoimmune hepatitis （AIH）. However, only 65% of the patients enter complete histological remission. Recently, budesonide （BUD） was reported to be a promising alternative. In this study we assessed the efficacy and safety of BUD in AIH. METHODS： Eighteen patients （12 women, 6 men; mean age 45.4±21 years） with AIH were treated with BUD （Budenofalk） 3 mg thrice daily and followed up for at least 24 wk. Seven patients also had features of primary biliary cirrhosis （n = 5） or primary sclerosing cholangitis （n = 2）. Advanced liver fibrosis or cirrhosis was present in RESULTS： Fifteen （83%） patients had a complete clinical and biochemical remission. Ten patients, including five with acute hepatitis, were given BUD as first-line therapy, of which seven enter remission. Three patients, two with liver cirrhosis, did not improve. All patients with second-line therapy experienced long-term remission. A histological remission was also seen in three patients. Clinically relevant BUD-induced side effects were recorded only in patients with liver cirrhosis （n = 4）. CONCLUSION： BUD is effective in remission induction in the majority of our patients with AIH. Side effects and treatment failure was mainly observed in patients with liver cirrhosis.

Etiopathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis(PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure.The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies(AMA).These reflect the presence of autoreactive T and B cells to the culprit antigens,the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes,chiefly pyruvate dehydrogenase(PDC-E2).The disease results from a combination of genetic and environmental risk factors.Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins.Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing,after a long latency,the emergence of clinical disease.Initiating mimetopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or,alternatively,environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic.A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells.In the effector phase the biliary ductular cell,by reason of itsproclivity to express the antigen PDC-E2 in the course of apoptosis,undergoes a multilineage immune attack comprised of CD4+ and CD8+ T cells and antibody.In this article,we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data,new developments and theories,and nominate directions for future research.

Fenofibrate for patients with asymptomatic primary biliary cirrhosis

AIM:Primary biliary cirrhosis (PBC) is a chronic, cholestatic disease of autoimmune etiology,the histology of which shows a destruction of the intrahepatic bile duct and portal inflammation. Ursodeoxycholic acid (UDCA) is now used as a first-line drug for asymptomatic PBC (aPBC) because it is reported that UDCA decreases mortality and prolongs the time of liver transplantation.However, only 20-30% of patients respond fully to UDCA.Recently,lipoprotein-lowering agents have been found to be effective for PBC.The aim of this study was to examine the safety and efficacy of fenofibrate, a member of the fibrate class of hypolipidemic and anti-inflammatory agent via peroxysome proliferatory-activated receptor α,in patients with aPBC.METHODS:Fenofibrate was administered for twelve weeks in nine patients with aPBC who failed to respond to UDCA.UDCA was used along with fenofibrate during the study.The data from aPBC patients were analyzed to assess the biochemical effect of fenofibrate during the study.RESULTS: The serum levels of alkaline phosphatase (ALP)(285±114.8IU/L) and immunoglobulin M (IgM) (255.8±85.9mg/dl) significantly decreased to 186.9±76.2IU/L and 192.9±67.5mg/dL respectively, after fenofibrate treatment in patients with aPBC (P<0.05). Moreover,the titer of antimitochondrial antibody (AMA) also decreased in 4 of 9 patients with aPBC. No adverse reactions were observed in any patients.CONCLUSION:Fenofibrate appears to be significantly effective in treating patients with aPBC who respond incompletely to UDCA alone.Although the mechanism of fenofibrate on aPBC has not yet been fully clarified,combination therapy using fenofibrate and UDCA might be related to the anti-immunological effects, such as the suppression of AMA production as well as its antiinflammatory effect.

Etiology of chronic pancreatitis:Has it changed in the last decade?

The evidence from recent surveys on chronic pancreatitis carried out around the world shows that alcohol remains the main factor associated with chronic pancreatitis, even if at a frequency lower than that reported previously. It has further conf irmed that heavy alcohol consumption and smoking are independent risk factors for chronic pancreatitis. Autoimmune pancreatitis accounts for 2%-4% of all forms of chronic pancreatitis, but this frequency will probably increase over the next few years. The rise in idiopathic chronic pancreatitis, especially in India, represents a black hole in recently published surveys. Despite the progress made so far regarding the possibility of establishing the hereditary forms of chronic pancreatitis and the recognition of autoimmune pancreatitis, it is possible that we are more inaccurate today than in the past in identifying the factors associated with chronic pancreatitis in our patients.

Autofluorescence excitation-emission matrices for diagnosis of colonic cancer

AIM: To investigate the autofluorescence spectroscopic differences in normal and adenomatous coionic tissues and to determine the optimal excitation wavelengths for subsequent study and clinical application. METHODS: Normal and adenomatous coionic tissues were obtained from patients during surgery. A FL/FS920 combined TCSPC spectrofluorimeter and a lifetime spectrometer system were used for fluorescence measurement. Fluorescence excitation wavelengths varying from 260 to 540 nm were used to induce the autofluorescence spectra, and the corresponding emission spectra were recorded from a range starting 20 nm above the excitation wavelength and extending to 800 nm. Emission spectra were assembled into a three-dimensional fluorescence spectroscopy and an excitation-emission matrix (EEM) to exploit endogenous fluorophores and diagnostic information. Then emission spectra of normal and adenomatous coionic tissues at certain excitation wavelengths were compared to determine the optimal excitation wavelengths for diagnosis of coionic cancer. RESULTS: When compared to normal tissues, low NAD (P)H and FAD, but high amino acids and endogenous phorphyrins of protoporphyrin IX characterized the high-grade malignant coionic tissues. The optimal excitation wavelengths for diagnosis of coionic cancer were about 340, 380, 460, and 540 nm. CONCLUSION: Significant differences in autofluorescence peaks and its intensities can be observed in normal and adenomatous coionic tissues. Autofluorescence EEMs are able to identify coionic tissues.

Helicobacter pylori infection and endocrine disorders:Is there a link?

Helicobacter pylori(H pylori) infection is a leading world-wide infectious disease as it affects more than half of the world population and causes chronic gastritis,peptic ulcer disease and gastric malignancies.The infection elicits a chronic cellular inflammatory response in the gastric mucosa.However,the effects of this local inflammation may not be confi ned solely to the digestive tract but may spread to involve extraintestinal tissues and/or organs.Indeed,H pylori infection has been epidemiologically linked to extra-digestive conditions and diseases.In this context,it has been speculated that H pylori infection may be responsible for various endocrine disorders,such as autoimmune thyroid diseases,diabetes mellitus,dyslipidemia,obesity,osteoporosis and primary hyperparathyroidism.This is a review of the relationship between H pylori infection and these endocrine disorders.

Inhibition of p38 mitogen-activated protein kinase attenuates experimental autoimmune hepatitis: Involvement of nuclear factor kappa B

To investigate the role of p38 mitogen-activated protein kinase （p38MAPK） in murine experimental autoimmune hepatitis （EAH）.METHODS： To induce EAH, the syngeneic S-100 antigen emulsified in complete Freud＇s adjuvant was injected intraperitoneally into adult male C57BI/6 mice. Liver injury was assessed by serum ALT and liver histology. The expression and activity of p38 MAPK were measured by Western blot and kinase activity assays. In addition, DNA binding activities of nuclear factor kappa B （NF-KB） were analyzed by electrophoretic mobility shift assay. The effects of SB203580, a specific p38 MAPK inhibitor, on liver injuries and expression of proinflammatory cytokines （interferon-y, IL-12, IL-1β and TNF-α） were observed.RESULTS： The activity of p38 MAPK and NF-~：B was increased and reached its peak 14 or 21 d after the first syngeneic S-100 administration. Inhibition of p38 MAPK activation by SB203580 decreased the activation of NF-~：B and the expression of proinflammatory cytokines. Moreover, hepatic injuries were improved significantly after SB203580 administration.

Immune mechanisms of Concanavalin A model of autoimmune hepatitis

As a chronic inflammatory disease of the liver,the pathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated,with prognosis and diagnosis remaining unsatisfied.Currently the only viable treatments of AIH are immunosuppressant application and liver transplantation.It is considered that lack of good animal AIH models is the main reason for the shortage of a simple and efficient cure.The Concanavalin A (Con A) model is a typical and well established model for investigating T-cell and macrophage dependent liver injury in mice,which closely mimics the pathogenesis mechanisms and pathological changes of patients,and is regarded as the best experimental model for AIH research so far.In this paper we eluci-dated the pathogenic mechanisms of AIH and the evolution of relative animal models.We go on to further focus on Con A-induced liver injury from the point of immunological mechanisms and the change of cytokine levels.Finally,we manifested the clinical significance of the AIH animal models and the challenges they would meet during their future development.

Nodular regenerative hyperplasia:Evolving concepts on underdiagnosed cause of portal hypertension

Nodular regenerative hyperplasia(NRH)is a rare liver condition characterized by a widespread benign transformation of the hepatic parenchyma into small regenerative nodules.NRH may lead to the development of non-cirrhotic portal hypertension.There are no published systematic population studies on NRH and our current knowledge is limited to case reports and case series.NRH may develop via autoimmune,hematological,infectious,neoplastic,or drug-related causes.The disease is usually asymptomatic,slowly or nonprogressive unless complications of portal hypertension develop.Accurate diagnosis is made by histopathology,which demonstrates diffuse micronodular transformation without fibrous septa.Lack of perinuclear collagen tissue distinguishes NRH from typical regenerative nodules in the cirrhotic liver.While the initial treatment is to address the underlying disease,ultimately the therapy is directed to the management of portal hypertension.The prognosis of NRH depends on both the severity of the underlying illness and the prevention of secondary complications of portal hypertension.In this review we detail the epidemiology,pathogenesis,diagnosis,management,and prognosis of NRH.