Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development.

BACKGROUND: One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. METHODS: A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. RESULTS: We validated decreased Arid1b mRNA and protein in Arid1b+/- mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/- cerebellum. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. LIMITATIONS: The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. CONCLUSIONS: This study represents a full validation and investigation of a novel model of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

A retrospective study of the clinical effectiveness of the treatment of genital co-infection with N. gonorrhoeae and C. trachomatis in Coventry.

Concomitant infection of Neisseria gonorrhoeae and Chlamydia trachomatis is frequent and it is common practice to prescribe ancillary treatment for chlamydial infection when infection with N. gonorrhoeae is suspected or confirmed. In Coventry cases are treated as they are diagnosed. Our objective was to determine the clinical effectiveness of treating gonorrhoea and chlamydial infection separately in cases of co-infection. Case notes of co-infection with N. gonorrhoeae and C. trachomatis diagnosed in Coventry GU clinic from March 1989 to February 2000 were reviewed retrospectively. There were 1250 episodes of gonorrhoea, 4127 of chlamydial infections, and both infections were found in 332 cases. The two infections were treated in 322 cases and in 235 cases were treated separately. Ten cases did not come back for treatment of chlamydial infection, which is less than one case per year and 0.2% of total chlamydial infection in 11 years. On the other hand, 918 (73%) of total number of gonorrhoea patients did not have to take unnecessary treatment for chlamydial infection. In some clinical settings co-infection with N. gonorrhoeae and C. trachomatis could be treated separately with significant success and in the long run this might prevent development of antibiotic resistance of C. trachomatis infection.

Sociodemography of genital Chlamydia trachomatis in Coventry, UK, 1992-6.

OBJECTIVE: To describe the sociodemographic and geographic risk factors for incident Chlamydia trachomatis genital infection. DESIGN: Cross sectional retrospective study of cases diagnosed in local genitourinary clinics. SETTING: Coventry, West Midlands, from 1992 to 1996. SUBJECTS: 582 female and 620 male Coventry residents aged 15-64 years diagnosed with one or more episodes of genital Chlamydia trachomatis infection by enzyme immunoassay. Subjects were assigned a Townsend deprivation score based on residence. The denominator population aged 15-64 years was derived from 1991 census data. RESULTS: The mean annual incidence of genital chlamydia was 151 episodes (95% CI 140-163) per 100,000 population in men and 138 episodes (95% CI 128-149) per 100,000 population in women. Highest subgroup incidence was observed in 15-19 year old black women (2367 (95% CI 1370-4560) per 100,000), and 20-24 year old black men (1951 (95% CI 1158-3220) per 100,000). In univariate analyses, the most important risk factor for chlamydia infection in males was being black (incidence 1377 (95% CI 1137-1652) per 100,000 for black v 133 (95% CI 122-145) per 100,000 for white; RR 10.4, p < 0.0001) and for women was young age (incidence 475 (95% CI 415-540) per 100,000 for age group 15-19 years v 52 (95% CI 45-60) per 100,000 for age group 25-64 years; RR 9.1, p < 0.0001). In Poisson regression models of first episodes of genital chlamydia, for both males and females the effect of ethnic group could not be fully explained by socioeconomic confounding. There were significant interactions between age and ethnic group for both sexes and between age and level of deprivation for men. Geographical analysis revealed a high incidence of genital chlamydia in estates on the edge of the city as well as the urban core. CONCLUSIONS: There is a complex interaction between geographical location, age, ethnic group, and social deprivation on the risk of acquiring genital Chlamydia trachomatis in Coventry. Better population based data are needed.

Penile intraepithelial neoplasia--a veiled lesion in genitourinary medicine.

Penile intraepithelial neoplasia (PIN) is a clinically well known condition. However, its diagnosis is often difficult. We present four cases of PIN, seen in our department. Various histological patterns ranging from PIN I to PIN III were noted in these cases.

Drosophila EcR-B ecdysone receptor isoforms are required for larval molting and for neuron remodeling during metamorphosis.

During the metamorphic reorganization of the insect central nervous system, the steroid hormone 20-hydroxyecdysone induces a wide spectrum of cellular responses including neuronal proliferation, maturation, cell death and the remodeling of larval neurons into their adult forms. In Drosophila, expression of specific ecdysone receptor (EcR) isoforms has been correlated with particular responses, suggesting that different EcR isoforms may govern distinct steroid-induced responses in these cells. We have used imprecise excision of a P element to create EcR deletion mutants that remove the EcR-B promoter and therefore should lack EcR-B1 and EcR-B2 expression but retain EcR-A expression. Most of these EcR-B mutant animals show defects in larval molting, arresting at the boundaries between the three larval stages, while a smaller percentage of EcR-B mutants survive into the early stages of metamorphosis. Remodeling of larval neurons at metamorphosis begins with the pruning back of larval-specific dendrites and occurs as these cells are expressing high levels of EcR-B1 and little EcR-A. This pruning response is blocked in the EcR-B mutants despite the fact that adult-specific neurons, which normally express only EcR-A, can progress in their development. These observations support the hypothesis that different EcR isoforms control cell-type-specific responses during remodeling of the nervous system at metamorphosis.

DHR3, an ecdysone-inducible early-late gene encoding a Drosophila nuclear receptor, is required for embryogenesis.

Response to the steroid hormone ecdysone in Drosophila is controlled by genetic regulatory hierarchies that include eight members of the nuclear receptor protein family. The DHR3 gene, located within the 46F early-late ecdysone-inducible chromosome puff, encodes an orphan nuclear receptor that recently has been shown to exert both positive and negative regulatory effects in the ecdysone-induced genetic hierarchies at metamorphosis. We used a reverse genetics approach to identify 11 DHR3 mutants from a pool of lethal mutations in the 46F region on the second chromosome. Two DHR3 mutations result in amino acid substitutions within the conserved DNA binding domain. Analysis of DHR3 mutants reveals that DHR3 function is required to complete embryogenesis. All DHR3 alleles examined result in nervous system defects in the embryo.

Gonorrhoea in Coventry 1991-1994: epidemiology, coinfection and evaluation of partner notification in the STD clinic.

The aim of this study is to analyse the epidemiology of gonorrhoea in the Coventry area between 1991-1994 and the implementation and outcome of partner notification. A total of 404 episodes in 382 patients comprised the study group. In Coventry, 97% of episodes were managed in the STD clinic. There was a decrease in female and heterosexual male cases from 172 cases in 1991 to 37 cases in 1994 and increase in homosexual male cases from 8 in 1991 to 13 in 1994 (P<0.0001). Chlamydial coinfection was found in 38%. Among patients with gonorrhoea, 33% were asymptomatic and 40% with gonorrhoea and chlamydia were asymptomatic. Ten per cent of index cases were asymptomatic as were 83% of contact cases (P<0.0001). The health advisers (HAs) interviewed 82% immediately and 94% at some time after diagnosis. Of the average 1.5 partners per patient identified, 0.31 partners per patient were already screened, another 0.4 partners per patient were traced, 0.37 partners per patient were not traced, and for 0.41 partners per patient notification outcome was unknown or unconfirmed. Partner notification of 278 index cases traced 163 primary or tertiary contacts, 115 were new cases of gonorrhoea.

Hepatitis B markers in heterosexual patients attending two genitourinary medicine clinics in the West Midlands.

OBJECTIVE: To determine the prevalence of hepatitis B virus (HBV) infection in heterosexual patients attending two genitourinary medicine (GUM) clinics in the West Midlands and to examine whether heterosexual activity is a risk factor for acquiring HBV infection with the view to extend HBV vaccination policies to cover this group. DESIGN: HBV markers were determined in the GUM study group and compared with that of the control groups. Responses to a questionnaire were used to examine sexual behaviour patterns that may be related to heterosexual acquisition of HBV infection. SETTING: The West Midlands, UK April 1992-January 1993. SUBJECTS: 788 male patients and 688 female patients attending GUM clinics were compared with 498 male blood donors and 563 females attending antenatal clinics for the seroprevalence of HBV markers. Potential risk factors related to heterosexual activity were assessed in 1436 patients in the study group. MAIN OUTCOME MEASURES: Prevalence of HBV markers in the GUM study group and the controls. The possible use of the risk factors examined as predictors for acquiring HBV infection. RESULTS: The seroprevalence of hepatitis B core antibody (anti-HBc) in GUM patients was 1.9% and 0.5% in the control group. In the study groups the prevalence of anti-HBc from Birmingham was 3.2% while that from Coventry was 0.8%. The low seroprevalence of HBV prevented a multiple logistic analysis. A limited regression analysis showed that being non-white (p < 0.001) and duration of sexual activity (p = 0.013) were risk factors for HBV infection. However, these two factors were poor predictors of the risk to exposure to HBV infection. CONCLUSION: The prevalence of HBV infection in heterosexual patients in the West Midlands is very low and does not provide any indications to broaden HBV vaccination into heterosexual patients attending GUM clinics. Risk factors were poor predictors of the exposure to HBV infection. This is partially due to the low prevalence of HBV infection in this study. Further studies are required before definitive conclusions are made regarding the potential predictive value of risk factors.

A survey on hepatitis B vaccination policies in genitourinary medicine in UK and Ireland.

OBJECTIVE: To determine the policies applied in genitourinary medicine (GUM) departments in the United Kingdom (UK) and Ireland with regard to hepatitis B vaccination. DESIGN: All genitourinary medicine consultants were sent a questionnaire requesting information concerning their selection criteria and the management of patients offered Hepatitis B vaccine. If no response was obtained a second questionnaire was sent. The survey was carried out in 1993. SETTING: All genitourinary medicine departments in UK and Ireland. PARTICIPANTS: 234 consultants were sent the questionnaire. 153 consultants responded. RESULTS: Overall, there was a 65.4% response rate to the questionnaire. Almost all genitourinary physicians would offer the vaccine to male homosexuals and up to 74% offer it to all male homosexuals, intravenous drug users (IVDU) and prostitutes. Of the genitourinary physicians, 96% agreed that hepatitis B virus (HBV) serological markers should be checked prior to or simultaneously with vaccination, yet there was no agreement as to which marker should be performed. Up to 79% of consultants recalled the patients to check their response to vaccination but only 61% offered long term follow up after vaccination. CONCLUSION: HBV vaccine is offered to all male homosexuals, IVDU and prostitutes in GUM departments. Currently, the vaccine is not generally offered to patients who present with sexually transmitted diseases. Almost all genitourinary physicians (96%) agree that HBV serological markers should be checked prior to or simultaneously with the start of the vaccination course and 80% would request hepatitis B surface antibody levels after vaccination to identify inadequate responders and non-responders. From this survey, there appears to be a need for uniform post-vaccination HBV screening and timing and frequency of booster doses.