Intrahepatic cholestasis of pregnancy:When should you look further?

Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy(ICP),a condition associated with significant fetal complications.Although the etiology of ICP is unclear in many cases,certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver disease.We report a kindred of Anglo-Celtic descent,among whom many members present with ICP,gallstones or cholestasis related to use of oral contraception.Genetic studies revealed a novel mutation in the ABCB4 gene,which codes for a phospholipid transport protein.The clinical significance of this mutation and the importance of identifying such patients are discussed.

Trefoil factors:Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma

AIM:To investigate trefoil factor(TFF) gene copy number,mRNA and protein expression as potential biomarkers in cholangiocarcinoma(CCA).METHODS:TFF mRNA levels,gene copy number and protein expression were determined respectively by quantitative reverse transcription polymerase chain reaction(PCR),quantitative PCR and immunohistochemistry in bile duct epithelium biopsies collected from individuals with CCA,precancerous bile duct dysplasia and from disease-free controls.The functional impact of recombinant human(rh) TFF2 peptide treatment on proliferation and epidermal growth factor receptor(EGFR) /mitogenactivated protein kinase(MAPK) signaling was assessed in the CCA cell line,KMBC,by viable cell counting and immunoblotting,respectively.RESULTS:TFF1,TFF2 and TFF3 mRNA expression was significantly increased in CCA tissue compared to disease-free controls,and was unrelated to gene copy number.TFF1 immunoreactivity was strongly increased in both dysplasia and CCA,whereas TFF2 immunoreactivity was increased only in CCA compared to diseasefree controls.By contrast,TFF3 immunoreactivity was moderately decreased in dysplasia and further decreased in CCA.Kaplan-Meier analysis found no association of TFF mRNA,protein and copy number with age,gender,histological subtype,and patient survival time.Treatment of KMBC cells with rhTFF2 stimulated proliferation,triggered phosphorylation of EGFR and downstream extracellular signal related kinase(ERK),whereas co-incubation with the EGFR tyrosine kinase inhibitor,PD153035,blocked rhTFF2-dependent proliferation and EGFR/ERK responses.CONCLUSION:TFF mRNA/protein expression is indicative of CCA tumor progression,but not predictive for histological sub-type or survival time.TFF2 is mitogenic in CCA via EGFR/MAPK activation.

Epithelial-mesenchymal Plasticity in Breast Cancer Metastasis

Transitions between epithelial and mesenchymal states, which we have termed Epithelial Mesenchymal Plasticity (EMP), are

Psychological consequences of a diagnosis of infertility in men:a systematic analysis

Almost half of infertility cases involve male infertility.Understanding the consequence of a diagnosis of male infertility,as a sole or partial contributor to the couples'infertility,to the mental health of men is required to ensure clinical care meets their psychological needs.The aim of this systematic analysis was to synthesize the evidence regarding whether men diagnosed with male factor infertility experience greater psychological distress than(1)men described as fertile and(2)men in couples with other infertility diagnoses.Online databases were searched using a combination of Medical Subject Headings(MeSH)headings and keywords relating to male infertility and psychological distress.The search yielded 1016 unique publications,of which 23 were included:8 case-control,14 prospective cohort,and 1 data linkage studies.Seven aspects of psychological distress were identified depression,anxiety,self-esteem,quality of life,fertility-related stress,general psychological stress or well-being,and psychiatric conditions.Case-control studies reported that men with male factor infertility have more symptoms of depression,anxiety and general psychological distress,worse quality of some aspects of life,and lower self-esteem than controls.When men with male factor infertility were compared to men in couples with other causes of infertility,there were few differences in the assessed aspects of psychological distress.Despite methodological limitations within the studies,this systematic analysis suggests that the experience of infertility,irrespective of its cause,negatively affects men's mental health and demonstrates the need for assisted reproduction technology(ART)providers to consider men undergoing assisted reproduction as individuals with their own unique support needs.

Nano-chromium picolinate and heat stress enhance insulin sensitivity in cross-bred sheep

This study evaluated the effects of heat stress(HS)and dietary nano chromium picolinate(nCrPic)on metabolic responses of sheep to an intravenous glucose tolerance test(IVGTT),an intravenous insulin tolerance test(ITT)and an intramuscular adrenocorticotropin hormone(ACTH)challenge in sheep.Thirty-six sheep housed in metabolic cages were randomly allocated within 3 dietary groups(0,400 and 800 mg/kg supplemental nCrPic)to either thermoneutral(22℃)or cyclic HS(22 to 40℃)conditions for 3 wk.Basal plasma glucose tended to be increased during HS(P=0.052)and decreased by dietary nCrPic(P=0.013)while plasma non-esterified fatty acid concentrations were decreased(P=0.010)by HS.Di-etary nCrPic reduced the plasma glucose area under the curve(P=0.012)while there were no significant effects of HS on plasma glucose area under the curve in response to the IVGTT.The plasma insulin response over the first 60 min after the IVGTT was decreased by HS(P=0.013)and dietary nCrPic(P=0.022)with the effects being additive.In response to the ITT plasma glucose reached a nadir sooner(P=0.005)in sheep exposed to HS,although there was no effect on the depth of the nadir.Dietary nCrPic decreased(P=0.007)the plasma glucose nadir after ITT.Over the duration of the ITT plasma insulin concentrations were lower in sheep exposed to HS(P=0.013)whereas there was no significant effect of supplemental nCrPic.There was no effect of either HS or nCrPic on cortisol response to ACTH.Dietary nCrPic supple-mentation decreased(P=0.013)mitogen-activated protein kinase-8(JNK)and increased(P=0.050)carnitine palmitoyltransferase 1B(CPT1B)mRNA expression in skeletal muscle.Results of this experiment demonstrated that animals under HS and supplemented with nCrPic had greater insulin sensitivity.

Australian children living with rare diseases:health service use and barriers to accessing care

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.

荧光原位杂交在滑膜肉瘤诊断中的应用

滑膜肉瘤是儿童及青少年期常见的软组织肿瘤，约占软组织恶性肿瘤的2％～10％。好发于大关节周围，也可见于其他关节、软组织，还可发生于肺、前列腺、肾等脏器。组织学可分为双相分化型、单相纤维型、单相上皮型、低分化型H0，其中前2种最常见。由于其形态多样，发病部位广泛，免疫组织化学染色又缺乏特异的抗体，有时会造成病理诊断的困难。细胞和分子遗传学研究发现，90％以上的滑膜肉瘤存在特异的t（X；18）（p11．2；q11．2），导致位于18号染色体SYT基因易位，和位于X染色体上SSX基因产生SYT—SSX融合基因。目前国内检测该融合基因均使用逆转录-聚合酶链反应（RT—PCR）。我们收集儿童滑膜肉瘤4例，探讨运用荧光原位杂交（FISH）法对甲醛固定、石蜡包埋组织检测其融合基因的可行性。

Dietary nano chromium picolinate can ameliorate some of the impacts of heat stress in cross-bred sheep

Two studies were conducted to evaluate the effect of nano chromium picolinate(nCrPic)during heat stress(HS)in sheep.In the initial study,36 Merino×Poll cross-bred sheep were individually penned and allocated to 3 dietary treatments(0,400 and 800μg/kg nCrPic)for 8 wk.Body composition was determined at the beginning and end of the experiment using dual energy X-ray absorptiometry.The sheep remained in their dietary groups but were then placed in metabolic cages and randomly allocated within the dietary group to differing ambient temperature regimes,i.e.,thermo-neutral(TN)(n=18)and HS(n=18),for 3 wk.Dietary nCrPic had no effect on growth performance and body composition during the initial study conducted under TN conditions.Heat stress decreased average daily feed intake(ADFI)(P=0.002)whereas sheep under HS had reduced average daily gain(ADG)and indeed lost weight(P<0.001).Dietary nCrPic increased both ADFI(P=0.041)and ADG(P=0.049)under both TH and HS conditions such that the performance of sheep receiving supplemental nCrPic and exposed to HS was similar to that of control sheep maintained under TN conditions.Heat stress increased rectal temperature(P<0.001)and respiration rate(P<0.001),particularly during the hottest parts of the day as indicated by interactions(P<0.001)between time of day and thermal treatment.Rectal temperature was lower in sheep fed nCrPic(P=0.050),particularly under peak HS conditions during the afternoon as indicated by the interactions between dietary nCrPic and time of day(P<0.001)and dietary nCrPic,thermal treat-ment and time of day(P=0.010).Similarly,respiration rate was lower in sheep fed nCrPic under peak HS conditions during the afternoon as indicated by the interactions between dietary nCrPic and thermal treatment(P<0.001)and dietary nCrPic and time of day(P=0.030).In conclusion,dietary nCrPic can partially ameliorate the negative effects of HS as indicated by the maintenance of ADFI and decreased physiological responses,such as elevations in rectal temperature and respiration rate.

Expanding the genetic landscape of Rett syndrome to include lysine acetyltransferase 6A(KAT6A)

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).

Infection-acquired versus vaccine-acquired immunity in an SIRWS model

In some disease systems,the process of waning immunity can be subtle,involving a complex relationship between the duration of immunitydacquired either through natural infection or vaccinationdand subsequent boosting of immunity through asymptomatic reexposure.We present and analyse a model of infectious disease transmission where primary and secondary infections are distinguished to examine the interplay between infection and immunity.Additionally we allow the duration of infection-acquired immunity to differ from that of vaccine-acquired immunity to explore the impact on long-term disease patterns and prevalence of infection in the presence of immune boosting.Our model demonstrates that vaccination may induce cyclic behaviour,and the ability of vaccinations to reduce primary infections may not lead to decreased transmission.Where the boosting of vaccine-acquired immunity delays a primary infection,the driver of transmission largely remains primary infections.In contrast,if the immune boosting bypasses a primary infection,secondary infections become the main driver of transmission under a sufficiently long duration of immunity.Our results show that the epidemiological patterns of an infectious disease may change considerably when the duration of vaccine-acquired immunity differs from that of infection-acquired immunity.Our study highlights that for any particular disease and associated vaccine,a detailed understanding of the waning and boosting of immunity and how the duration of protection is influenced by infection prevalence are important as we seek to optimise vaccination strategies.

Neonatal neuroimaging after repair of congenital diaphragmatic hernia and long-term neurodevelopmental outcome

Objective Previous outcome reports of congenital diaphragmatic hernia(CDH)have described neuroimaging anomalies and neurodevelopmental impairment.However,the link between imaging and outcome has not been described.We aimed to determine whether routine postoperative neonatal neuroimaging in infants with CDH detects later neurodevelopmental impairment.Methods In a prospective cohort study within a clinical service in The Royal Children’s Hospital Newborn Intensive Care.Cerebral ultrasound was performed in 81 children and MRI in 57 children who subsequently underwent neurodevelopmental follow-up after surgery for CDH.MRI scans were analyzed using a scoring system designed to identify injury,maturation and volume loss.Neurodevelopmental assessment occurred at 2 years(48)and neurocognitive assessment at 5 years(26)and/or 8 years(27).Brain imaging scores corrected for gestational age at scan time were correlated with outcome measures,adjusting for known clinical confounders.results Clinically significant findings were identified on MRI of 16(28%)infants.Mean scores were in the normal range for all domains assessed at each age.Language impairment was seen in 23%at 2 years and verbal intellectual impairment in 25%at 8 years.Mean cognitive scores were lower in 2-year-old children with white matter injury on MRI(p=0.03).Mean motor scores were lower in 2-year-old children with brain immaturity(p=0.01).Associations between MRI and 5-year and 8-year assessments were no longer significant when adjusting for known clinical confounders.Conclusions Neuroimaging abnormalities were associated with worse neurodevelopment at 2 years,but not with later neurocognitive outcomes,after accounting for clinical risk factors.

Absence of human papillomavirus in nasopharyngeal swabs from infants in a population at high risk of human papillomavirus infection

Maternal urogenital human papillomavirus(HPV)infection may place neonates at risk of HPV acquisition and subsequently lower respiratory infections as HPV can influence development of immunity.The respiratory HPV prevalence is not known in remote-dwelling Aboriginal infants,who are at high risk of respiratory infection and where the population prevalence of urogenital HPV in women is high.These data are necessary to inform HPV vaccination regimens.A retrospective analysis using PCR specific for HPV was performed on 64 stored nasopharyngeal swabs from remote-dwelling Aboriginal infants<6 months of age,with and without hospitalised pneumonia.HPV DNA was not detected in any specimen.Despite the negative result,we cannot exclude a role for HPV in respiratory infections affecting infants in this population;however,our data do not support HPV as an important contributor to acute respiratory infection in remote-dwelling Aboriginal children.