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BackgroundDespite international treatment guidelines currently advocating oral anticoagulants (OACs) as the only appropriate stroke prevention therapy for patients with atrial fibrillation (AF) and evidence that OACs can greatly reduce the risk of stroke with similar risk of bleeding compared with aspirin, the underuse of OACs in patients with AF is common globally, especially in Asia. This study aimed to identify the barriers to prescribing and using OACs among long-term aspirin users with AF.MethodFace-to-face interviews were conducted with fourteen eligible patients with AF using a semi-structured interview guide. The interview recordings were transcribed verbatim and data was analyzed according to the principles of thematic analysis.ResultsFive themes were developed: awareness of AF symptoms and diagnosis; knowledge and understanding of AF and stroke prevention therapy; role of decision-making in prescribing; willingness to switch from aspirin to OACs; and impact of OAC regimen on daily living. The majority of the patients were not aware of the symptoms and diagnosis of AF and only had a vague understanding of the illness and stroke prevention therapy, leading to their minimal involvement in decisions relating to their treatment. Some patients and their caregivers were particularly concerned about the bleeding complications from OACs and perceived aspirin to be a suitable alternative as they find the adverse effects from aspirin manageable and so preferred to remain on aspirin if switching to OACs was not compulsory. Lastly, the lifestyle modifications required when using warfarin, e.g. alternative dosing regimen, diet restriction, were seen as barriers to some patients and caregivers.ConclusionThe findings revealed patients’ knowledge gap in AF management which may be targeted using educational interventions to improve patients’ understanding of AF and its management and hence encourage active participation in the decision-making of their treatment in the future.

Background: Despite international treatment guidelines currently advocating oral anticoagulants (OACs) as the only appropriate stroke prevention therapy for patients with atrial fibrillation (AF) and evidence that OACs can greatly reduce the risk of stroke with similar risk of bleeding compared with aspirin, the underuse of OACs in patients with AF is common globally, especially in Asia. This study aimed to identify the barriers to prescribing and using OACs among long-term aspirin users with AF.Method: Face-to-face interviews were conducted with fourteen eligible patients with AF using a semi-structured interview guide. The interview recordings were transcribed verbatim and data was analyzed according to the principles of thematic analysis.Results: Five themes were developed: awareness of AF symptoms and diagnosis; knowledge and understanding of AF and stroke prevention therapy; role of decision-making in prescribing; willingness to switch from aspirin to OACs; and impact of OAC regimen on daily living. The majority of the patients were not aware of the symptoms and diagnosis of AF and only had a vague understanding of the illness and stroke prevention therapy, leading to their minimal involvement in decisions relating to their treatment. Some patients and their caregivers were particularly concerned about the bleeding complications from OACs and perceived aspirin to be a suitable alternative as they find the adverse effects from aspirin manageable and so preferred to remain on aspirin if switching to OACs was not compulsory. Lastly, the lifestyle modifications required when using warfarin, e.g. alternative dosing regimen, diet restriction, were seen as barriers to some patients and caregivers. Conclusion: The findings revealed patients’ knowledge gap in AF management which may be targeted using educational interventions to improve patients’ understanding of AF and its management and hence encourage active participation in the decision-making of their treatment in the future.

The development and function of the heart is governed by a conserved set of transcription factors (TFs) that regulate gene expression in a cell-type, time point and stimulus driven manner. Of these core cardiac TFs, the most ubiquitously expressed is the zinc finger protein GATA4. In cardiomyocytes, GATA4 is central to proliferation, differentiation, hypertrophy and induction of pro-survival pathways. In cardiac endothelial cells, it is required for valve and septal development, although the exact mechanisms remain unclear. To regulate such a wide array of functions in a spatially and temporally controlled manner, GATA4 interacts with specific protein partners, the majority of whom have been identified in cardiomyocytes. However, a complete understanding of the protein interactome of GATA4, particularly in cardiac endothelial cells, has not yet been achieved. Using a mass spectrometry-based approach, we have identified a series of novel GATA4 interacting partners in cardiac endothelial cells. 3xFlag GATA4 was stably overexpressed via retroviral transduction in the TC13 cardiac endothelial precursor cell line, immunoprecipitated from nuclear protein extracts and sent for HPLC-ESI-MS/MS. Several novel GATA4 interacting partners were identified including the chaperone protein Heat Shock Protein 70 (HSP70), the inducible orphan nuclear receptor Nerve Growth Factor 1β (NGFIβ, NUR77) and the Drosophila-Binding/Human Splicing protein family members Non-POU Domain Containing Octamer Binding Protein (NONO) and Paraspeckle 1 (PSPC1). Chapter 1 discusses the interaction between GATA4 and HSP70 and its role in cardiomyocyte survival upon exposure to chemotherapeutic agent Doxorubicin (DOX). HSP70 binds directly to GATA4, preventing DOX-mediated cleavage and degradation by Caspase-1, cardiomyocyte cell death and heart failure. Chapter 2 focuses on the cooperative interaction between GATA4 and NUR77 in cardiac microvascular endothelial cells and its central role in myocardial angiogenesis in response to pressure overload. The GATA4-NUR77 complex transactivates the promoter of Angiopoietin-Like 7 (ANGPTL7), a secreted pro-angiogenic chemotactic factor, triggering endothelial cell proliferation and tube formation in cultured cardiac endothelial cells and increasing myocardial capillary density in vivo. Chapter 3 discusses the interaction between GATA4 and the DBHS proteins NONO and PSPC1 in the regulation of cardiac development. These proteins play opposing roles when bound to GATA4 as PSPC1 enhances GATA4 activation of critical cardiac promoter targets and NONO acts as a rheostat to repress GATA4 activity. In vivo, loss of NONO results in left ventricular non-compaction consistent with humans with loss-of-function mutations. However, simultaneous Gata4 haploinsufficiency partially rescues this phenotype. Together, this data identifies multiple novel cell type and time point specific GATA4 protein partners and sheds light on GATA4 regulatory mechanisms in cardiac development and disease.

Public engagement in medication management has become more and more important in promoting population health. A public engagement workshop attended by 78 members of the geriatric community, family carers as well as professionals from academic research, industry and regulatory agencies entitled 'How to improve medicines for older people?' took place on the 2nd July 2013 at the University College London (UCL) School of Pharmacy. The main aim of the event was to provide a dynamic environment for information exchange and to identify ways of improving current and future geriatric drug therapy. The day opened with presentations from UCL School of Pharmacy researchers on the use of medicines at home, formulations, administration devices and multi-component compliance aids (MCAs) whilst a representative from UCL Interaction Centre gave an insightful presentation on human errors and resilience strategies regarding medication use. These opening presentations encouraged participants to share their own experiences as well as initiating a lively debate. Following the plenary presentations, the workshop was divided into 8 groups for parallel discussion session. These opinion sharing sessions witnessed fruitful discussions between patients, carers and researchers. The day closed with a panel session of representatives from the European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory Agency (MHRA), the Geriatric Medicines Society and Guy's and St. Thomas' NHS Foundation Trust (GSTT). Participants were encouraged to voice their questions, concerns and recommendations about medications. The main concern expressed by both patients and carers from the workshop were (but are not limited to) formulation changes, MCA accessibility difficulties, interactions of different medicines, carers' concerns with the administration of medicines and not having enough knowledge of services provided by community pharmacists i.e. medicines use reviews (MURs) or new medicine service (NMS). Overall, this workshop created a useful forum for members of the geriatric community, their carers as well as research and industrial professionals to have an input in the improvement and management of geriatric drug therapy and this event also provided an excellent opportunity for the researchers to share the latest research innovations with attendees.

INTRODUCTION: Type 1 diabetes (T1D) in children and adolescents is increasing worldwide with a particular increase in children

Plain English Summary A one day public engagement workshop was held to focus on the priorities of older people about research and practice in health and social care. Seventy-five older people from the general public and a variety of backgrounds attended this event to share their views and discuss what should be prioritised. The main aim of this workshop was to identify and prioritise issues that are important to older people that would benefit from further research, as well as create an environment for older people to share ideas and problems related to these important issues. Key priorities brought up by participants included loneliness and isolation, support and training for professional and family carers, post-surgical care, negative perceptions of older people and inequalities related to public services and healthcare. Participants further suggested older people should be actively involved in all stages of the research process. Abstract As the world’s population ages, there is an increasing need for research that addresses the priorities of older people. A public engagement workshop focusing on the priorities of older people for research and practice in health and social care was attended by seventy-five people aged 70 years and above in London, United Kingdom (UK). The workshop aimed to identify and prioritise issues important to older people that would benefit from further research and act as a platform to promote sharing of ideas and problems related to these important issues. Key priorities emerged including loneliness and isolation, support and training for professional and family carers, post-surgical care, negative perceptions of older people and inequalities related to public services and healthcare. Participants further suggested older people should be actively involved in all stages of the research process.

Dementia is fast becoming a global concern due to a demographic shift towards an older population. Many studies have shown that caring for a family member or friend has a profound and negative impact on the physical, emotional and psychosocial aspects of the caregivers’ life. One significant activity that a family caregiver undertakes is assistance with the management of medicines. This review was undertaken to ascertain what the issues are that affect optimal medicines use from the perspectives of people living with dementia and their caregivers, both in the community and care home settings. A literature search was conducted using electronic databases, employing a combination of search terms. A total of 16 studies met the inclusion criteria. Six broad themes were identified, together with some recommendations to improve medicines use in people with dementia. Challenges to medicines use centred on medicines management and administration, the impact on the caregiver and care recipient, their partnership and interface with formal care. Future research should focus on developing targeted interventions that can overcome these challenges to achieve optimal medicines use.

BACKGROUND: Type 1 diabetes (T1D) in children and young people is increasing worldwide with a particular increase in children under the age of 5 years. Fewer than one in six children and young people achieve glycosylated fraction of haemoglobin (HbA1c) values in the range identified as providing best future outcomes. There is an urgent need for clinic-based pragmatic, feasible and effective interventions that improve both glycaemic control and quality of life (QoL). The intervention offers both structured education, to ensure young people know what they need to know, and a delivery model designed to motivate self-management. OBJECTIVE: To assess the feasibility of providing a clinic-based structured educational group programme incorporating psychological approaches to improve long-term glycaemic control, QoL and psychosocial functioning in a diverse range of young people. DESIGN: The study was a pragmatic, cluster randomised control trial with integral process and economic evaluation. SETTING: Twenty-eight paediatric diabetes services across London, south-east England and the Midlands. RANDOMISATION: Minimised by clinic size, age (paediatric or adolescent) and specialisation (district general hospital clinic or teaching hospital/tertiary clinic). ALLOCATION: Half of the sites were randomised to the intervention arm and half to the control arm. Allocation was concealed until after clinics had consented and the first participant was recruited. Where possible, families were blind to allocation until recruitment finished. PARTICIPANTS: Forty-three health-care practitioners (14 teams) were trained in the intervention. The study recruited 362 children aged 8-16 years, diagnosed with T1D for > 12 months, with a mean 12-month HbA1c level of ≥ 8.5%. INTERVENTION: Two 1-day workshops taught intervention delivery. A detailed manual and resources were provided. The intervention consists of four group education sessions led by a paediatric diabetes specialist nurse with another team member. OUTCOMES: The primary outcome was glycaemic control, assessed at the individual level using venous HbA1c values, measured at baseline, 12 and 24 months. Secondary outcomes were directly and indirectly related to diabetes management, including hypoglycaemic episodes, hospital admissions, diabetes regimen, knowledge, skills and responsibility for diabetes management, intervention compliance, clinic utilisation, emotional and behavioural adjustment, and general and diabetes-specific QoL. PROCESS EVALUATION: Questionnaires, semistructured interviews, informal discussion following observation sessions, fieldwork notes and case note review were used to collect qualitative and quantitative data from key stakeholder groups at specific time points in the trial. STATISTICAL ANALYSES: Primary and secondary analyses were intention-to-treat comparisons of outcomes at 12 and 24 months, using analysis of covariance with a random effect for clinic. Prespecified subgroup analyses based on age, gender, initial HbA1c value and socioeconomic status were estimated from models that included an interaction term. The economic analysis compared long-term costs and predicted quality-adjusted life-years (QALYs). RESULTS: The intervention did not improve HbA1c at 12 months [intervention effect 0.11; 95% confidence interval (CI) -0.28 to 0.50; p = 0.584] or 24 months (intervention effect 0.03; 95% CI -0.36 to 0.41; p = 0.891). A total of 298/362 patients (82.3%) provided blood samples at 12-month follow-up, and 284/362 (78.5%) provided blood samples at 24-month follow-up. Follow-up questionnaires were completed by 307 patients (85.3%) at 12 months and by 295 patients (81.5%) at 24 months. Intervention group parents at 12 months (95% CI 0.74; 0.03 to 1.52) and young people at 24 months (0.85; 95% CI 0.03 to 1.61) had higher scores on the diabetes family responsibility questionnaire. Young people reported reduced happiness with body weight at 12 months (-0.56; 95% CI -1.03 to -0.06). Only 68% of groups were run. Of the 180 families recruited, 96 (53%) attended at least one module. Reasons for low uptake included difficulties organising groups, and work and school commitments. Young people with higher HbA1c levels were less likely to attend. Parents and young people who attended groups described improved family relationships, improved knowledge and understanding, greater confidence and increased motivation to manage diabetes. Twenty-four months after the intervention, nearly half of the young people reported that the groups had made them want to try harder and that they had carried on trying. A high-quality, complex, pragmatic trial of structured education can be delivered alongside standard care in NHS diabetes clinics. Health-care providers benefited from behaviour change skill training and can deliver pragmatic aspects of a National Institute for Health and Care Excellence (NICE)-compliant structured education programme after relatively brief training. The process evaluation provides insight into aspects of the model, and highlights strengths and aspects that may have contributed to the failure to influence primary and secondary outcomes. Current NHS practice dominates CASCADE (Child and Adolescent Structured Competencies Approach to Diabetes Education) in that it achieves the same number of QALYs at a lower cost. The mean cost of providing the intervention was £5098 per site or £683 per child. Members of paediatric diabetes services trained to deliver the CASCADE structured education package using behaviour change techniques did not improve glycaemic control in patients compared with control subjects 1 and 2 years after the intervention. The training workshops for practitioners were well evaluated; however, more intensive training was needed. The intervention cost £683 per patient but was not cost-effective because it did not improve metabolic control. CONCLUSIONS: A high-quality, complex, pragmatic trial of structured education can be successfully conducted alongside standard care in NHS diabetes clinics. Pragmatic components of a NICE-compliant structured education programme can be successfully delivered following a relatively brief 2-day training while paediatric health-care professionals benefit from training in behaviour change skills. The study provides invaluable information on barriers and opportunities regarding future, similar interventions. A low dropout rate and good attendance for the subgroup that attended the intervention suggests there might be improved uptake if offered to young people with lower HbA1c. Testing whether this approach can be more successful with a robust ongoing supervisory element should be a target of further research. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52537669. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 20. See the NIHR Journals Library website for further project information.

The sequence of events involved in the neurodegeneration caused by transmissible spongiform encephalopathies is not yet known. Using a murine scrapie model in which neurodegeneration in the hippocampus is restricted to the CA2, we show an up-regulation of the proapoptotic markers Fas and caspase 3 early in the incubation period prior to disease-specific prion protein (PrP) deposition and clinical signs. These results suggest that activation of Fas and caspase 3 are involved in the early pathological sequence of events during murine scrapie, and that these proapoptotic markers may be a specific method for early detection of neurodegeneration.

The PrP gene of the host exerts a major influence over the outcome of transmissible spongiform encephalopathy (TSE) disease, but the mechanism by which this is achieved is not understood. We have introduced a specific mutation into the endogenous murine PrP gene using gene targeting to produce transgenic mice with a single amino acid alteration (proline to leucine) at amino acid position 101 in their PrP protein (P101L). The effect of this alteration on incubation time, targeting and PrP(Sc) formation has been studied in TSE-infected animals. Transgenic mice carrying the P101L mutation in PrP have remarkable differences in incubation time and targeting of central nervous system pathology compared with wild-type littermates, following inoculation with infectivity from human, hamster, sheep and murine sources. This single mutation can alter incubation time across three species barriers in a strain-dependent manner. These findings suggest a critical role for the structurally 'flexible' region of PrP in agent replication and targeting of TSE pathology.

INTRODUCTION: For England and Wales, Section 17 of the Mental Health Act 1983 allows for compulsorily detained patients to have trial leave (TL) between hospitals or from hospital to community to allow a period of testing readiness for a change in residency and/or legal status. The aim of this study was to document the use of TL for the largest sub-group of such patients within two discharge cohorts from one high security hospital and to test for correlates. METHOD: Data were collected from the special hospitals' case register for two Broadmoor Hospital discharge cohorts, 1984 and 1990-94, of offender patients with hospital orders under Home Office restrictions on discharge (Section 37/41). RESULTS: In 1984, only two of the 29 people leaving special hospital did so under trial leave arrangements, but by 1990 to 1994, 71% of restricted hospital order departures were under trial leave (92/130), a significant change in practice. Focusing on only the later cohort, women were disproportionately more likely to leave in this way. Trial leave was used more for patients with an index offence of homicide, similarly for violent offences but less so for sex offences. Nature of disorder did not have any bearing on the use of trial leave. Use of trial leave did not significantly shorten length of stay within the special hospital. CONCLUSION: Trial leave has become the most usual route out of special hospital, and is the departure route used almost exclusively for women patients, yet there appears to be no obvious advantage for the patient in shortening length of stay in high security. However, there is no way of knowing how long patients would have stayed had the option of trial leave not been available to them. Furthermore, no advantage for the public was found in the preferential use of TL for discharges to the community.

Background Few follow-up studies of mentally disordered offenders have taken into account time spent in the community at risk of reoffending when calculating reconviction rates. Method This small exploratory study examined the effect of discharge destination (community or hospital) on reconviction over a nine-year period in an annual discharge cohort (1984) of special hospital patients with personality disorder, controlling for time spent ‘at risk’ in the community. Results Those discharged directly to the community spent significantly more time at risk in the community during follow-up but they were no more likely to be reconvicted than those discharged via a less secure hospital. Discussion One possible explanation is that less secure hospital units are not specifically equipped to treat people with a personality disorder. Alternatively, clinicians may be correctly identifying patients who are at greater risk of reoffending and thus recommending a more staged rehabilitation back to the community. It was apparent that there are very few official data available about placements following absolute discharge. The implications for this and other studies of this type are discussed.

BackgroundSpecial hospitals in England provide psychiatric care and treatment in high security. Their future is often questioned.AimsTo test for variation in demand for high-security psychiatric services over one 10-year period.MethodThis study was from the special hospitals' case registers and hospital records. The main measures were numbers and annual rates for referrals and beds offered; the Mental Health Act 1983 (MHA) classification of mental disorder; adjusted population rates by health region; admission episodes; legal category of detention; admission source and type of offence.ResultsReferrals to special hospitals showed no decrease during the 10 years; an apparent increase may reflect under-recording before 1992. Admissions fell by about 16% over the 10 years, but with regional variation. Women, civil cases, admissions under the MHA classifications of psychopathic disorder or mental impairment and directly from a court on a hospital order were most affected. There was an increase in admissions of pre-trial and sentenced male prisoners, and of transferred hospital order patients from other hospitals.ConclusionsThere is continuing demand from all parts of the country for high-security hospital beds. The smaller numbers admitted appear to include more demanding cases.

BackgroundA considerable proportion of patients with personality disorder are discharged directly to the community from special (high-security) hospitals.AimsTo examine whether patients with personality disorder discharged directly to the community are more likely to be re-convicted than those transferred to psychiatric hospitals of lesser security.MethodRe-conviction data for a f ive-to nine-year follow-up were collected for a four-year (1988–1991) special hospital discharge cohort of patients with personality disorder.ResultsIndividuals discharged directly to the community were not significantly more likely to be re-convicted than those transferred to less secure psychiatric hospitals. However, patients discharged to the community without formal conditions of supervision were more likely to be re-convicted than those discharged to the community with conditions or those transferred to other psychiatric hospitals.ConclusionsFormal supervision after discharge may be more important than actual destination in influencing the likelihood of re-conviction.

This study aimed to investigate whether implicit memory is preserved in children with traumatic brain injury (TBI). A fragmented picture-completion procedure (Snodgrass, Smith, Feenan, & Corwin, 1987) was used to compare implicit and explicit memory of 12 children with severe long-term TBI and 12 controls, matched for age and gender. On the implicit memory task, both the TBI and control groups were found to show significant priming. In addition, the extent of priming for the two groups was not found to be different. On the explicit memory task, however, the TBI group was found to perform significantly more poorly than the control group. These results are consistent with those reported in the adult TBI literature and have implications for understanding and rehabilitating memory impairments in children with TBI.

This article presents findings from a survey of 186 first year nursing and midwifery students that relate to their smoking and alcohol consumption. Of the students sampled, 28% were cigarette smokers. This is higher than the smoking rate of 25% for the adult population in the UK. The majority of the students who smoked said that they would like to stop smoking. Most of the students (86.5%) reported having drunk alcohol on at least one occasion during the previous week, with 26.5% having had a drink on three or four days. The amount consumed over the week ranged from no drinks to 90, with the mean being 13.72. Worryingly, 74% had exceeded the daily benchmarks for low-risk drinking on at least one occasion during the week for which consumption was reported, and 55% were drinking at binge levels. The findings raise concerns for the future health of many of our students and for their roles as health promoters.

BackgroundPrevious research has shown that there are gender differences in reoffending after discharge from medium-secure units, but these have not been adequately explained.AimsTo investigate gender differences in reoffending after discharge from medium-secure psychiatric units.MethodAll people discharged from medium-secure units in England and Wales between April 1997 and March 1998 were followed up for 1 year (n=959; 12% women). Reoffending was estimated by collecting reconviction data from the Home Office's Offenders' Index or from files at the mental health unit up to 2 years after discharge.ResultsWomen were less likely than men to be reconvicted within 2 years of discharge (9% v. 16%, OR=0.49, 95% CI 0.25 – 0.98). Adjustments for history of self-harm, drug or alcohol problems and previous offending substantially reduced the gender difference. In the full model the OR was 0.97 (95% CI 0.45–2.12).ConclusionsSome or all of the gender differences in reoffending between men and women are explained by self-harm, alcohol and drug problems and previous criminal history.

The sequence of events involved in the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs) is not yet known. Using a murine scrapie model in which neurodegeneration in the hippocampus is restricted to CA2, we show that pyramidal neuron damage and death by an apoptotic mechanism occur early in the incubation period, prior to the appearance of CA2 disease-specific accumulation of PrP and the onset of clinical disease. We suggest that the initial hippocampal pathological event in this model is dendritic dysfunction and activation of an apoptotic pathway rather than PrP accumulation.

BackgroundIt has been argued that many patients in special hospital beds do not need to be there. In the 1990s there were initiatives to discharge women and people with learning difficulties.AimsTo test for trends in special hospital discharges and to examine annual resident cohorts.MethodThis study was from case registers and hospital records. The main measures were numbers and annual rates for referrals and beds offered; the Mental Health Act 1983 (MHA) classification of mental disorder; adjusted population rates by region; admission episodes; legal category of detention; admission source and type of offence.ResultsThe median annual number of residents was 1859 (range 1697–1910), with an 8% fall for the period. This particularly affected people in mental impairment categories. Numbers were sustained in the male mental illness groups. Discharges, mainly to other institutions, increased. There was no overall change over the 10 years in length of stay for treatment, but successive admission cohorts from 1986 did show some reduction, even with solely remand order cases excluded.ConclusionsService planners need a longitudinal perspective on service use. Trends over 10 years to both fewer admissions and more discharges have reduced the special hospital population, but despite new treatments for schizophrenia, men under mental illness classification, as well as transfer from other secure settings, have gone against this trend.

In order to investigate mutations linked to human TSEs, we have used the technique of gene targeting to introduce specific mutations into the endogenous murine PrP gene which resulted in a P101L substitution (Prnp a101L ) in the murine PrP gene. This mutation is equivalent to the 102L mutation in the human PrP gene which is associated with Gerstmann-Straussler syndrome. Since the mutated gene is in the correct chromosomal location and control of the mutant gene expression is identical to that of the wild type murine PrP gene, the precise effect of the 101L mutation in the uninfected and TSE infected mouse can be investigated in this transgenic model. Mice homozygous for this mutation (101LL) while showing no spontaneous TSE disease were more susceptible to TSE disease than wild type mice following inoculation with GSS infectivity. Disease was transmitted from these mice to mice both with and without the Prnp a101L allele. The 101L mutation does not therefore produce spontaneous genetic disease in mice but does dramatically alter incubation periods following TSE infection. Additionally, a rapid TSE transmission was demonstrated associated with extremely low amounts of PrPSc.

A mutation equivalent to P102L in the human PrP gene, associated with Gerstmann-Straussler syndrome (GSS), has been introduced into the murine PrP gene by gene targeting. Mice homozygous for this mutation (101LL) showed no spontaneous transmissible spongiform encephalopathy (TSE) disease, but had incubation times dramatically different from wild-type mice following inoculation with different TSE sources. Inoculation with GSS produced disease in 101LL mice in 288 days. Disease was transmitted from these mice to both wild-type (226 days) and 101LL mice (148 days). In contrast, 101LL mice infected with ME7 had prolonged incubation times (338 days) compared with wild-type mice (161 days). The 101L mutation does not, therefore, produce any spontaneous genetic disease in mice but significantly alters the incubation time of TSE infection. Additionally, a rapid TSE transmission was demonstrated despite extremely low levels of disease-associated PrP.

A case of combined, selective, hypothalamic hypothyroidism and secondary adrenal insufficiency is described. Serum levels of thyroid-stimulating hormone (TSH), before and after thyrotropin-releasing factor (TRF) administration, were in the range generally considered to be indicative of primary, rather than secondary, hypothyroidism. Hence, the clinical usefulness of serum TSH levels to unequivocally provide an accurate distinction between primary and secondary hypothyroidism must be questioned. The paucity of clinical findings suggestive of adrenal insufficiency in this case is emphasized, and the usefulness of adrenal screening tests in hypothyroid subjects seems clear. ( Arch Intern Med 139:99-100, 1979)