Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the additional sex combs like 3 (ASXL3) gene. To date, there have been fewer than 10 reported patients. OBJECTIVES: Here, we delineate the BRPS phenotype further by describing a series of 12 previously unreported patients identified by the Deciphering Developmental Disorders study. METHODS: Trio-based exome sequencing was performed on all 12 patients included in this study, which found a de novo truncating mutation in ASXL3. Detailed phenotypic information and patient images were collected and summarised as part of this study. RESULTS: By obtaining genotype:phenotype data, we have been able to demonstrate a second mutation cluster region within ASXL3. This report expands the phenotype of older patients with BRPS; common emerging features include severe intellectual disability (11/12), poor/ absent speech (12/12), autistic traits (9/12), distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12), hypotonia (11/12) and significant feeding difficulties (9/12) when young. DISCUSSION: Similarities in the patients reported previously in comparison with this cohort included their distinctive craniofacial features, feeding problems, absent/limited speech and intellectual disability. Shared behavioural phenotypes include autistic traits, hand-flapping, rocking, aggressive behaviour and sleep disturbance. CONCLUSIONS: This series expands the phenotypic spectrum of this severe disorder and highlights its surprisingly high frequency. With the advent of advanced genomic screening, we are likely to identify more variants in this gene presenting with a variable phenotype, which this study will explore.

Sharp truth: health care workers remain at risk of bloodborne infection.

BACKGROUND: In 2013, new regulations for the prevention of sharps injuries were introduced in the UK. All health care employers are required to provide the safest possible working environment by preventing or controlling the risk of sharps injuries. AIMS: To analyse data on significant occupational sharps injuries among health care workers in England, Wales and Northern Ireland before the introduction of the 2013 regulations and to assess bloodborne virus seroconversions among health care workers sustaining a blood or body fluid exposure. METHODS: Analysis of 10 years of information on percutaneous and mucocutaneous exposures to blood or other body fluids from source patients infected with a bloodborne virus, collected in England, Wales and Northern Ireland through routine surveillance of health care workers reported for the period 2002-11. RESULTS: A total of 2947 sharps injuries involving a source patient infected with a bloodborne virus were reported by health care workers. Significant sharps injuries were 67% higher in 2011 compared with 2002. Sharps injuries involving an HIV-, hepatitis B virus- or hepatitis C virus (HCV)-infected source patient increased by 107, 69 and 60%, respectively, between 2002 and 2011. During the study period, 14 health care workers acquired HCV following a sharps injury. CONCLUSIONS: Our data show that during a 10-year period prior to the introduction of new regulations in 2013, health care workers were at risk of occupationally acquired bloodborne virus infection. To prevent sharps injuries, health care service employers should adopt safety-engineered devices, institute safe systems of work and promote adherence to standard infection control procedures.

Occupational transmission of hepatitis C in healthcare workers and factors associated with seroconversion: UK surveillance data.

The study aims were to describe a case series of occupationally acquired hepatitis C (HCV) infections in UK healthcare workers and examine factors associated with transmission using exposure data reported to the Health Protection Agency between July 1997 and December 2007. Fifteen reported cases of documented HCV seroconversion occurred after percutaneous exposure, the majority from hollow-bore needles used in the source patient's vein or artery and contaminated with blood or blood-stained fluid. The seroconversion rate was 2.2% (14/626). In multivariable analysis of healthcare workers with percutaneous exposure to blood or blood-stained fluid, we demonstrate that blood sampling procedures (odds ratio [OR], 5.75; 95% CI, 1.33-24.91; P = 0.01) and depth of injury (OR for deep vs superficial injury, 21.99; 95% CI, 2.02-239.61; P = 0.02) are independently associated with a greater risk of HCV seroconversion. This is the first UK study of occupationally acquired HCV in healthcare workers. It has reinforced our knowledge of risk factors for HCV transmission. Most of these exposures and transmissions were preventable. Healthcare employers should provide regular education on the risks of occupational exposure and prevention through standard infection control procedures. They should ensure the availability of effective prevention measures and facilitate prompt reporting and adequate follow-up of exposures.

COL4A1 mutations associated with a characteristic pattern of intracranial calcification.

Intracranial calcification (ICC) is a relatively common radiological finding in children undergoing investigation for neurological disorders. Many causes are recognised, and ICC is often regarded as a non-specific sign.From an ongoing study of ICC, we identified 5 patients with characteristic radiological features, in whom a mutation in the COL4A1 gene was found.All patients had CT and MR imaging. MR images demonstrated features of periventricular leukomalacia with irregular dilatation of the lateral ventricles with or without porencephaly, loss of hemispheric white matter volume, and high signal on T2 and FLAIR sequences within periventricular and deep white matter. Calcification was apparent on MR in 4 patients. CT scans demonstrated spot and linear calcification in the subependymal region and around areas of porencephaly. Calcification was also visible in the deep cerebral white matter and basal ganglia. 1 patient showed calcification in the central pons.ICC occurs in COL4A1-related disease. The radiological features are distinct from other conditions demonstrating recognisable patterns of ICC, such as congenital cytomegalovirus infection and Aicardi-Goutiéres syndrome. In the absence of a known risk factor for periventricular leukomalacia, the presence of these radio-logical findings should suggest the possibility of COL4A1-related disease.

De novo variants in CNOT3 cause a variable neurodevelopmental disorder.

As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

Prevalence and socio-economic distribution of hazardous patterns of alcohol drinking: study of alcohol consumption in men aged 25-54 years in Izhevsk, Russia.

AIM: To estimate the prevalence of hazardous drinking and its socio-economic distribution among Russian men. DESIGN: Participants were an age-stratified, population-based random sample of men aged 25-54 years living in Izhevsk, a city in the Urals, Russia. Interviewers administered questionnaires to cohabiting proxy respondents about behavioural indicators of hazardous drinking derived from frequency of hangover, frequency of drinking beverage spirits, episodes in the last year of extended periods of drunkenness during which the participant withdraws from normal life (zapoi), consumption of alcoholic substances not intended to be drunk (surrogates) and socio-economic position. Logistic regression was used to examine associations between socio-economic position and indicators of hazardous drinking in the past year. FINDINGS: Of 1750 men, 79% drank spirits and 8% drank surrogates at least sometimes in the past year; 25% drank spirits and 4% drank surrogates at least weekly and 10% had had an episode of zapoi in the past year. After adjustment for other socio-economic factors, education was strongly associated with indicators of hazardous drinking. Men with the lowest level of education compared to the highest level of education had an odds ratio of surrogate drinking of 7.7 (95% CI 3.2-18.5), of zapoi of 5.2 (2.3-11.8) and of frequent hangover of 3.7 (1.8-7.4). These indicators of hazardous drinking were also independently strongly associated with being unemployed (versus employed) and with levels of household wealth/amenities. Associations of all these variables with daily consumption of beverage spirits were weaker. CONCLUSION: Using a novel range of indicator variables of hazardous drinking, this paper shows that the prevalence of these behaviours is high among working-age men in this Russian city. Moreover, these hazardous behaviours show very clear socio-economic patterns, with particularly high prevalence among those who have had the least education and are not in employment. In contrast, more conventional measures of heavy drinking, based on frequency of consumption of beverage spirits, are less prevalent and show much weaker associations with socio-economic position.

Universal treatment success among healthcare workers diagnosed with occupationally acquired acute hepatitis C.

Healthcare workers (HCWs) are at risk of occupationally acquired hepatitis C. In the UK, 17 HCWs were diagnosed with occupationally acquired acute hepatitis C between 2002 and 2011. All 17 cases involved percutaneous injuries from hollowbore needles, 16 known to be contaminated with blood. Of these 17 HCWs, 15 received antiviral therapy and 14 are known to have achieved viral clearance. Treatment success was irrespective of genotype. The successful treatment of HCWs emphasizes the need for UK guidelines on the management of occupationally acquired acute hepatitis C.

Physicochemical and biological characterization of recombinant human inhibin A.

Recombinant human inhibin A was isolated from recombinant mammalian cell line culture media. Two forms of inhibin were identified with Mr of 34 and 31 Kd composed of subunits (alpha, beta) of 24 and 15 Kd and 21 and 15 Kd respectively. Both forms are bioactive in an inhibin in vitro bioassay and immunoactive with potencies comparable to or higher than purified bovine inhibin. Amino acid analyses and NH2-terminal sequences of each of the subunits are consistent with those predicted from their cDNA structures. The inhibin alpha- but not beta-subunit is glycosylated based on its binding to the lectins concanavalin A and wheat germ lectin. The difference in molecular weight of 31 and 34 Kd inhibin is attributed to variation in glycosylation of the alpha-subunit. The 31+34 Kd inhibin is heterogeneous on isoelectric focusing gels consisting of four isoforms in the pH range 6.2-7.6. Inhibition also exhibits in vivo biological activity by suppressing serum FSH but not LH in castrate male rats. These physicochemical and biological characteristics of recombinant human inhibin are similar to those described for native inhibin isolated from a variety of other species.

Lymphangioleiomyomatosis and tuberous sclerosis.

Tuberous sclerosis (TSC) is an inherited disorder best known for its association with severe learning difficulties, epilepsy, behavioural problems, skin and renal pathology Lymphangioleiomyomatosis (LAM), characterized by alveolar smooth muscle proliferation and cystic destruction of parenchyma, occurs as an infrequent symptomatic pulmonary complication in TSC and as a very rare sporadic disease in those without signs of TSC. Considered a generalized and progressive cystic lung disease that is difficult to treat with a poor prognosis, it has been reported almost exclusively in women, most commonly presenting with dyspnoea and pneumothorax in those of childbearing age. We investigated the clinical features and prognosis of LAM in patients with TSC including the effects of treatment, stratified by the method of diagnosis of LAM (i.e. histological or radiological). We found histological proof of diagnosis in 10 of 21 patients with TSC and symptomatic lung disease, onset in childhood in four, three males with LAM, individuals with apparently focal disease, great variation in clinical course and no clear treatment benefit. In those with TSC, symptomatic LAM is infrequent but causes a significant morbidity and mortality It was not possible to detect predisposing factors, other than being female. Males with apparent LAM should be rigorously investigated.

Healthcare workers' perceptions of occupational exposure to blood-borne viruses and reporting barriers: a questionnaire-based study.

BACKGROUND: Healthcare workers (HCWs) are at significant risk of exposure to blood-borne viruses (BBV). AIM: To investigate HCW perceptions concerning occupational exposures to BBV and possible barriers involved in reporting incidents. METHODS: A total of 120 HCWs based at the Dental Institute, King's College Hospital NHS Foundation Trust, completed an anonymous questionnaire as part of a multicentre study. FINDINGS: Eighty-six percent (99/115) of respondents worried about developing a BBV infection at work. Of those who feared hepatitis C virus (HCV) the most, 69% (31/45) also believed that HCV posed the greatest risk to their health, versus 53% (10/19) and 13% (5/40) with regard to hepatitis B virus (HBV) and HIV infection, respectively (P < 0.001). Of respondents with ≥21 years of health service experience, 75% (18/24) knew the risk of HIV transmission versus 13% (2/16) of respondents with <5 years of health service experience (P = 0.002). All (23/23) respondents with ≥21 years of service were aware of HIV PEP versus 20% (12/60) with <21 years of service. Ninety-two percent of respondents (104/113) agreed that it was important to report all body fluid exposure incidents but only 58% (28/48) had reported all their exposure incidents. Fifty-nine percent (60/102) agreed that an electronic reporting system would improve reporting of such incidents. CONCLUSIONS: This study identified a need to improve HCWs' knowledge of BBV infection risks and their management. Data gathered in this study will be used to inform the development of a web-based system for the surveillance of occupational exposures to BBV in the UK.

HIV prone occupational exposures: epidemiology and factors associated with initiation of post-exposure prophylaxis.

BACKGROUND: Occupational exposures to bloodborne viruses are very common. Whilst occupational HIV transmissions are rare, the serious physical, psychological and cost implications of potential transmission make this an important public health topic. European and UK guidelines recommend HIV post-exposure prophylaxis (PEP) as a valuable tool of preventing occupational HIV infection. Yet one in five UK healthcare workers did not initiate PEP despite having been exposed to an HIV-positive source patient. The aim of the study is to examine factors associated with PEP uptake behaviour. METHODS: The study is based on an analysis of the UK Health Protection Agency surveillance database of 'Significant Occupational Exposures to Bloodborne Viruses in Healthcare Workers'. Associations between possible predicting factors and PEP-uptake have been examined with univariate analysis and logistic regression modelling. RESULTS: Univariate analysis and logistic regression found significant associations between PEP-uptake and visible blood on the device (p<0.0001) and a linear relationship with increasing injury depth (p<0.0001). Doctors were significantly more likely to start PEP than nurses (OR 1.88, 1.16; 3.02). Multiple imputation of missing values did not significantly alter these results. CONCLUSIONS: PEP-uptake was associated with known transmission risk factors, suggesting awareness of current guidelines. The significant differences in PEP-uptake across occupation categories may be due to differential risk perceptions or other underlying factors. This is the first national study to examine PEP-uptake following occupational exposures to HIV. Further research and exploration of these findings are warranted, to understand the role of PEP-uptake behaviour in preventing occupational HIV transmission.

Monitoring the effectiveness of HIV and STI prevention initiatives in England, Wales, and Northern Ireland: where are we now?

Primary and secondary prevention are essential components of the response to HIV and sexually transmitted infections (STIs). We present findings from nationally implemented HIV/STI prevention interventions. In 2003, of those attending STI clinics at least 64% of men who have sex with men (MSM) and 55% of heterosexuals accepted a confidential HIV test; 88% of all HIV infections in women giving birth in England were diagnosed before delivery; 85% of MSM eligible for hepatitis B vaccination received a first dose of vaccine at their first STI clinic attendance; 74% of STI clinic attendees for emergency appointments, and 20% of those for routine appointments were seen within 48 hours of initiating an appointment; the National Chlamydia Screening Programme in England found a positivity of 10% and 13% among young asymptomatic women and men, respectively. Prevention initiatives have seen recent successes in limiting further HIV/STI transmission. However, more work is required if current levels of transmission are to be reduced.

On the subjectivity of personality theory.

Every theorist of personality views the human condition from the unique perspective of his own individuality. As a consequence, personality theories are strongly influenced by personal and subjective factors. These influences are partially responsible for the present day lack of consensus in psychology as to basic conceptual frameworks for the study of man. The science of human personality can achieve a greater degree of consensus and generality only if it begins to turn back on itself and question its own psychological foundations. The role of subjective and personal factors in this field can be studied and made more explicit by means of a psychobiographical method which interprets the major ideas of personality theories in the light of the formative experiences in the respective theorists' lives. This method is briefly illustrated by an examination of the influence of personal experiences on theoretical concepts in the work of Carl Jung, Carl Rogers, Wilhelm Reich, and Gordon Allport. The subjective factors disclosed by psychobiographical analysis can bee seen to interact with influences stemming from the intellectual and historical context within which the theorist work. The psychobiographical study of personality theory is only one part of a larger discipline, the psychology of knowledge, which would study the role of subjective and personal factors in the structure of man's knowledge in general.

Ethical approval for research involving geographically dispersed subjects: unsuitability of the UK MREC/LREC system and relevance to uncommon genetic disorders.

OBJECTIVES: To assess the process involved in obtaining ethical approval for a single-centre study involving geographically dispersed subjects with an uncommon genetic disorder. DESIGN: Observational data of the application process to 53 local research ethics committees (LRECs) throughout Wales, England and Scotland. The Multicentre Research Ethics Committee (MREC) for Wales had already granted approval. RESULTS: Application to the 53 LRECs required 24,552 sheets of paper and took two months of the researcher's time. The median time taken for approval was 39 days with only seven (13%) of committees responding within the recommended 21 days. In at least nineteen cases (36%) a subcommittee considered the application. Thirty-three committees (62%) accepted the proposal without amendments but, of the remainder, four (8%) requested changes outside of the remit of LRECs. DISCUSSION: Difficulties still exist with the system for obtaining ethical approval for studies involving a single centre but with patients at multiple sites, as is often required for genetic observational research. As such studies differ from true multicentre studies, it may be advantageous to develop a separate and specific process of application to ensure that resources are not unnecessarily expended in the quest for ethical approval.

Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.

Tuberous sclerosis (TSC [MIM 191090 and MIM 191100]) is an autosomal dominant disorder characterized by hamartomas in many organs. Two thirds of cases are sporadic and are thought to represent new mutations. TSC is caused by mutations affecting either of the presumed tumor-suppressor genes, TSC1 and TSC2. Both appear to function as tumor suppressors, because somatic loss or intragenic mutation of the corresponding wild-type allele is seen in the associated hamartomas. Here we report the first comprehensive mutation analysis of TSC1 and TSC2 in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons and using pulsed-field gel electrophoresis and conventional Southern blot analysis and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185). Twenty-two patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (eight cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (eight cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein. Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P=.0145). These data provide the first representative picture of the distribution and spectrum of mutations across the TSC1 and TSC2 loci in clinically ascertained TSC and support a difference in severity of TSC1- and TSC2-associated disease.

Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells.

Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, K(d) for binding to RARs = 2-5 nM) inhibited colony formation (by 50%) by all three lines at 16-34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12-22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RARbeta, and an antagonist with predominant activity at RARbeta and RARgamma (AGN194431) inhibited colony formation at concentrations (approximately 100 nM) commensurate with a K(d)value of 70 nM at RARgamma. An RARalpha antagonist (AGN194301) was less potent (IC(50) approximately 200 nM), but was more active than specific agonists of RARalpha and of betagamma. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARgamma-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma.

Recent trends in HIV and other STIs in the United Kingdom: data to the end of 2002.

Sexual health in the United Kingdom has deteriorated in recent years with further increases in HIV and other sexually transmitted infections (STIs) reported in 2002. This paper describes results from the available surveillance data in the United Kingdom from the Health Protection Agency and its national collaborators. The data sources range from voluntary reports of HIV/AIDS from clinicians, CD4 cell count monitoring, a national census of individuals living with HIV, and the Unlinked Anonymous Programme, to statutory reports of STIs from genitourinary medicine (GUM) clinics and enhanced STI surveillance systems. In 2002, an estimated 49500 adults aged over 15 years were living with HIV in the United Kingdom, of whom 31% were unaware of their infection. Diagnoses of new HIV infections have doubled from 1997 to 2002, mainly driven by heterosexuals who acquired their infection abroad. HIV transmission also continues within the United Kingdom, particularly among homo/bisexual men who, in 2002, accounted for 80% of all newly diagnosed HIV infections acquired in the United Kingdom. New diagnoses of syphilis have increased eightfold, and diagnoses of chlamydia and gonorrhoea have doubled from 1997 to 2002 overall; STI rates disproportionately affect homo/bisexual men and young people. Effective surveillance is essential in the provision of timely information on the changing epidemiology of HIV and other STIs; this information is necessary for the targeting of prevention efforts and through providing baseline information against which progress towards targets can be monitored.