Spermatogenesis involves extremely marked cellular, genetic and chromatin changes resulting in the generation of the highly specialized sperm cell. Proteomics allows the identification of the proteins that compose the...Spermatogenesis involves extremely marked cellular, genetic and chromatin changes resulting in the generation of the highly specialized sperm cell. Proteomics allows the identification of the proteins that compose the spermatogenic cells and the study of their function. The recent developments in mass spectrometry （MS） have markedly increased the throughput to identify and to study the sperm proteins. Catalogs of thousands of testis and spermatozoan proteins in human and different model species are becoming available, setting up the basis for subsequent research, diagnostic applications and possibly the future development of specific treatments. The present review intends to summarize the key genetic and chromatin changes at the different stages of spermatogenesis and in the mature sperm cell and to comment on the presently available proteomic studies.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
It is well know that the nuclei of spermatogenic cells experience one of the most extremely marked chromatin changes known in cells. At the end of spermatogenesis, the histones are removed in many species and the DNA ...It is well know that the nuclei of spermatogenic cells experience one of the most extremely marked chromatin changes known in cells. At the end of spermatogenesis, the histones are removed in many species and the DNA is condensed by the highly positively charged protamines forming highly compact nucleoprotamine complexes.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: Unilateral sporadic vestibular schwannomas (USVS) are caused by inactivating somatic mutations of both alleles of the neurofibromatosis 2 (NF2) tumor suppressor gene. Unilateral sporadic vestibular schwann...Background: Unilateral sporadic vestibular schwannomas (USVS) are caused by inactivating somatic mutations of both alleles of the neurofibromatosis 2 (NF2) tumor suppressor gene. Unilateral sporadic vestibular schwannomas have a widely-varying growth patterns whose causes are poorly understood. Objective: We examined the relationships between an index of USVS growth, and genetic abnormalities and pathological growth indices. Subjects and Methods: Single-strand conformational polymorphism analysis and heteroduplex methods were used to screen for mutations in all 17 exons of the NF2 gene in USVS from 63 patients. Loss of heterozygosity (LOH) analyses were also carried out. An index of USVS growth (clinical growth index, CGI) was calculated as maximum tumor diameter divided by duration of symptoms. The immunohistochemical growthindices were based on monoclonal antibodies to Ki-67 and another tumor cell proliferation marker (platelet-derived growth factor (PDGF)). Results: CGI was highly variable and did not significantly decrease with increasing age at diagnosis. Either somatic NF2 mutations or LOH was found in 88% of tumors. PDGF and Ki-67 increased significantly with increasing age at diagnosis, and PDGF was lower in tumors with LOH than in those without LOH. In multiple linear regression analysis, CGI was significantly higher in people with higher PDGF, after accounting for age at diagnosis and LOH. Conclusion: An index of USVS growth increases with increasing PDGF, after accounting for age and LOH.展开更多
Pathogenic variants in methyl-Cp G protein 2(MECP2;OMIM300005)result in an X-linked,severe,and progressive epigenetic disorder,Rett syndrome(RTT,OMIM:312750),that predominantly affects females(Rett,1966).Using Neul’s...Pathogenic variants in methyl-Cp G protein 2(MECP2;OMIM300005)result in an X-linked,severe,and progressive epigenetic disorder,Rett syndrome(RTT,OMIM:312750),that predominantly affects females(Rett,1966).Using Neul’s revised diagnostic criteria,affected individuals can be clinically classified as classic or atypical RTT(Neul et al.,2010).展开更多
Over the last 12 years, the Wales Cancer Biobank (WCB) has consented to more than 2000 patients with colorectal cancer (CRC). From these patients, clinical data has been collected and patients have been followed throu...Over the last 12 years, the Wales Cancer Biobank (WCB) has consented to more than 2000 patients with colorectal cancer (CRC). From these patients, clinical data has been collected and patients have been followed through their cancer journey. Clinical data from these patients have been analyzed to identify any correlation between disease grade and outcome. In a small cohort, consisting of 407 patients, WCB has performed genetic analysis on patient primary tumor samples, identifying and characterizing mutations in the KRAS, NRAS, BRAF, PIK3CA and TP53 genes. The majority of patients with CRC who were consented to WCB were male with a mean age of 69 years and received surgery as the primary treatment for their disease. Pathology and disease-free survival data confirmed worse prognoses associated with more advanced disease. Heterogeneity within the primary tumor was explored in a subgroup of patients. Analysis of the KRAS and TP53 genes confirmed that more than 40% of CRC patients who were tested, harbored a genetic mutation within these genes in their primary tumor. Due to the limited sample size tested, most mutations did not show significant differences in disease-free survival, however, mutation of the BRAF gene did show a decrease in the disease specific survival, in keeping with the published data. Analysis of the patients diagnosed with CRC within the Biobank has provided us with valuable information on the status of CRC disease and treatment within the Welsh population. Over 12 years of consenting, we have witnessed significant changes in the information that researchers are interested in when sourcing samples for translational research. The development of new drugs that are tailored to the genetics of a cancer is emerging and at WCB we are focusing our collections on samples and data that meet the needs of this ever-evolving field.展开更多
Atelosteogenesis type II (AO2) and diastrophic dysplasia (DTD) are two recessively inherited, severe skeletal dysplasias caused by mutations in the SLC26A2 gene. AO2 is an invariably lethal condition, while DTD patien...Atelosteogenesis type II (AO2) and diastrophic dysplasia (DTD) are two recessively inherited, severe skeletal dysplasias caused by mutations in the SLC26A2 gene. AO2 is an invariably lethal condition, while DTD patients may reach adult life, although both diseases have overlapping diagnostic features. Here we report a patient with an intermediate phenotype between AO2 and DTD and present the successful application of preimplantation genetic diagnosis (PGD) in this situation. Sequencing of SLC26A2 alleles in the infant identified two compound heterozygous mutations, p.Arg178Ter and p.Arg279Trp, of paternal and maternal origin, respectively. At request from the parents, PGD was developed by haplotype mapping of parental SLC26A2 alleles in eleven five-day embryos. Transference to the mother was attempted twice, finally resulting in pregnancy and delivery of a healthy baby. This exemplifies the utility of PGD for inherited lethal conditions with a significant risk of recurrence, and highlights the importance of accurate diagnosis of skeletal dysplasias with prenatal manifestation.展开更多
Hereditary diffuse gastric cancer(HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alte...Hereditary diffuse gastric cancer(HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene(CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.展开更多
Objectives: The basic mechanisms of cervical incompetence remain unknown although preliminary histological, biochemical and DNA studies suggest connective tissue pathology may be a contributing factor. Certain connect...Objectives: The basic mechanisms of cervical incompetence remain unknown although preliminary histological, biochemical and DNA studies suggest connective tissue pathology may be a contributing factor. Certain connective tissue disorders are known to be associated with obstetric complications. Utilising a standardised established scoring system for connective tissue laxity, this study aimed to test the relationship between clinical evidence of connective tissue laxity and cervical incompetence. Methods: This case-control study involved pregnant and non-pregnant women with a history of mid-trimester pregnancy loss in the absence of major bleeding, infection and uterine abnormalities and a control group of women with uncomplicated obstetric histories. Relevant medical details were obtained. Connective tissue laxity was assessed utilizing the Beighton scoring system. Potential confounding factors, including age, pregnancy and gestation were explored. Results: The frequency of connective tissue laxity between the cases [n = 29] was not statistically different from the controls [n = 58] [p = 0.391] suggesting a lack of association between cervical incompetence and clinical evidence of connective tissue laxity. Conclusion: Although no clear evidence of connective tissue laxity was demonstrated, it is possible that cervical incompetence is associated with abnormal connective tissue. But this abnormality is different from the defect that underlies joint hypermobility and skin elasticity.展开更多
AIM:To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil.METHODS:A consecutive...AIM:To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil.METHODS:A consecutive sample of patients with CRC were interviewed regarding personal and family histories of cancer.Clinical data and pathology features of the tumor were obtained from chart review.RESULTS:Of the 212 CRC patients recruited,61 (29%) reported a family history of CRC,45 (21.2%) were diagnosed under age 50 years and 11 (5.2%) had more than one primary CRC.Family histories consistent with Amsterdam and revised Bethesda criteria for LS were identified in 22 (10.4%) and 100 (47.2%) patients,respectively.Twenty percent of the colorectal tumors had features of the high microsatellite instability phenotype,which was associated with younger age at CRC diagnosis and with Bethesda criteria (P < 0.001).Only 5.3% of the patients above age 50 years had been previously submitted for CRC screening and only 4% of patients with suspected LS were referred for genetic risk assessment.CONCLUSION:A significant proportion of patients with CRC were at high risk for LS.Education and training of health care professionals are essential to ensure proper management.展开更多
Objective:To evaluate the correlation between glucose-6-phosphate-dehydrogenase(G6PD) deficiency and neonatal jaundice.Methods:Prospective,observational case-control study was conducted on 490 newborns admitted to Hos...Objective:To evaluate the correlation between glucose-6-phosphate-dehydrogenase(G6PD) deficiency and neonatal jaundice.Methods:Prospective,observational case-control study was conducted on 490 newborns admitted to Hospital de Clinicas de Porto Alegre for phototherapy, who all experienced 35 or more weeks of gestation,from March to December 2007.Enzymatic screening of G6PD activity was performed,followed by PCR.Results:There was prevalence of 4.6% and a boy-girl ratio of 3:1 in jaundiced newborns.No jaundiced neonate with ABO incompatibility presented G6PD deficiency,and no Mediterranean mutation was found.A higher proportion of deficiency was observed in Afro-descendants.There was no association with UGT1A1 variants. Conclusions:G6PD deficiency is not related to severe hyperbilirubinemia and considering the high miscegenation in this area of Brazil,other gene interactions should be investigated.展开更多
The objectives of this study were to assess the safety and efficacy of intralesionally administered diclofenac in the treatment of cutaneous neurofibromas in patients with NF1. This was a proof-of-concept, prospective...The objectives of this study were to assess the safety and efficacy of intralesionally administered diclofenac in the treatment of cutaneous neurofibromas in patients with NF1. This was a proof-of-concept, prospective, safety and efficacy study of the effect of intralesionally administered diclofenac 25 mg/ml given once a week to 3 target cutaneous neurofibromas for 4 consecutive weeks. Overall, there was no significant change in neurofibroma size. During the study, some treated lesions developed signs of necrosis and fell off after a few weeks, but none of the control neurofibromas fell off. There were no significant changes in patient’s vital signs. A few adverse events occurred, mostly at the injection sites. During the study, some neurofibromas developed necrosis after the diclofenac injections and eventually detached from the patient. Overall, diclofenac was well tolerated, suggesting minimal systemic exposure, which required confirmation and further studies, including bioavailability analysis.展开更多
Objective: To explore the effect of Compound Danshen Injection combined with Labetalol on liver function and placental growth factor in patients with eclampsia. Methods: Seventy patients with eclampsia who were treate...Objective: To explore the effect of Compound Danshen Injection combined with Labetalol on liver function and placental growth factor in patients with eclampsia. Methods: Seventy patients with eclampsia who were treated in the Hospital from February 2017 to February 2019 were enrolled. The patients were divided into two groups according to the random number table, with 35 cases in each group. The Observation group was treated with Labetalol, and the combined therapy group was treated with Compound Danshen Injection combined with Labetalol. The liver function [alanine aminotransferase, aspartate aminotransferase, total protein, and albumin], hemorheology indicators, placental growth factor and serum insulin-like growth factor-1 and clinical indicators in the two groups were analyzed. Results: After treatment, the levels of alanine aminotransferase and aspartate aminotransferase in the combined therapy group were significantly lower than those in the Observation group. The levels of total protein and albumin in the combined therapy group were significantly higher than those in the Observation group (P<0.05). After treatment, the high-cut and low-cut whole blood viscosity, plasma viscosity and erythrocyte rigidity index in the combined therapy group were significantly lower than the Observation group, and the difference was statistically significant (P<0.05). After treatment, the levels of PLGF and IGF-1 in the combined therapy group were significantly higher than those in the Observation group, and the difference was statistically significant (P<0.05). After treatment, the gestational age, neonatal weight index, placental weight and neonatal 1 min Apgar score in the combined therapy group were significantly higher than the Observation group, and the difference was statistically significant (P<0.05). Conclusion: For patients with eclampsia, Compound Danshen Injection combined with Labetalol is with great safety, which can help stabilize their condition, and improve their liver function and placental growth factor status.展开更多
This short report describes a model for international collaboration on perinatal health that is innovative,highly-productive and challenging. The model,funded by the U.S. March of Dimes Foundation and entitled the &...This short report describes a model for international collaboration on perinatal health that is innovative,highly-productive and challenging. The model,funded by the U.S. March of Dimes Foundation and entitled the 'March of Dimes Global Network for Maternal and Infant Health(GNMIH)' ,allows developing country experts to more easily share their knowledge,experience,skills and materials in ways that can improve women's,maternal,newborn and child health in lower-income countries. This report begins with a brief description of the March of Dimes and its Global Programs which oversees the GNMIH. It then discusses the structure of the GNMIH,with an emphasis on the benefits and challenges of working within the network,and concludes with a brief description of the acti-vities of network members.展开更多
Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hip...Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau(VHL)syndrome.Methods:A non-systematic narrative review of original articles,meta-analyses,and random-ized trials was conducted,including articles in the pre-clinical setting to support relevant find-ings.Results:VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma.Affected individuals inherit a germline mutation in one VHL allele,and any somatic event that disrupt the other allele can trigger mutations,chromosomal rearrange-ments,or epigenetic regulations leading to oncogenesis.From a clinical perspective,patients continuously develop multiple primary tumors.Conclusion:Because VHL is considered a rare disease,very limited evidence is available for diagnosis,surveillance,active treatment with local or systemic therapy and follow-up.展开更多
Background: Cutis laxa is an extremely rare disorder characterized by marked skin laxity. Few cases of cutis laxa have been described worldwide. Clinical presentation and mode of inheritance show considerable heteroge...Background: Cutis laxa is an extremely rare disorder characterized by marked skin laxity. Few cases of cutis laxa have been described worldwide. Clinical presentation and mode of inheritance show considerable heterogeneity; autosomal dominant, autosomal recessive, and X-linked recessive forms have been reported. Only 3 mutations in the elastin gene have been described as the genetic cause of the autosomal dominant form of cutis laxa. Observations: A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged and were clinically diagnosed as having cutis laxa. Mutational analysis of the elastin gene evidenced a novel mutation (2292delC) that predicts a frameshift in the coding region and causes translation to proceed into the 3-untranslated region. This would replace the C-terminal amino acid of the normal elastin protein with a novel sequence. Conclusion: This article is the fourth report of autosomal dominant cutis laxa to appear in the literature in which a mutation in the elastin gene has been correlated with the disease.展开更多
Aim: To describe and compare the characteristics of acute fracture and chronic non-fracture pain in children with osteogenesis imperfecta (OI). Methods: A questionnaire about fracture-related pain and prospective 7-d ...Aim: To describe and compare the characteristics of acute fracture and chronic non-fracture pain in children with osteogenesis imperfecta (OI). Methods: A questionnaire about fracture-related pain and prospective 7-d diary about non-fracture-related pain was completed by a random sample of 35 children aged 5-18 from a UK national OI service. Main outcome measures included pain intensity, location, frequency, quality, coping strategies and analgesia use. Results: Most children reported moderate to severe pain associated with fractures and less intense non-fracture pain (p < 0.001). Pain intensity was significantly higher in the children who used analgesics (p < 0.001). The quality of fracture and non-fracture pain differed only for affective words, which were less frequently used to describe non-fracture pain (p = 0.002). More activities of daily living (ADLs) were affected by fracture pain than by non-fracture pain (p < 0.001). Children reported more frequent use of approach coping strategies with fracture pain and more frequent use of distraction for non-fracture pain (p < 0.01). There were no differences in non-fracture pain intensity, duration, quality, effect on ADLs or coping between children who did or did not take bisphosphonates. Conclusions: Pain is a common occurrence for children with OI and is both acute and chronic in nature, interfering with children’ s daily living activities. OI pain may not be optimally treated because many children experienced moderate to severe pain despite use of analgesics and/or coping strategies.展开更多
AIM: To describe human leukocyte antigen(HLA) alleles in individuals with Down syndrome and alopecia areata. METHODS: A cross-sectional study was conducted, which evaluated 109 individuals. Ten with down syndrome(DS) ...AIM: To describe human leukocyte antigen(HLA) alleles in individuals with Down syndrome and alopecia areata. METHODS: A cross-sectional study was conducted, which evaluated 109 individuals. Ten with down syndrome(DS) and alopecia areata(AA), ten with DS without AA and ten with AA without DS, and their fami-lies. The individuals were matched by gender and age. The following data were computed: gender, age, ethnic group, karyotype, clinical presentation and family history of alopecia areata. Descriptive analysis: measures of central tendency and frequency distribution. Inferential analysis: Fisher's exact test to compare categorical data between the three groups and Kruskal-Wallis ANOVA test for numerical data.RESULTS: Seventy per cent of evaluated individuals in the DS and AA group were male; presented mean age of 18.6(SD ± 7.2) years and 70% were Caucasian. We observed involvement of the scalp, with a single lesion in 10% and multiple in 90% of subjects. It was observed that there is no significant difference in the frequency distributions of the alleles HLA loci A, B, C, DRB1 and DQB1 of subjects studied. However, according to Fisher's exact test, there is a trend(P = 0.089) of DS group to present higher proportions of HLA-A 36 and HLA-B 15 than the AA group and AA and DS group.CONCLUSION: There was a tendency for the DS group, to present proportion of HLA-A 36 and HLA-B 15 higher than the AA group and group of individuals with AA and DS. However, there was no significant difference in the frequency distribution of the alleles.展开更多
Background Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare.We aimed to determine health service utilization by Australian children with rare di...Background Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare.We aimed to determine health service utilization by Australian children with rare diseases and barriers to access-ing healthcare.Methods Parents completed an online survey on health professional and emergency department(ED)presentations,hospi-talization,and barriers to accessing services.Potential barriers to service access included residential location(city,regional,remote)and child health-related functioning,determined using a validated,parent-completed measure-of-function tool.Results Parents of 462 children with over 240 rare diseases completed the survey.Compared with the general population,these children were more likely to be hospitalized[odds ratio(OR)=17.25,95%confidence interval(CI)=15.50-19.20]and present to the ED(OR=4.15,95%CI=3.68-4.68)or a family physician(OR=4.14,95%CI=3.72-4.60).Child functional impairment was nil/mild(31%),moderate(48%)or severe(22%).Compared to children with nil/mild impair-ment,those with severe impairment were more likely to be hospitalized(OR=13.39,95%CI=7.65-23.44)and present to the ED(OR=11.16,95%CI=6.46-19.27).Most children(75%)lived in major cities,but children from regional(OR=2.78,95%CI=1.72-4.55)and remote areas(OR=9.09,95%CI=3.03-25.00)experienced significantly more barriers to healthcare access than children from major cities.Barriers included distance to travel,out-of-pocket costs,and lack of specialist medical and other health services.Conclusions Children with rare diseases,especially those with severe functional impairment have an enormous impact on health services,and better integrated multidisciplinary services with patient-centered care are needed.Access must be improved for children living in rural and remote settings.展开更多
文摘Spermatogenesis involves extremely marked cellular, genetic and chromatin changes resulting in the generation of the highly specialized sperm cell. Proteomics allows the identification of the proteins that compose the spermatogenic cells and the study of their function. The recent developments in mass spectrometry （MS） have markedly increased the throughput to identify and to study the sperm proteins. Catalogs of thousands of testis and spermatozoan proteins in human and different model species are becoming available, setting up the basis for subsequent research, diagnostic applications and possibly the future development of specific treatments. The present review intends to summarize the key genetic and chromatin changes at the different stages of spermatogenesis and in the mature sperm cell and to comment on the presently available proteomic studies.
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.
文摘It is well know that the nuclei of spermatogenic cells experience one of the most extremely marked chromatin changes known in cells. At the end of spermatogenesis, the histones are removed in many species and the DNA is condensed by the highly positively charged protamines forming highly compact nucleoprotamine complexes.
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: Unilateral sporadic vestibular schwannomas (USVS) are caused by inactivating somatic mutations of both alleles of the neurofibromatosis 2 (NF2) tumor suppressor gene. Unilateral sporadic vestibular schwannomas have a widely-varying growth patterns whose causes are poorly understood. Objective: We examined the relationships between an index of USVS growth, and genetic abnormalities and pathological growth indices. Subjects and Methods: Single-strand conformational polymorphism analysis and heteroduplex methods were used to screen for mutations in all 17 exons of the NF2 gene in USVS from 63 patients. Loss of heterozygosity (LOH) analyses were also carried out. An index of USVS growth (clinical growth index, CGI) was calculated as maximum tumor diameter divided by duration of symptoms. The immunohistochemical growthindices were based on monoclonal antibodies to Ki-67 and another tumor cell proliferation marker (platelet-derived growth factor (PDGF)). Results: CGI was highly variable and did not significantly decrease with increasing age at diagnosis. Either somatic NF2 mutations or LOH was found in 88% of tumors. PDGF and Ki-67 increased significantly with increasing age at diagnosis, and PDGF was lower in tumors with LOH than in those without LOH. In multiple linear regression analysis, CGI was significantly higher in people with higher PDGF, after accounting for age at diagnosis and LOH. Conclusion: An index of USVS growth increases with increasing PDGF, after accounting for age and LOH.
基金supported by the Victorian Government’s Operational Infrastructure Support ProgramResearch Training Program scholarship(to S.K.)+2 种基金supported by Italian Ministry of Health Young Investigator(GR-2011-02347754 to E.L.)Fondazione Istituto di Ricerca PediatricaeCittàdella Speranza(18-04 to E.L.)supported by the Australian NHMRC Centre of Research Excellence in Speech and Language Neurobiology(CRE-SLANG)(1116976)
文摘Pathogenic variants in methyl-Cp G protein 2(MECP2;OMIM300005)result in an X-linked,severe,and progressive epigenetic disorder,Rett syndrome(RTT,OMIM:312750),that predominantly affects females(Rett,1966).Using Neul’s revised diagnostic criteria,affected individuals can be clinically classified as classic or atypical RTT(Neul et al.,2010).
文摘Over the last 12 years, the Wales Cancer Biobank (WCB) has consented to more than 2000 patients with colorectal cancer (CRC). From these patients, clinical data has been collected and patients have been followed through their cancer journey. Clinical data from these patients have been analyzed to identify any correlation between disease grade and outcome. In a small cohort, consisting of 407 patients, WCB has performed genetic analysis on patient primary tumor samples, identifying and characterizing mutations in the KRAS, NRAS, BRAF, PIK3CA and TP53 genes. The majority of patients with CRC who were consented to WCB were male with a mean age of 69 years and received surgery as the primary treatment for their disease. Pathology and disease-free survival data confirmed worse prognoses associated with more advanced disease. Heterogeneity within the primary tumor was explored in a subgroup of patients. Analysis of the KRAS and TP53 genes confirmed that more than 40% of CRC patients who were tested, harbored a genetic mutation within these genes in their primary tumor. Due to the limited sample size tested, most mutations did not show significant differences in disease-free survival, however, mutation of the BRAF gene did show a decrease in the disease specific survival, in keeping with the published data. Analysis of the patients diagnosed with CRC within the Biobank has provided us with valuable information on the status of CRC disease and treatment within the Welsh population. Over 12 years of consenting, we have witnessed significant changes in the information that researchers are interested in when sourcing samples for translational research. The development of new drugs that are tailored to the genetics of a cancer is emerging and at WCB we are focusing our collections on samples and data that meet the needs of this ever-evolving field.
基金The authors would like to thank the subjects reported here and Hospital de Clínicas de Porto Alegre Research Fund 12-0467 for supporting this publication.
文摘Atelosteogenesis type II (AO2) and diastrophic dysplasia (DTD) are two recessively inherited, severe skeletal dysplasias caused by mutations in the SLC26A2 gene. AO2 is an invariably lethal condition, while DTD patients may reach adult life, although both diseases have overlapping diagnostic features. Here we report a patient with an intermediate phenotype between AO2 and DTD and present the successful application of preimplantation genetic diagnosis (PGD) in this situation. Sequencing of SLC26A2 alleles in the infant identified two compound heterozygous mutations, p.Arg178Ter and p.Arg279Trp, of paternal and maternal origin, respectively. At request from the parents, PGD was developed by haplotype mapping of parental SLC26A2 alleles in eleven five-day embryos. Transference to the mother was attempted twice, finally resulting in pregnancy and delivery of a healthy baby. This exemplifies the utility of PGD for inherited lethal conditions with a significant risk of recurrence, and highlights the importance of accurate diagnosis of skeletal dysplasias with prenatal manifestation.
基金Supported by National Medical Research Council Transition Award(to Joanne Ngeow)
文摘Hereditary diffuse gastric cancer(HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene(CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.
文摘Objectives: The basic mechanisms of cervical incompetence remain unknown although preliminary histological, biochemical and DNA studies suggest connective tissue pathology may be a contributing factor. Certain connective tissue disorders are known to be associated with obstetric complications. Utilising a standardised established scoring system for connective tissue laxity, this study aimed to test the relationship between clinical evidence of connective tissue laxity and cervical incompetence. Methods: This case-control study involved pregnant and non-pregnant women with a history of mid-trimester pregnancy loss in the absence of major bleeding, infection and uterine abnormalities and a control group of women with uncomplicated obstetric histories. Relevant medical details were obtained. Connective tissue laxity was assessed utilizing the Beighton scoring system. Potential confounding factors, including age, pregnancy and gestation were explored. Results: The frequency of connective tissue laxity between the cases [n = 29] was not statistically different from the controls [n = 58] [p = 0.391] suggesting a lack of association between cervical incompetence and clinical evidence of connective tissue laxity. Conclusion: Although no clear evidence of connective tissue laxity was demonstrated, it is possible that cervical incompetence is associated with abnormal connective tissue. But this abnormality is different from the defect that underlies joint hypermobility and skin elasticity.
文摘AIM:To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil.METHODS:A consecutive sample of patients with CRC were interviewed regarding personal and family histories of cancer.Clinical data and pathology features of the tumor were obtained from chart review.RESULTS:Of the 212 CRC patients recruited,61 (29%) reported a family history of CRC,45 (21.2%) were diagnosed under age 50 years and 11 (5.2%) had more than one primary CRC.Family histories consistent with Amsterdam and revised Bethesda criteria for LS were identified in 22 (10.4%) and 100 (47.2%) patients,respectively.Twenty percent of the colorectal tumors had features of the high microsatellite instability phenotype,which was associated with younger age at CRC diagnosis and with Bethesda criteria (P < 0.001).Only 5.3% of the patients above age 50 years had been previously submitted for CRC screening and only 4% of patients with suspected LS were referred for genetic risk assessment.CONCLUSION:A significant proportion of patients with CRC were at high risk for LS.Education and training of health care professionals are essential to ensure proper management.
基金Supported by FIPE.CnPq.Capes-Reuni and the Postgraduate Program of UFRGS
文摘Objective:To evaluate the correlation between glucose-6-phosphate-dehydrogenase(G6PD) deficiency and neonatal jaundice.Methods:Prospective,observational case-control study was conducted on 490 newborns admitted to Hospital de Clinicas de Porto Alegre for phototherapy, who all experienced 35 or more weeks of gestation,from March to December 2007.Enzymatic screening of G6PD activity was performed,followed by PCR.Results:There was prevalence of 4.6% and a boy-girl ratio of 3:1 in jaundiced newborns.No jaundiced neonate with ABO incompatibility presented G6PD deficiency,and no Mediterranean mutation was found.A higher proportion of deficiency was observed in Afro-descendants.There was no association with UGT1A1 variants. Conclusions:G6PD deficiency is not related to severe hyperbilirubinemia and considering the high miscegenation in this area of Brazil,other gene interactions should be investigated.
文摘The objectives of this study were to assess the safety and efficacy of intralesionally administered diclofenac in the treatment of cutaneous neurofibromas in patients with NF1. This was a proof-of-concept, prospective, safety and efficacy study of the effect of intralesionally administered diclofenac 25 mg/ml given once a week to 3 target cutaneous neurofibromas for 4 consecutive weeks. Overall, there was no significant change in neurofibroma size. During the study, some treated lesions developed signs of necrosis and fell off after a few weeks, but none of the control neurofibromas fell off. There were no significant changes in patient’s vital signs. A few adverse events occurred, mostly at the injection sites. During the study, some neurofibromas developed necrosis after the diclofenac injections and eventually detached from the patient. Overall, diclofenac was well tolerated, suggesting minimal systemic exposure, which required confirmation and further studies, including bioavailability analysis.
基金2019 Provincial key research project of Hebei province (20191432)
文摘Objective: To explore the effect of Compound Danshen Injection combined with Labetalol on liver function and placental growth factor in patients with eclampsia. Methods: Seventy patients with eclampsia who were treated in the Hospital from February 2017 to February 2019 were enrolled. The patients were divided into two groups according to the random number table, with 35 cases in each group. The Observation group was treated with Labetalol, and the combined therapy group was treated with Compound Danshen Injection combined with Labetalol. The liver function [alanine aminotransferase, aspartate aminotransferase, total protein, and albumin], hemorheology indicators, placental growth factor and serum insulin-like growth factor-1 and clinical indicators in the two groups were analyzed. Results: After treatment, the levels of alanine aminotransferase and aspartate aminotransferase in the combined therapy group were significantly lower than those in the Observation group. The levels of total protein and albumin in the combined therapy group were significantly higher than those in the Observation group (P<0.05). After treatment, the high-cut and low-cut whole blood viscosity, plasma viscosity and erythrocyte rigidity index in the combined therapy group were significantly lower than the Observation group, and the difference was statistically significant (P<0.05). After treatment, the levels of PLGF and IGF-1 in the combined therapy group were significantly higher than those in the Observation group, and the difference was statistically significant (P<0.05). After treatment, the gestational age, neonatal weight index, placental weight and neonatal 1 min Apgar score in the combined therapy group were significantly higher than the Observation group, and the difference was statistically significant (P<0.05). Conclusion: For patients with eclampsia, Compound Danshen Injection combined with Labetalol is with great safety, which can help stabilize their condition, and improve their liver function and placental growth factor status.
文摘This short report describes a model for international collaboration on perinatal health that is innovative,highly-productive and challenging. The model,funded by the U.S. March of Dimes Foundation and entitled the 'March of Dimes Global Network for Maternal and Infant Health(GNMIH)' ,allows developing country experts to more easily share their knowledge,experience,skills and materials in ways that can improve women's,maternal,newborn and child health in lower-income countries. This report begins with a brief description of the March of Dimes and its Global Programs which oversees the GNMIH. It then discusses the structure of the GNMIH,with an emphasis on the benefits and challenges of working within the network,and concludes with a brief description of the acti-vities of network members.
文摘Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau(VHL)syndrome.Methods:A non-systematic narrative review of original articles,meta-analyses,and random-ized trials was conducted,including articles in the pre-clinical setting to support relevant find-ings.Results:VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma.Affected individuals inherit a germline mutation in one VHL allele,and any somatic event that disrupt the other allele can trigger mutations,chromosomal rearrange-ments,or epigenetic regulations leading to oncogenesis.From a clinical perspective,patients continuously develop multiple primary tumors.Conclusion:Because VHL is considered a rare disease,very limited evidence is available for diagnosis,surveillance,active treatment with local or systemic therapy and follow-up.
文摘Background: Cutis laxa is an extremely rare disorder characterized by marked skin laxity. Few cases of cutis laxa have been described worldwide. Clinical presentation and mode of inheritance show considerable heterogeneity; autosomal dominant, autosomal recessive, and X-linked recessive forms have been reported. Only 3 mutations in the elastin gene have been described as the genetic cause of the autosomal dominant form of cutis laxa. Observations: A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged and were clinically diagnosed as having cutis laxa. Mutational analysis of the elastin gene evidenced a novel mutation (2292delC) that predicts a frameshift in the coding region and causes translation to proceed into the 3-untranslated region. This would replace the C-terminal amino acid of the normal elastin protein with a novel sequence. Conclusion: This article is the fourth report of autosomal dominant cutis laxa to appear in the literature in which a mutation in the elastin gene has been correlated with the disease.
文摘Aim: To describe and compare the characteristics of acute fracture and chronic non-fracture pain in children with osteogenesis imperfecta (OI). Methods: A questionnaire about fracture-related pain and prospective 7-d diary about non-fracture-related pain was completed by a random sample of 35 children aged 5-18 from a UK national OI service. Main outcome measures included pain intensity, location, frequency, quality, coping strategies and analgesia use. Results: Most children reported moderate to severe pain associated with fractures and less intense non-fracture pain (p < 0.001). Pain intensity was significantly higher in the children who used analgesics (p < 0.001). The quality of fracture and non-fracture pain differed only for affective words, which were less frequently used to describe non-fracture pain (p = 0.002). More activities of daily living (ADLs) were affected by fracture pain than by non-fracture pain (p < 0.001). Children reported more frequent use of approach coping strategies with fracture pain and more frequent use of distraction for non-fracture pain (p < 0.01). There were no differences in non-fracture pain intensity, duration, quality, effect on ADLs or coping between children who did or did not take bisphosphonates. Conclusions: Pain is a common occurrence for children with OI and is both acute and chronic in nature, interfering with children’ s daily living activities. OI pain may not be optimally treated because many children experienced moderate to severe pain despite use of analgesics and/or coping strategies.
文摘AIM: To describe human leukocyte antigen(HLA) alleles in individuals with Down syndrome and alopecia areata. METHODS: A cross-sectional study was conducted, which evaluated 109 individuals. Ten with down syndrome(DS) and alopecia areata(AA), ten with DS without AA and ten with AA without DS, and their fami-lies. The individuals were matched by gender and age. The following data were computed: gender, age, ethnic group, karyotype, clinical presentation and family history of alopecia areata. Descriptive analysis: measures of central tendency and frequency distribution. Inferential analysis: Fisher's exact test to compare categorical data between the three groups and Kruskal-Wallis ANOVA test for numerical data.RESULTS: Seventy per cent of evaluated individuals in the DS and AA group were male; presented mean age of 18.6(SD ± 7.2) years and 70% were Caucasian. We observed involvement of the scalp, with a single lesion in 10% and multiple in 90% of subjects. It was observed that there is no significant difference in the frequency distributions of the alleles HLA loci A, B, C, DRB1 and DQB1 of subjects studied. However, according to Fisher's exact test, there is a trend(P = 0.089) of DS group to present higher proportions of HLA-A 36 and HLA-B 15 than the AA group and AA and DS group.CONCLUSION: There was a tendency for the DS group, to present proportion of HLA-A 36 and HLA-B 15 higher than the AA group and group of individuals with AA and DS. However, there was no significant difference in the frequency distribution of the alleles.
基金an Australian Research Council Linkage Project grant scheme(No.LP110200277)The funding sources had no role in the study design+5 种基金in the collection,analysis and interpretation of datain the writing of the reportand in the decision to submit the paper for publication.During the period of the research,ZY held a Fellowship from the Sydney Medical School Foundation and LH was funded by a National Health and Medical Research Council of Australia Senior Research Fellowship(No.1117105)EJE was supported by a National Health and Medical Research Council of Australia Practitioner Fellowship(No.1021480)a Medical Research Futures Fund Next Generation Fellowship(No.1135959)CJ's Chair in Genomic Medicine is supported by The Royal Children's Hospital Foundation.
文摘Background Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare.We aimed to determine health service utilization by Australian children with rare diseases and barriers to access-ing healthcare.Methods Parents completed an online survey on health professional and emergency department(ED)presentations,hospi-talization,and barriers to accessing services.Potential barriers to service access included residential location(city,regional,remote)and child health-related functioning,determined using a validated,parent-completed measure-of-function tool.Results Parents of 462 children with over 240 rare diseases completed the survey.Compared with the general population,these children were more likely to be hospitalized[odds ratio(OR)=17.25,95%confidence interval(CI)=15.50-19.20]and present to the ED(OR=4.15,95%CI=3.68-4.68)or a family physician(OR=4.14,95%CI=3.72-4.60).Child functional impairment was nil/mild(31%),moderate(48%)or severe(22%).Compared to children with nil/mild impair-ment,those with severe impairment were more likely to be hospitalized(OR=13.39,95%CI=7.65-23.44)and present to the ED(OR=11.16,95%CI=6.46-19.27).Most children(75%)lived in major cities,but children from regional(OR=2.78,95%CI=1.72-4.55)and remote areas(OR=9.09,95%CI=3.03-25.00)experienced significantly more barriers to healthcare access than children from major cities.Barriers included distance to travel,out-of-pocket costs,and lack of specialist medical and other health services.Conclusions Children with rare diseases,especially those with severe functional impairment have an enormous impact on health services,and better integrated multidisciplinary services with patient-centered care are needed.Access must be improved for children living in rural and remote settings.
