BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic charact...BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic characteristics of patients with mucopolysaccharidosis type 6 and their outcomes using the Russian Federation's national registry,as per the Russian registry,and compare them with previously published data.METHODS In a retrospective cohort study,clinical,laboratory data,molecular genetic analysis results,and enzyme replacement therapy(ERT)data were extracted and analyzed from the Russian MPSⅥregistry for 53 patients,comprising 26 males(49.1%)and 27 females(50.9%).RESULTS The median age of first symptoms was 2 years,ranging from the first months of life to 20 years.A positive family history of MPSⅥwas reported in 19/53(35.8%)patients,a negative family history in 24(45.3%),and missing information in 10(18.9%).The main features of the disease were hepatomegaly(n=23;60.5%),splenomegaly(n=15,39.5%),involvement of otolaryngological organs(n=24/33;72.7%),umbilical and inguinal hernia(n=19/36;52.8%),heart involvement(n=26/32;81.3%)with valve involvement(n=25/26;96.2%)and linear growth delay(n=30/39,76.9%).Two patients(3.8%)died.The most common variants identified in the ARSB gene were c.454C>T and c.194C>T.At the time of data collection,ERT had ever received 48/53(90.5%)patients.CONCLUSION No correlation was observed between the age of onset of the first symptoms,the severity of clinical manifestations,enzyme activity,or nucleotide variants in the ARSB gene.展开更多
Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 ...The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 at the Cheung Kung Hai Conference Center, William MW Mong Block, Li Ka Shing Faculty of Medicine, the University of Hong Kong. Other co-organizers included the University of Hong Kong and Chinese Society of Medical Genetics. A satellite conference ＂ACGA-WZMC International Symposium of Genetics and Translational Medicine＂, co-organized with Wenzhou Medical College and Chinese Society of Medical Genetics, was held from June 12-14, 2008 at Wenzhou, Zhejiang Province of China.展开更多
In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1]....In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-Lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1L)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient care.Therefore,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.展开更多
BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causi...BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causing gene was identified as a mutation in the MECP2 gene,which is found in approximately 80%of patients diagnosed with Rett syndrome.Although chromosomal changes resulting in del(15)(q11q13)are usually associated with Angelman and Prader-Willi syndrome,very few cases,if any,of Rett syndrome with terminal 15q22-qter deletion have been published in English literature.CASE SUMMARY In this study,we report an unusual and rare clinical presentation of Rett syndrome in a 12-year-old Sudanese girl.The patient was brought in by her parents,complaining of gradual onset of abnormal walking,abnormal hand movement,loss of speech,and mental retardation for ten years.There was no reported history of convulsions or loss of consciousness.Clinical examination revealed microcephaly with no other apparent dysmorphic features,intact cranial nerves,and abnormal gait.She showed repetitive and stereotyped behaviors,including hand flapping,stimming,and chest pounding,which were concomitant with autism spectrum disorder.Magnetic resonance imaging and electroencephalography investigations were normal,and cytogenetic analysis showed 46,XX,del(15)(q22qter).Further molecular analysis using whole sequencing of MECP2 revealed an alteration cytosine>thymine at nucleotide 401,leading to phenylalanine replacing a serine at amino acid position 134.CONCLUSION This case,the first reported instance of Rett syndrome in Sudan,is of significant interest.The patient carries both the MECP2 gene mutation and the chromosome 15q22-qter deletion,which may explain the autistic behavior with atypical presentation of Rett syndrome.This report expands the genetic diversity of Rett syndrome,demonstrating how co-occurring 15q22-qter deletions can reshape MECP2-associated phenotypes in Rett syndrome.展开更多
BACKGROUND Mucopolysaccharidosis type Ⅱ(MPS Ⅱ)is a chronic inherited disease with multiorgan involvement,a progressive course,and restricted life expectancy.AIM To evaluate the predictors of fatal outcomes in MPS Ⅱ...BACKGROUND Mucopolysaccharidosis type Ⅱ(MPS Ⅱ)is a chronic inherited disease with multiorgan involvement,a progressive course,and restricted life expectancy.AIM To evaluate the predictors of fatal outcomes in MPS Ⅱ patients.METHODS In the retrospective cohort study,the clinical,laboratory data and enzyme replacement therapy(ERT)(84.2%)of about 160 patients were extracted and analyzed from the Russian MPS Ⅱ registry,with death as a primary outcome.We compared patients who died(n=20;12.5%)with severe form(n=13;68.4%)and attenuated form(n=6,31.6%)to 140 alive patients.RESULTS Fatal outcomes occurred in 5%,35%,20%,and 40%of patients before 10,10-14,15-19,and≥20 years.The most common causes of death were cardiovascular(29.4%),respiratory failure(17.6%),including pneumonia(17.6%),and their associations(17.6%)and MPS Ⅱ progression(11.8%).Acute or chronic respiratory failure was in 53%.Died patients had higher birth weight,higher age of diagnosis,and start of ERT.Hydrocephalus,hydrocephalus bypass surgery,epilepsy,difficulty swallowing,and impaired movement after 12 years of age were significantly more common in the deceased patients.Cox regression analysis has revealed the following time-dependent covariates of the lethal outcome:1^(st)-year psychomotor development delay,delayed mental and speech development,hydrocephalus,swallow disorders,impossible walking at age>12 years,respiratory disorders,tracheostomy,neuronopathic form.CONCLUSION Increased birth weight,delayed diagnosis and the start of ERT,and development of neuronopathic form with impossible walking after 12 years were the main predictors of the fatal outcome.展开更多
BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have bee...BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have been associated with worsening LVDD in patients with diabetes over time.However,the utility of BNP as a diagnostic marker in diabetes is controversial,as BNP levels are often low in overweight individuals.AIM To examine the effectiveness of BNP levels and fragmented QRS(fQRS)on electrocardiography for diagnosing LVDD in patients with type 2 diabetes.METHODS This retrospective cohort study included 303 patients with type 2 diabetes(67.4±12.3 years old)with preserved ejection fraction(EF)≥50%admitted to Toyama University Hospital for glycemic management and comorbidity evaluation between November 2017 and April 2021.All participants underwent plasma BNP measurement,electrocardiography,and echocardiography.Cardiologists who were blinded to the BNP results assessed the electrocardiograms and echocardiograms.Subgroup analyses were conducted for overweight individuals.RESULTS Receiver operating characteristic(ROC)curve analysis determined optimal BNP cut-off values of 34.8 pg/mL and 7.2 pg/mL for diagnosing LVDD in non-overweight[area under the ROC curve(AUC):0.70]and overweight(AUC:0.55)groups,respectively(P=0.040).In the overweight subgroup,fQRS showed greater diagnostic accuracy for LVDD(AUC:0.67),indicating moderate diagnostic utility compared with the low performance of the BNP cutoff of 35 pg/mL(AUC:0.52)(P=0.010).Multivariate analyses confirmed that fQRS was superior to BNP for LVDD diagnosis regardless of the patient’s weight.CONCLUSION A BNP level≥35 pg/mL in non-overweight individuals may be a reliable LVDD marker.Additionally,fQRS was more effective than BNP in diagnosing LVDD irrespective of the patient’s weight.fQRS can complement BNP in the early detection of LVDD,especially in overweight patients,potentially improving early detection and mitigating progression to heart failure with preserved EF in patients with type 2 diabetes.展开更多
In recent years,significant insights have been gathered into the effectiveness of lifestyle interventions in the treatment of chronic non-communicable diseases(NCD).To speed up the implementation of evidence-based lif...In recent years,significant insights have been gathered into the effectiveness of lifestyle interventions in the treatment of chronic non-communicable diseases(NCD).To speed up the implementation of evidence-based lifestyle medicine,we developed a research agenda in collaboration with Dutch experts in treating NCD,using a hybrid Delphi approach.The research agenda focuses on four key themes:(1)promoting sustainable behavioural change at patient,healthcare professional and organisational levels;(2)optimising research designs,methodology and outcomes for the evaluation of effectiveness and implementation of lifestyle medicine modalities in healthcare practice;(3)elucidating biological mechanisms underlying successful lifestyle interventions and(4)advancing data infrastructure to ensure accessible data for citizens,healthcare professionals,researchers and health insurers for monitoring and evaluation of health and lifestyle outcomes.Collectively,the identified knowledge questions across these four themes provide guidance for(applied)research towards lifestyle medicine in healthcare.展开更多
Introduction Advances in clinical genomics have raised the importance of integrating genomic medicine across healthcare systems,including primary care.Primary care presents an ideal environment to offer equitable and ...Introduction Advances in clinical genomics have raised the importance of integrating genomic medicine across healthcare systems,including primary care.Primary care presents an ideal environment to offer equitable and efficient access to genetic services.Familial hypercholesterolaemia(FH)is a preventable and treatable cause of premature heart disease and represents a health condition that can be successfully diagnosed and managed in primary care.This study describes a process for tailoring a primary-tertiary shared care model for FH to optimise health professional and patient engagement.Methods Data were collected through semistructured interviews(n=10)with stakeholders in New South Wales,Australia.Interviews gathered feedback on how to tailor a shared care model for FH between tertiary and primary care services.Reflexive thematic analysis was used to analyse interview transcripts.Results Analysis generated three main themes:(1)current process for genetic testing and management,(2)challenges with genetic testing for FH in primary care and(3)components needed to enable a tertiary-initiated shared care model.Participants considered the model of care acceptable and could be successfully implemented,provided key supports were in place to assist general practitioners.Based on these results,a process model for integrating genetic testing for other conditions into primary care settings was developed,using FH as an exemplar.Conclusion The process model for tailoring of a primary-tertiary model of care for FH can be applied across a range of primary care services and treatable genetic conditions.展开更多
Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibi...Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.展开更多
Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world...Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.展开更多
Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as on...Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of beth hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.展开更多
The 5-1ipoxygenase activating protein,an important regulator in the biosynthesis of proinflammatory leukotrienes,has been reported to confer risks for cardiovascular diseases and stroke.The purpose of this study is to...The 5-1ipoxygenase activating protein,an important regulator in the biosynthesis of proinflammatory leukotrienes,has been reported to confer risks for cardiovascular diseases and stroke.The purpose of this study is to assess whether genetic variants in the ALOX5AP encoding the 5-1ipoxygenase activating protein will influence the risk for stroke in the Chinese population.A total of 1773 patients with stroke and 1713 controls were recruited from seven clinical centers.Polymorphisms of SG13S114T/A and SG13S89G/A in the ALOX5AP were genotyped by the polymerase chain reaction and the restriction enzyme analysis.The multivariate logistic regression model was used to exclude the influence of the conventional vascular risk factors on stroke.The frequency of SG13S114A allele in the ALOX5AP was significantly higher in male patients with thrombotic stroke(33.6%)than in controls(29.2%;P=0.014).The SG13S 114AA genotype was significantly associated with a 1.62-fold risk for thrombotic stroke in men(95%confidence interval,1.11 to 2.35;P=0.012).The SG13S89G/A variant was not associated with stroke or its subtypes.Haplotype analysis showed no significant differences between stroke patients and controls.The present study suggested that a common genetic variant SG13Sll4T/A in the ALOX5AP gene is associated with an increased risk for atherothrombotic stroke in Chinese males,and racial differences in allele and genotype frequencies may account partially for the different association findings between populations.展开更多
AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean...AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean age, 44 ＋ 12 years） with chronic hepatitis C, genotype 1, received treatment with peg-interferon plus ribavirin. Genotyping of rs12979860 was per- formed on peripheral blood DNA. Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment. Serum viral load, ami- notransferase activity, and insulin level were measured. Insulin resistance index, body mass index, waist/hip ratio, percentage of body fat and fibrosis progression rate were calculated. Applied dose of interferon and ribavirin, platelet and neutrophil count and hemoglobin level were measured. RESULTS： A sustained virological response （SVR） was significantly associated with IL28B polymorphism （CC vs -l-r allele： odds ratio （OR）, 25; CC vs CT allele： OR, 5.4）, inflammation activity （G 〈 1 vs G 〉 1： OR, 3.9）, fibrosis （F 〈 1 vs F 〉 1： OR, 5.9）, platelet count （〉 200 × 109/L vs 〈 200 ×109/L： OR, 4.7; OR in patients with genotype CT： 12.8）, fatty liver （absence vs presence of steatosis： OR, 4.8）, insulin resistance index （〈 2.5 vs 〉 2.5： OR, 3.9）, and baseline HCV viral load （〈 106 IU/mL vs 〉 106 IU/mL： OR, 3.0）. There was no association with age, sex, aminotransferases activity, body mass index, waist/hip ratio, or percentage body fat. There was borderline significance （P = 0.064） of increased fibrosis in patients with the I-I allele, and no differences in the insulin resistance index between groups of patients with CC, CT and -IF alleles （P = 0.12）. Spearman＇s rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605, respectively （P 〈 0.001）. Significant dif- ferences were found in the insulin resistance index （P = 0.01） between patients with and without steatosis. Patients with the C-I- allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon （P = 0.07）. CONCLUSION： IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy. Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.展开更多
Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the resul...Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers.The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization;the integral risks of full mutation expansion were approximately 6.0%,43.8%, and 100% for premutation alleles with 55—74, 75—89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG(adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75—89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXSassociated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.展开更多
Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a fami...Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.展开更多
The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitocho...The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.展开更多
Klinefelter syndrome （KS） is the set of symptoms that result from the presence of an extra X chromosome in males. Postnatal population-based KS screening will enable timely diagnosis of this common chromosomal disea...Klinefelter syndrome （KS） is the set of symptoms that result from the presence of an extra X chromosome in males. Postnatal population-based KS screening will enable timely diagnosis of this common chromosomal disease, providing the opportunity for early intervention and therapy at the time point when they are most effective and may prevent later symptoms or complications. Therefore, through this study, we introduced a simple high-resolution melting （HRM） assay for KS screening and evaluated its clinical sensitivity and specificity in three medical centers using 1373 clinical blood samples. The HRM assay utilized a single primer pair to simultaneously amplify specific regions in zinc finger protein, X-linked （ZFX） and zinc finger protein, Y-linked （ZFY）. In cases of KS, the ratios of ZFX/ZFYare altered compared to those in normal males. As a result, the specific melting profiles differ and can be differentiated during data analysis. This HRM assay displayed high analytical specificity over a wide range of template DNA amounts （5 ng-50 ng） and reproducibility, high resolution for detecting KS mosaicism, and high clinical sensitivity （100%） and specificity （98.1%）. Moreover, the HRM assay was rapid （2 h per run）, inexpensive （0.2 USD per sample）, easy to perform and automatic, and compatible with both whole blood samples and dried blood spots. Therefore, this HRM assay is an ideal postnatal population-based KS screening tool that can be used for different age groups.展开更多
BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have bee...BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.展开更多
Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. Micro RNAs(mi RNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus(HCMV)...Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. Micro RNAs(mi RNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus(HCMV) in its infection and pathogenesis. In the present study, the DNA replication inhibitor Geminin(GMNN) was identified to be a direct target of hcmv-mi R-US5-1. Overexpression of hcmv-mi R-US5-1 could block the accumulation of GMNN during HCMV infection, and the decrease of GMNN expression caused by hcmv-mi R-US5-1 or GMNN specific si RNA reduced HCMV DNA copies in U373 cells. Meanwhile, ectopic expression of hcmv-mi R-US5-1 and consequent lower expression of GMNN influenced host cell cycle and proliferation. These results imply that hcmv-mi R-US5-1 may affect viral replication and host cellular environment by regulating expression kinetics of GMNN during HCMV infection.展开更多
文摘BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic characteristics of patients with mucopolysaccharidosis type 6 and their outcomes using the Russian Federation's national registry,as per the Russian registry,and compare them with previously published data.METHODS In a retrospective cohort study,clinical,laboratory data,molecular genetic analysis results,and enzyme replacement therapy(ERT)data were extracted and analyzed from the Russian MPSⅥregistry for 53 patients,comprising 26 males(49.1%)and 27 females(50.9%).RESULTS The median age of first symptoms was 2 years,ranging from the first months of life to 20 years.A positive family history of MPSⅥwas reported in 19/53(35.8%)patients,a negative family history in 24(45.3%),and missing information in 10(18.9%).The main features of the disease were hepatomegaly(n=23;60.5%),splenomegaly(n=15,39.5%),involvement of otolaryngological organs(n=24/33;72.7%),umbilical and inguinal hernia(n=19/36;52.8%),heart involvement(n=26/32;81.3%)with valve involvement(n=25/26;96.2%)and linear growth delay(n=30/39,76.9%).Two patients(3.8%)died.The most common variants identified in the ARSB gene were c.454C>T and c.194C>T.At the time of data collection,ERT had ever received 48/53(90.5%)patients.CONCLUSION No correlation was observed between the age of onset of the first symptoms,the severity of clinical manifestations,enzyme activity,or nucleotide variants in the ARSB gene.
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
文摘The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 at the Cheung Kung Hai Conference Center, William MW Mong Block, Li Ka Shing Faculty of Medicine, the University of Hong Kong. Other co-organizers included the University of Hong Kong and Chinese Society of Medical Genetics. A satellite conference ＂ACGA-WZMC International Symposium of Genetics and Translational Medicine＂, co-organized with Wenzhou Medical College and Chinese Society of Medical Genetics, was held from June 12-14, 2008 at Wenzhou, Zhejiang Province of China.
基金Diponegoro University WCRU grant(No.118-03/UN7.6.1/PP/2021).
文摘In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-Lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1L)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient care.Therefore,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.
文摘BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causing gene was identified as a mutation in the MECP2 gene,which is found in approximately 80%of patients diagnosed with Rett syndrome.Although chromosomal changes resulting in del(15)(q11q13)are usually associated with Angelman and Prader-Willi syndrome,very few cases,if any,of Rett syndrome with terminal 15q22-qter deletion have been published in English literature.CASE SUMMARY In this study,we report an unusual and rare clinical presentation of Rett syndrome in a 12-year-old Sudanese girl.The patient was brought in by her parents,complaining of gradual onset of abnormal walking,abnormal hand movement,loss of speech,and mental retardation for ten years.There was no reported history of convulsions or loss of consciousness.Clinical examination revealed microcephaly with no other apparent dysmorphic features,intact cranial nerves,and abnormal gait.She showed repetitive and stereotyped behaviors,including hand flapping,stimming,and chest pounding,which were concomitant with autism spectrum disorder.Magnetic resonance imaging and electroencephalography investigations were normal,and cytogenetic analysis showed 46,XX,del(15)(q22qter).Further molecular analysis using whole sequencing of MECP2 revealed an alteration cytosine>thymine at nucleotide 401,leading to phenylalanine replacing a serine at amino acid position 134.CONCLUSION This case,the first reported instance of Rett syndrome in Sudan,is of significant interest.The patient carries both the MECP2 gene mutation and the chromosome 15q22-qter deletion,which may explain the autistic behavior with atypical presentation of Rett syndrome.This report expands the genetic diversity of Rett syndrome,demonstrating how co-occurring 15q22-qter deletions can reshape MECP2-associated phenotypes in Rett syndrome.
文摘BACKGROUND Mucopolysaccharidosis type Ⅱ(MPS Ⅱ)is a chronic inherited disease with multiorgan involvement,a progressive course,and restricted life expectancy.AIM To evaluate the predictors of fatal outcomes in MPS Ⅱ patients.METHODS In the retrospective cohort study,the clinical,laboratory data and enzyme replacement therapy(ERT)(84.2%)of about 160 patients were extracted and analyzed from the Russian MPS Ⅱ registry,with death as a primary outcome.We compared patients who died(n=20;12.5%)with severe form(n=13;68.4%)and attenuated form(n=6,31.6%)to 140 alive patients.RESULTS Fatal outcomes occurred in 5%,35%,20%,and 40%of patients before 10,10-14,15-19,and≥20 years.The most common causes of death were cardiovascular(29.4%),respiratory failure(17.6%),including pneumonia(17.6%),and their associations(17.6%)and MPS Ⅱ progression(11.8%).Acute or chronic respiratory failure was in 53%.Died patients had higher birth weight,higher age of diagnosis,and start of ERT.Hydrocephalus,hydrocephalus bypass surgery,epilepsy,difficulty swallowing,and impaired movement after 12 years of age were significantly more common in the deceased patients.Cox regression analysis has revealed the following time-dependent covariates of the lethal outcome:1^(st)-year psychomotor development delay,delayed mental and speech development,hydrocephalus,swallow disorders,impossible walking at age>12 years,respiratory disorders,tracheostomy,neuronopathic form.CONCLUSION Increased birth weight,delayed diagnosis and the start of ERT,and development of neuronopathic form with impossible walking after 12 years were the main predictors of the fatal outcome.
基金Supported by the JSPS KAKENHI,No.JP21K10300 and No.JP24K02714.
文摘BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have been associated with worsening LVDD in patients with diabetes over time.However,the utility of BNP as a diagnostic marker in diabetes is controversial,as BNP levels are often low in overweight individuals.AIM To examine the effectiveness of BNP levels and fragmented QRS(fQRS)on electrocardiography for diagnosing LVDD in patients with type 2 diabetes.METHODS This retrospective cohort study included 303 patients with type 2 diabetes(67.4±12.3 years old)with preserved ejection fraction(EF)≥50%admitted to Toyama University Hospital for glycemic management and comorbidity evaluation between November 2017 and April 2021.All participants underwent plasma BNP measurement,electrocardiography,and echocardiography.Cardiologists who were blinded to the BNP results assessed the electrocardiograms and echocardiograms.Subgroup analyses were conducted for overweight individuals.RESULTS Receiver operating characteristic(ROC)curve analysis determined optimal BNP cut-off values of 34.8 pg/mL and 7.2 pg/mL for diagnosing LVDD in non-overweight[area under the ROC curve(AUC):0.70]and overweight(AUC:0.55)groups,respectively(P=0.040).In the overweight subgroup,fQRS showed greater diagnostic accuracy for LVDD(AUC:0.67),indicating moderate diagnostic utility compared with the low performance of the BNP cutoff of 35 pg/mL(AUC:0.52)(P=0.010).Multivariate analyses confirmed that fQRS was superior to BNP for LVDD diagnosis regardless of the patient’s weight.CONCLUSION A BNP level≥35 pg/mL in non-overweight individuals may be a reliable LVDD marker.Additionally,fQRS was more effective than BNP in diagnosing LVDD irrespective of the patient’s weight.fQRS can complement BNP in the early detection of LVDD,especially in overweight patients,potentially improving early detection and mitigating progression to heart failure with preserved EF in patients with type 2 diabetes.
基金funded by a special programof the Dutch Ministry of Health, Welfare and Sport (Ministerie van Volksgezondheid,Welzijn en SportGrant Number N/A).
文摘In recent years,significant insights have been gathered into the effectiveness of lifestyle interventions in the treatment of chronic non-communicable diseases(NCD).To speed up the implementation of evidence-based lifestyle medicine,we developed a research agenda in collaboration with Dutch experts in treating NCD,using a hybrid Delphi approach.The research agenda focuses on four key themes:(1)promoting sustainable behavioural change at patient,healthcare professional and organisational levels;(2)optimising research designs,methodology and outcomes for the evaluation of effectiveness and implementation of lifestyle medicine modalities in healthcare practice;(3)elucidating biological mechanisms underlying successful lifestyle interventions and(4)advancing data infrastructure to ensure accessible data for citizens,healthcare professionals,researchers and health insurers for monitoring and evaluation of health and lifestyle outcomes.Collectively,the identified knowledge questions across these four themes provide guidance for(applied)research towards lifestyle medicine in healthcare.
基金supported by a NSW Health Translational Research Grant Scheme(H22/4011)a Heart Foundation Vanguard Grant(105721).
文摘Introduction Advances in clinical genomics have raised the importance of integrating genomic medicine across healthcare systems,including primary care.Primary care presents an ideal environment to offer equitable and efficient access to genetic services.Familial hypercholesterolaemia(FH)is a preventable and treatable cause of premature heart disease and represents a health condition that can be successfully diagnosed and managed in primary care.This study describes a process for tailoring a primary-tertiary shared care model for FH to optimise health professional and patient engagement.Methods Data were collected through semistructured interviews(n=10)with stakeholders in New South Wales,Australia.Interviews gathered feedback on how to tailor a shared care model for FH between tertiary and primary care services.Reflexive thematic analysis was used to analyse interview transcripts.Results Analysis generated three main themes:(1)current process for genetic testing and management,(2)challenges with genetic testing for FH in primary care and(3)components needed to enable a tertiary-initiated shared care model.Participants considered the model of care acceptable and could be successfully implemented,provided key supports were in place to assist general practitioners.Based on these results,a process model for integrating genetic testing for other conditions into primary care settings was developed,using FH as an exemplar.Conclusion The process model for tailoring of a primary-tertiary model of care for FH can be applied across a range of primary care services and treatable genetic conditions.
基金supported by grants from the National Key R&D Program of China(2019YFA0801603)the Guangdong High Level Innovation Research Institute(2021B0909050004)+2 种基金the National Natural Science Foundation of China(32330044,32170951,82201615,and 82101393)the Natural Science Foundation of Jiangsu Province(BK20201255 and BK20210008)the Fundamental Research Funds for the Central Universities(021414380533).
文摘Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
基金supported by the project from National Basic Research Priorities Program of China (2014CB541702)National Natural Science Foundation of China (31671305)
文摘Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.
文摘Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of beth hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.
基金supported by Key Project of Chinese National Programs for Fundamental Rearch and Development(973 Program)(No.G2000056901).
文摘The 5-1ipoxygenase activating protein,an important regulator in the biosynthesis of proinflammatory leukotrienes,has been reported to confer risks for cardiovascular diseases and stroke.The purpose of this study is to assess whether genetic variants in the ALOX5AP encoding the 5-1ipoxygenase activating protein will influence the risk for stroke in the Chinese population.A total of 1773 patients with stroke and 1713 controls were recruited from seven clinical centers.Polymorphisms of SG13S114T/A and SG13S89G/A in the ALOX5AP were genotyped by the polymerase chain reaction and the restriction enzyme analysis.The multivariate logistic regression model was used to exclude the influence of the conventional vascular risk factors on stroke.The frequency of SG13S114A allele in the ALOX5AP was significantly higher in male patients with thrombotic stroke(33.6%)than in controls(29.2%;P=0.014).The SG13S 114AA genotype was significantly associated with a 1.62-fold risk for thrombotic stroke in men(95%confidence interval,1.11 to 2.35;P=0.012).The SG13S89G/A variant was not associated with stroke or its subtypes.Haplotype analysis showed no significant differences between stroke patients and controls.The present study suggested that a common genetic variant SG13Sll4T/A in the ALOX5AP gene is associated with an increased risk for atherothrombotic stroke in Chinese males,and racial differences in allele and genotype frequencies may account partially for the different association findings between populations.
文摘AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean age, 44 ＋ 12 years） with chronic hepatitis C, genotype 1, received treatment with peg-interferon plus ribavirin. Genotyping of rs12979860 was per- formed on peripheral blood DNA. Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment. Serum viral load, ami- notransferase activity, and insulin level were measured. Insulin resistance index, body mass index, waist/hip ratio, percentage of body fat and fibrosis progression rate were calculated. Applied dose of interferon and ribavirin, platelet and neutrophil count and hemoglobin level were measured. RESULTS： A sustained virological response （SVR） was significantly associated with IL28B polymorphism （CC vs -l-r allele： odds ratio （OR）, 25; CC vs CT allele： OR, 5.4）, inflammation activity （G 〈 1 vs G 〉 1： OR, 3.9）, fibrosis （F 〈 1 vs F 〉 1： OR, 5.9）, platelet count （〉 200 × 109/L vs 〈 200 ×109/L： OR, 4.7; OR in patients with genotype CT： 12.8）, fatty liver （absence vs presence of steatosis： OR, 4.8）, insulin resistance index （〈 2.5 vs 〉 2.5： OR, 3.9）, and baseline HCV viral load （〈 106 IU/mL vs 〉 106 IU/mL： OR, 3.0）. There was no association with age, sex, aminotransferases activity, body mass index, waist/hip ratio, or percentage body fat. There was borderline significance （P = 0.064） of increased fibrosis in patients with the I-I allele, and no differences in the insulin resistance index between groups of patients with CC, CT and -IF alleles （P = 0.12）. Spearman＇s rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605, respectively （P 〈 0.001）. Significant dif- ferences were found in the insulin resistance index （P = 0.01） between patients with and without steatosis. Patients with the C-I- allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon （P = 0.07）. CONCLUSION： IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy. Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.
基金supported by the National Natural Science Foundation of China(82071662,to Q.G.)。
文摘Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers.The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization;the integral risks of full mutation expansion were approximately 6.0%,43.8%, and 100% for premutation alleles with 55—74, 75—89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG(adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75—89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXSassociated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.
文摘Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.
文摘The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.
文摘Klinefelter syndrome （KS） is the set of symptoms that result from the presence of an extra X chromosome in males. Postnatal population-based KS screening will enable timely diagnosis of this common chromosomal disease, providing the opportunity for early intervention and therapy at the time point when they are most effective and may prevent later symptoms or complications. Therefore, through this study, we introduced a simple high-resolution melting （HRM） assay for KS screening and evaluated its clinical sensitivity and specificity in three medical centers using 1373 clinical blood samples. The HRM assay utilized a single primer pair to simultaneously amplify specific regions in zinc finger protein, X-linked （ZFX） and zinc finger protein, Y-linked （ZFY）. In cases of KS, the ratios of ZFX/ZFYare altered compared to those in normal males. As a result, the specific melting profiles differ and can be differentiated during data analysis. This HRM assay displayed high analytical specificity over a wide range of template DNA amounts （5 ng-50 ng） and reproducibility, high resolution for detecting KS mosaicism, and high clinical sensitivity （100%） and specificity （98.1%）. Moreover, the HRM assay was rapid （2 h per run）, inexpensive （0.2 USD per sample）, easy to perform and automatic, and compatible with both whole blood samples and dried blood spots. Therefore, this HRM assay is an ideal postnatal population-based KS screening tool that can be used for different age groups.
基金Supported by Sanming Project of Medicine in Shenzhen of China,No.SZSM201612074
文摘BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.
基金supported by the National Natural Science Foundation of China (81371788 and 81171580)the Specialized Research Fund for the Doctoral Program of Higher Education (20112104110012)the Outstanding Scientific Fund of Shengjing Hospital
文摘Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. Micro RNAs(mi RNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus(HCMV) in its infection and pathogenesis. In the present study, the DNA replication inhibitor Geminin(GMNN) was identified to be a direct target of hcmv-mi R-US5-1. Overexpression of hcmv-mi R-US5-1 could block the accumulation of GMNN during HCMV infection, and the decrease of GMNN expression caused by hcmv-mi R-US5-1 or GMNN specific si RNA reduced HCMV DNA copies in U373 cells. Meanwhile, ectopic expression of hcmv-mi R-US5-1 and consequent lower expression of GMNN influenced host cell cycle and proliferation. These results imply that hcmv-mi R-US5-1 may affect viral replication and host cellular environment by regulating expression kinetics of GMNN during HCMV infection.
