Measurement of changes in uterine and fibroid volume during treatment of heavy menstrual bleeding (HMB).

STUDY QUESTION: Does application of an unbiased method for analysis of magnetic resonance (MR) images reveal any effect on uterine or fibroid volume from treatment of heavy menstrual bleeding (HMB) with three 12-week courses of the selective progesterone receptor modulator ulipristal acetate (SPRM-UPA)? SUMMARY ANSWER: Application of an unbiased method for analysis of MR images showed that treatment of HMB with SPRM-UPA was not associated with a significant reduction in the volume of the uterus or in the volume of uterine fibroids. WHAT IS KNOWN ALREADY: SPRM-UPA shows therapeutic efficacy for treating HMB. However, the mechanism of action (MoA) is not well understood and there have been mixed reports, using potentially biased methodology, regarding whether SPRM-UPA has an effect on the volume of the uterus and fibroids. STUDY DESIGN SIZE DURATION: In a prospective clinical study (with no comparator), 19 women with HMB were treated over a period of 12 months with SPRM-UPA and uterine and fibroid size were assessed with high resolution structural MRI and stereology. PARTICIPANTS/MATERIALS SETTING METHODS: A cohort of 19 women aged 38-52 years (8 with and 11 without fibroids) were treated with three 12-week courses of 5 mg SPRM-UPA given daily, with four weeks off medication in-between treatment courses. Unbiased estimates of the volume of uterus and total volume of fibroids were obtained at baseline, and after 6 and 12 months of treatment, by using the Cavalieri method of modern design-based stereology in combination with magnetic resonance imaging (MRI). MAIN RESULTS AND THE ROLE OF CHANCE: Bland-Altman plots showed good intra-rater repeatability and good inter-rater reproducibility for measurement of the volume of both fibroids and the uterus. For the total patient cohort, two-way ANOVA did not show a significant reduction in the volume of the uterus after two or three treatment courses of SPRM-UPA (P = 0.51), which was also the case when the groups of women with and without fibroids were considered separately (P = 0.63). One-way ANOVA did not show a significant reduction in total fibroid volume in the eight patients with fibroids (P = 0.17). LIMITATIONS REASONS FOR CAUTION: The study has been performed in a relatively small cohort of women and simulations that have subsequently been performed using the acquired data have shown that for three time points and a group size of up to 50, with alpha (Type I Error) and beta (Type II Error) set to 95% significance and 80% power, respectively, at least 35 patients would need to be recruited in order for the null hypothesis (that there is no significant reduction in total fibroid volume) to be potentially rejected. WIDER IMPLICATIONS OF THE FINDINGS: The imaging protocol that we have developed represents a generic paradigm for measuring the volume of the uterus and uterine fibroids that can be readily incorporated in future studies of medical treatments of HMB. In the present study, SPRM-UPA failed to produce a significant reduction in the volume of the uterus or the total volume of fibroids (which were present in approximately half of the patients) after either two or three 12-week courses of treatment. This finding represents a new insight in respect of the management of HMB using treatment strategies that target hormone-dependence. STUDY FUNDING/COMPETING INTERESTS: The UPA Versus Conventional Management of HMB (UCON) trial was funded by the EME Programme (Medical Research Council (MRC) and National Institutes of Health Research (NIHR)) (12/206/52). The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care.Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. H.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (All paid to Institution) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc., and Myovant Sciences GmbH. H.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. L.W. has received grant funding from Roche Diagnostics (Paid to Institution). All other authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: The study reported here is an embedded mechanism of action study (no comparator) within the UCON clinical trial (registration ISRCTN: 20426843).

Combination GnRH antagonists for endometriosis: Balancing efficacy with side effects.

Endometriosis is a chronic pain condition affecting 1 in 10 women. There is an unmet need for better medical treatments for endometriosis. We spotlight trials of a single preparation combined HRT-GnRH antagonist (Relugolix) by Giudice et al.,1 for endometriosis-associated pain.

Dichloroacetate as a possible treatment for endometriosis-associated pain: a single-arm open-label exploratory clinical trial (EPiC).

BACKGROUND: Endometriosis (where endometrial-like tissue is found outside the uterus) affects ~ 176 million women worldwide and can lead to debilitating pelvic pain. There is an unmet need for new medical treatment options for endometriosis. Pelvic peritoneal mesothelial cells of women with endometriosis exhibit detrimental metabolic reprogramming that creates an environment favouring the formation and survival of endometriosis lesions. We have generated powerful preclinical proof-of-concept data to show that it is possible to correct this metabolic phenotype using dichloroacetate (DCA), a non-hormonal compound previously used to treat rare metabolic disorders in children. We plan a single-arm, open-label, single site exploratory clinical trial to inform the design of a future randomised controlled trial (RCT) to determine the efficacy of DCA for the treatment of endometriosis-associated pain. METHODS: We will recruit 30 women with endometriosis-associated pain over a 6-month period. All participants will receive approximately 6.25 mg/kg oral DCA capsules twice daily for 6 weeks, with a dose increase to approximately 12.5 mg/kg twice daily for a further 6 weeks if their pain has not been adequately controlled on this dose regime and side-effects are acceptable. If pain is adequately controlled with minimal side-effects, the lower dose will be continued for a further 6 weeks. The primary objective is to determine whether it is possible to achieve acceptable recruitment and retention rates within the defined exclusion and inclusion criteria. Secondary objectives are to determine the acceptability of the trial to participants, including the proposed methods of recruitment, treatment, follow-up frequency and number of questionnaires. The recruitment rate will be determined by the proportion of patients recruited from the pool of eligible women. The retention rate will be determined by the proportion of participants who attended the final trial visit. DISCUSSION: This is a feasibility study to explore effectiveness and acceptability of the proposed field methodology (recruitment, retention, study processes and compliance with treatment). The results will be used to inform the design of a future RCT. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04046081 Registered 6 August 2019.

Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.

STUDY QUESTION: What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? SUMMARY ANSWER: UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. WHAT IS KNOWN ALREADY: Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking. STUDY DESIGN SIZE, DURATION: Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9-12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38-52 with fibroids were derived from institutional tissue archives. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. MAIN RESULTS AND THE ROLE OF CHANCE: UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding. STUDY FUNDING/COMPETING INTEREST(S): H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.

Doping in sport: an analysis of sanctioned UK rugby union players between 2009 and 2015.

To inform anti-doping policy and practice, it is important to understand the complexities of doping. The purpose of this study was to collate and systematically examine the reasoned decisions published by UK Anti-Doping for doping sanctions in rugby union in the UK since the introduction of the 2009 World Anti-Doping Code. Case files were content analysed to extract demographic information and details relating to the anti-doping rule violation (ADRV), including individuals' explanations for how/why the ADRV occurred. Between 2009 and 2015, 49 rugby union players and one coach from across the UK were sanctioned. Over 50% of the cases involved players under the age of 25, competing at sub-elite levels. Reasons in defence of the ADRV focused on functional use and lifestyle factors rather than performance enhancement. An a priori assessment of the "need", "risk" and "consequence" of using a substance was not commonplace; further strengthening calls for increasing the reach of anti-doping education. The findings also deconstruct the view that "doped" athletes are the same. Consequently, deepening understanding of the social and cultural conditions that encourage doping remains a priority.

Using the prototype willingness model to predict doping in sport.

To enable preventive measures to be designed, it is important to identify modifiable distal and proximal factors underlying doping behavior. This study investigated aspects of the prototype willingness model in relation to doping. A cross-sectional study was conducted involving 729 competitive athletes. Following ethical approval, athletes (mean age = 28.8 ± 10.1 years; 63% male) completed an online questionnaire, which assessed doping-related attitudes, norms, prototype perceptions, outcome expectancies, and behavioral willingness. Using hierarchical multiple regression analysis, 54.4% of the total variance in willingness to dope was explained. Specifically, past doping, attitudes, and favorability of performance enhancing substance user prototypes were the strongest unique predictors of willingness to dope. Athletes appeared most willing to dope if they were to suffer an injury, a dip in performance, or think others are doping and getting away with it. National-level athletes displayed significantly greater willingness to dope (Kruskal-Wallis γ2 = 35.9, P < 0.001) and perceived themselves as significantly more similar to a doper (Kruskal-Wallis γ2 = 13.4, P = 0.004) than athletes competing at any other level. The findings highlight the importance of extending anti-doping provision beyond elite-level sport and the need to target athletes' doping-related perceptions.

Reporting doping in sport: national level athletes' perceptions of their role in doping prevention.

This paper qualitatively explores national level athletes' willingness to report doping in sport. Following ethical approval, semi-structured interviews were conducted with nine national level athletes from rugby league (n = 5) and track and field athletics (n = 4). Thematic analysis established the main themes within the data. Contextual differences existed around the role that athletes perceived they would play if they became aware of doping. Specifically, track and field athletes would adopt the role of a whistle-blower and report individuals who were doping in their sport. In comparison, the rugby league players highlighted a moral dilemma. Despite disagreeing with their teammates' actions, the players would adhere to a code of silence and refrain from reporting doping. Taking these findings into account, prevention programs might focus on changing broader group and community norms around doping. In doing so, community members' receptivity to prevention messages may increase. Moreover, developing skills to intervene (e.g., speaking out against social norms that support doping behavior) or increasing awareness of reporting lines could enhance community responsibility for doping prevention. In sum, the findings highlight the need to consider the context of sport and emphasize that a one-size-fits-all approach to anti-doping is problematic.

The relationship of oxidative stress, adiposity and metabolic risk factors in healthy Black and White American youth.

UNLABELLED: What is already known about this subject African Americans are disproportionately affected by obesity and other metabolic risk factors in comparison to White Americans. Increasing prevalence of obesity has been associated with concomitant increases in childhood hypertension, dyslipidaemia and type 2 diabetes. Oxidative stress is associated with obesity in both adults and children. What this study adds Oxidative stress is positively associated with total body fat and truncal fat, but not with body mass index (BMI) or BMI z-score in healthy youth. Oxidative stress is associated with diastolic blood pressure in African American but not in White American healthy youth. BACKGROUND: Oxidative stress is elevated in obese youth, but less is known regarding racial disparities in the relationship of oxidative stress with metabolic risk factors. OBJECTIVES: To determine the relationship between oxidative stress and metabolic risk factors, adiposity, leptin, adiponectin and cardiovascular fitness (VO2PEAK ) in healthy African American and White American youth. METHODS: A marker of oxidative stress (F2 -isoprostane), validated markers of metabolic risk factors, fitness and body composition were measured in African American (n = 82) and White American (n = 76) youth (8-17 years old) recruited over a range of BMI percentiles (4th to 99th). RESULTS: F2 -isoprostane concentration was positively correlated with percentage body fat (r = 0.198) and percentage truncal fat (r = 0.173), but was not different between African American and White American males and females (P = 0.208). African American youth had significantly higher mean systolic and diastolic blood pressure (P = 0.023 and P = 0.011, respectively), body weight, BMI percentile and Tanner stage. After adjusting for gender, age, BMI and Tanner stage, African American youth varied from White Americans in the association of F2 -isoprostane with diastolic blood pressure (P = 0.047), but not with systolic blood pressure, triglycerides, VO2PEAK or homeostatic model assessment for insulin resistance (all P > 0.05). CONCLUSIONS: Oxidative stress, as measured by urinary F2 -isoprostane concentrations, was positively associated with percent body fat and truncal fat in youth. Oxidative stress levels were similar among African American and White American youth. Among markers of the metabolic syndrome, a significant difference between African American and White American youth was demonstrated only in the association of oxidative stress with diastolic blood pressure.

Gateway to doping? Supplement use in the context of preferred competitive situations, doping attitude, beliefs, and norms.

Nutritional supplement (NS) use is widespread in sport. This study applied an integrated social cognitive approach to examine doping attitudes, beliefs, and self-reported doping use behavior across NS users (n = 96) and nonusers (n = 116). Following ethical approval, 212 competitive athletes (age mean = 21.4, s = 4.5; 137 males) completed self-reported measures of doping-related social cognitions and behaviors, presented in an online format where completion implied consent. Significantly more NS users (22.9%) reported doping compared with nonusers (6.0%; U = 4628.0, P < 0.05). NS users presented significantly more positive attitudes toward doping (U = 3152.0, P < 0.05) and expressed a significantly greater belief that doping is effective (U = 3152.0, P < 0.05). When presented with the scenario that performance-enhancing substances are effective and increase the possibility of winning, NS users were significantly more in favor of competing in situations that allow doping (U = 3504.5, P < 0.05). In sum, doping use is three-and-a-half times more prevalent in NS users compared with nonusers. This finding is accompanied by significant differences in doping attitudes, norms, and beliefs. Thus, this article offers support for the gateway hypothesis; athletes who engage in legal performance enhancement practices appear to embody an "at-risk" group for transition toward doping. Education should be appropriately targeted.

Experiencing rights within positive, person-centred support networks of people with intellectual disability in Australia.

BACKGROUND: This research describes issues related to human rights as they arose within the everyday lives of people in nine personal support networks that included adult Australians with an intellectual disability (ID). METHOD: The research was part of a wider 3-year ethnographic study of nine personal support networks. A major criterion for recruitment was that people in these networks were committed to actively developing the positive, meaningful future of an adult family member with an ID. Data were collected from November 2007 to March 2011 via interviews, participant observations and analysed within the framework of situational analysis. Findings were checked with network members. RESULTS: The issue of rights was challenging to network members. Subtle rights violations could have a major impact on an individual with a disability. Network members worked to protect the rights of people with ID by building and maintaining an empathic and respectful support network, developing the person's self-confidence and autonomy and ensuring that the person with an ID was an active member of the personal support network. CONCLUSION: The maintenance of rights within a supportive environment remains a difficult task. It can be facilitated by a deep knowledge and respect for the person being supported, the promotion of his or her active participation in the planning and provision of support, and an experimental and reflective approach.

The role of informal networks in providing effective work opportunities for people with an intellectual disability.

Being in paid employment is socially valued, and is linked to health, financial security and time use. Issues arising from a lack of occupational choice and control, and from diminished role partnerships are particularly problematic in the lives of people with an intellectual disability. Informal support networks are shown to influence work opportunities for people without disabilities, but their impact on the work experiences of people with disability has not been thoroughly explored. The experience of 'work' and preparation for work was explored with a group of four people with an intellectual disability (the participants) and the key members of their informal support networks (network members) in New South Wales, Australia. Network members and participants were interviewed and participant observations of work and other activities were undertaken. Data analysis included open, conceptual and thematic coding. Data analysis software assisted in managing the large datasets across multiple team members. The insight and actions of network members created and sustained the employment and support opportunities that effectively matched the needs and interests of the participants. Recommendations for future research are outlined.

Emerging impact of CTA/perfusion CT on acute stroke thrombolysis in a community hospital.

Our objective was to retrospectively review the emerging role of CT, CTA, and perfusion CT (pCT) in the hyperacute stroke population of a community hospital. We reviewed 50 consecutive patients' records and imaging studies, who were treated with thrombolytic therapy within 6 h of symptom onset. Multidetector CT, CTA, and pCT studies were evaluated. Subsequent CT, magnetic resonance, or angiographic studies when available were correlated. Patients' clinical data at admission and outcomes at discharge were evaluated. Complications were tabulated. Of the 50 patients treated with thrombolytics, 37 had CT/CTA/pCT, the others non-contrast CT only. CT blood volume defect was present in a total of 14 patients, presaging permanent infarct in all. Arterial clot was seen in 28/37 CTAs (carotid "T" 6, MCA 16, vertebrobasilar 6). Viable penumbra was shown in 20/37; rescued penumbra was depicted after treatment in 14. 39 patients were treated with intravenous, nine with intra-arterial, two with both forms of thrombolysis. Modified Rankin score showed clinical improvement in 58%, three patients had complete recovery. Subsequent bleed was shown in two (4%), symptomatic in one (2%). Two patients died. Our experience suggests advanced CT is more sensitive to ischemia than routine CT, that salvageable penumbra can be identified, and that triage of patients with acute stroke for thrombolysis with CT/CTA/pCT is more robust than routine CT alone, and may improve outcomes in the community hospital setting.

The relationship between the epidermal growth factor (EGF) 5'UTR variant A61G and melanoma/nevus susceptibility.

The inheritance of a G allele in position 61 in the 5'UTR of the epidermal growth factor (EGF) gene has been reported to increase melanoma susceptibility, a finding we have investigated in this study. The most potent phenotypic risk factor for melanoma is the atypical mole syndrome (AMS) phenotype. Our hypothesis is that the AMS is genetically determined and that nevus genes are also low penetrance melanoma susceptibility genes. We report that the G allele frequencies were the same in 697 healthy women and 380 melanoma cases (OR 0.97, 95% CI 0.8-1.2 p=0.76). We therefore found no evidence that this polymorphism is a melanoma susceptibility gene. Furthermore, we found no evidence that the polymorphism controls the nevus phenotype (nevus number, number atypical nevi or AMS phenotype). We did find some evidence that the G allele may be associated with decreased tumor Breslow thickness (OR 0.5, 95% CI 0.3-0.9) for the A/A genotype versus A/G and G/G combined in tumors of thickness >3.5 vs < or =3.5 mm and may therefore act as a predictor of survival, although this finding is not in accord with the original report. This is the second study to find no association between EGF +61 and melanoma susceptibility.

Clinical characteristics of patients with unicoronal synostosis and mutations of fibroblast growth factor receptor 3: a preliminary report.

Clinical teaching dictates that isolated unicoronal synostosis is sporadic in occurrence and is possibly related to intrauterine constraint. Despite this, isolated reports document a familial occurrence. It has previously been recognized that there may be a familial pattern of inheritance. Recently, mutations in fibroblast growth factor receptors (FGFRs) have been implicated in several syndromic craniosynostoses. At the authors' institution, mutations in FGFR3, located at chromosome 4p16, have been found to cause coronal synostosis. Two cases of unicoronal synostosis were found to have the same Pro250Arg missense mutation in FGFR3. This finding suggested that all patients with a diagnosis of unicoronal synostosis be screened for the FGFR3 mutation. Between January and December of 1996, patients with a diagnosis of plagiocephaly at the Children's Hospital of Philadelphia were evaluated for the FGFR3 mutation. Thirty-seven patients with unicoronal synostosis had mutational studies. Two additional patients were known to have the FGFR3 mutation at the onset of the study. Of the 37 patients screened, four were found to have the FGFR3 mutation, for a total of six patients with both unicoronal synostosis and the FGFR3 mutation. All patients with unicoronal synostosis were evaluated for facial dysmorphology and operative outcome. The six patients with the FGFR3 mutation had more severe cranial dysmorphology and were more likely to need surgical revision than those without the FGFR3 mutation. The occurrence of the FGFR3 mutation among patients with unicoronal synostosis provides evidence for a genetic basis of certain forms of plagiocephaly. The clinical, radiologic, and molecular findings will be an important addition to the surgical management and counseling of patients with unicoronal synostosis.

The role of family preservation therapists in facilitating use of aftercare services.

OBJECTIVE: The aims were to: (1) examine the process that family preservation therapists use when developing and implementing aftercare plans, and (2) examine how family preservation therapists perceive the availability and accessibility of community services that families need after short-term family preservation services. METHOD: Focus groups were conducted with therapists (n = 26) from five agencies that provide family preservation services in a large Midwest city. One agency was the local public child welfare agency, and the other four were nonprofit agencies with state contracts to provide family preservation services. RESULTS: Therapists viewed aftercare services as important and necessary, yet perceived barriers to families' use of aftercare services. Therapists undertook a number of activities to help families access and use services, though some therapists took a less active role than others did in helping families link to services. It was perceived that more follow-up was needed to ensure service use. Participants viewed certain services as especially difficult to access or unavailable, including services for men and adolescents. CONCLUSIONS: More explicit and focused attention to facilitating service use is needed. This can be accomplished by therapists focusing on service use during assessment and treatment planning. Regular follow-ups after short-term family preservation services for the purpose of helping families to productively use services may be needed. However, systemic changes are also needed to ensure that needed services are available and accessible.

Xenopus rhodopsin promoter. Identification of immediate upstream sequences necessary for high level, rod-specific transcription.

To understand the mechanisms that control the cell-specific visual pigment gene transcription, the Xenopus rhodopsin 5' regulatory region has been characterized in vivo using transient transfection of Xenopus embryos and transgenesis. The principal control sequences were located within -233/+41, a region with significant conservation with mammalian rhodopsin genes. DNase footprinting indicated seven distinct regions that contain potential cis-acting elements. Sequences near the initiation site (-45/+41, basal region) were essential, but not sufficient, for rod-specific transcription. Two negative regulatory regions were found, one between -233 to -202, with no apparent similarity to known elements, and a second Ret-1-like CAAT (-136/-122) motif. Deletion of either sequence led to a 2-3-fold increase in expression levels, without a change in rod specificity. Sequences between -170 to -146, which contain an E-box motif, were necessary for high level expression in transgenic tadpoles but not in transient transfections. Sequences between -84 and -58, which contained an NRE-like consensus were found to be necessary for high level expression in both assays. Although expression levels were modulated by various proximal sequences in the rhodopsin promoter, none of the tested sequences were found to be necessary for rod specificity. Promoter constructs with a consensus BAT-1 sequence in conjunction with an NRE-like element upstream of the basal promoter directed low level green fluorescent protein expression in the central nervous system in transgenic tadpoles. These results suggest that rod cell-specific expression of rhodopsin is controlled by redundant elements in the proximal promoter.

A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family.

The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumours, commonly astrocytoma. Germline deletions of the region on 9p21 containing the CDKN2A and CDKN2B genes and CDKN2A exon 1beta have been reported in kindreds, implicating contiguous tumour suppressor gene deletion as a cause of this syndrome. We describe a family characterized by multiple melanoma and neural cell tumours segregating with a germline deletion of the p14(ARF)-specific exon 1beta of the CDKN2A gene. This deletion does not affect the coding or minimal promoter sequences of either the CDKN2A or CDKN2B genes. Our results are consistent with either: (i) loss of p14(ARF) function being the critical abnormality associated with this syndrome, rather than contiguous loss of both the CDKN2A and CDKN2B genes as suggested previously; or (ii) disruption of expression of p16 by mechanisms as yet unknown.

Demograghic and socio-economic determinants of community and hospital services costs for people with HIV/AIDS in London.

We examined the influence of demographic, social and economic background of people with HIV/AIDS in London on total community and hospital services costs. This was a retrospective study of community and hospital service use, needs and costs based on structured questionnaires administered by trained interviewers and costing information obtained from the service purchasers and providers, based on two Genito-urinary Medicine clinics in London: the Jefferiss Wing at St. Mary's Hospital and Patric Clements at the Central Middlesex Hospital, London, England. The subjects were 225 HIV infected patients (105 asymptomatic, 59 symptomatic non-AIDS and 61 AIDS). We found that over and above well established determinants of health care costs for HIV infected people such as disease stage and transmission category, social and economic factors such as employment and support of a living-in partner significantly reduced community services costs. Private health insurance had a similar effect, though only a small proportion of HIV people had such cover. The cost of community services for HIV infected non-European Union nationals, mainly of African origin, was one quarter that for the European Union nationals. Community services costs were highest for heterosexually infected women and lowest for heterosexually infected men after adjusting for other factors. Hospital services costs were significantly higher for HIV infected people lacking educational qualifications and employment. We conclude that access to community care for HIV infected non-EU nationals appears to be very poor as the cost of their community services was one quarter that for the EU nationals after adjusting for the effects of transmission category, disease stage, living with a partner, employment and having a private health insurance. Additional incentives for informal care for HIV infected people could be a cost-effective way to improve their community health service provisions.

TWIST gene mutation in a patient with radial aplasia and craniosynostosis: further evidence for heterogeneity of Baller-Gerold syndrome.

The term Baller-Gerold syndrome was coined by Cohen [1979: Birth Defects 15(5B): 13-63] to designate the phenotype of craniosynostosis and radial aplasia. It is thought to be a rare autosomal recessive condition, which, in some patients, presents with additional abnormalities, such as polymicrogyria, mental retardation or anal atresia. A phenotypic overlap of Baller-Gerold and Roberts-SC phocomelia syndrome was noted when a patient with bicoronal synostosis and bilateral radial hypoplasia was found to have premature centromere separation, a finding characteristic of Roberts syndrome [Huson et al.,1990: J Med Genet 27:371-375]. Other cases of presumed Baller-Gerold syndrome were rediagnosed as Fanconi pancytopenia, Rothmund-Thomson syndrome or VACTERL association. These reports led to a narrowed redefinition of Baller-Gerold syndrome based on the exclusion of cytogenetic and hematopoetic abnormalities and the absence of additional malformations in patients with craniosynostosis and preaxial upper limb abnormalities. Here we report on a patient with unilateral radial aplasia and bicoronal synostosis without additional malformations and without chromosome breakage, who fits this narrow definition of Baller-Gerold syndrome. We identified a novel TWIST gene mutation in this patient, a Glu181Stop mutation predicting a premature termination of the protein carboxy-terminal to the helix 2 domain. This report provides further evidence that Baller-Gerold is of heterogeneous cause, and a thorough evaluation is indicated to identify a possibly more specific diagnosis, including Saethre-Chotzen syndrome. This differential diagnosis is of particular importance, as it is an autosomal dominant trait. Therefore, the recurrence risk for parents of an affected child can be 50% if one parent carries the mutation, as opposed to the 25% recurrence risk for autosomal recessive inheritance. Offspring of the affected patient also have a 50% risk to inherit the mutation, while the risk to bear an affected offspring for an autosomal recessive trait is very low.

Analysis and treatment of severe trigonocephaly.

A retrospective analysis of seven patients with clinically severe trigonocephaly was performed, including a review of preoperative and postoperative computed tomography scans. A method of analyzing the trigonocephalic deformity was developed. This is based on determination of the angular severity of the forehead (110 +/- 4 degrees) and the length of half of the supraorbital bar (40 +/- 3 mm). This central angle was found to be relatively constant in this population. Using simple trigonometric relationships, a rationale for the alternative method of reconstruction used in these patients is presented. This technique is based on transverse expansion of the supraorbital bar, transposition of the lateral orbital rim, expansion of the temporal fossa, and recontouring the orbital aperture. As a separate consideration and step, the bony interorbital distance is widened.