The feasibility of using the EQ-5D-3L with adults with mild to moderate learning disabilities within a randomized control trial: a qualitative evaluation.

BACKGROUND: In trials incorporating a health economic evaluation component, reliable validated measures for health-related quality of life (HRQOL) are essential. The EQ-5D is the preferred measure for cost-effectiveness analysis in UK trials. This paper presents a qualitative evaluation of the use of the EQ-5D-3L in a feasibility randomised control trial with participants who had a mild- to  moderate learning disability and type 2 diabetes. METHODS: Researchers administered the EQ-5D-3L to 82 participants at baseline and 77 at follow-up. After each interview, researchers rated the ease of administering the EQ-5D-3L and made free-text entries on the administration experience. For a subset of 16 interviews, researchers audio-recorded more detailed journal entries. Ease of administration data were analysed using descriptive statistics. Free-text responses were subject to a basic content analysis. The EQ-5D-3L-related journal entries were transcribed, coded and analysed thematically. RESULTS: Over half of participants were perceived to experience difficulty answering some or all of the items in the EQ-5D-3L (60% at baseline; 54% at follow-up). Analysis of the free-text entries and audio journals identified four themes that question the use of the EQ-5D-3L in this population. The first theme is related to observations of participant intellectual ability and difficulties, for example, in understanding the wording of the measure. Theme 2 is related to the normalisation of adjustments for impairments, which rendered the measure less sensitive in this population. Theme 3 is related to researcher adaptation and non-standard administration. An overarching fourth theme was identified in that people with learning disabilities were viewed as 'unreliable witnesses' by both researchers and supporters. CONCLUSIONS: It is recommended that the EQ-5D-3L should not be used in isolation to assess health-related quality of life outcomes in trials research in adults with a learning disability. Further research is required to develop and evaluate a version of the EQ-5D appropriate for this population in trials research. It is unrealistic to expect that adjustments to the wording alone will deliver an appropriate measure: supporter or researcher involvement will almost always be required. This requirement needs to be factored into the development and administration guidelines of any new version of the EQ-5D for adults with a learning disability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41897033 [registered 21 January 2013].

Characterizing adults with Type 2 diabetes mellitus and intellectual disability: outcomes of a case-finding study.

AIMS: To report the results of a case-finding study conducted during a feasibility trial of a supported self-management intervention for adults with mild to moderate intellectual disability and Type 2 diabetes mellitus, and to characterize the study sample in terms of diabetes control, health, and access to diabetes management services and support. METHODS: We conducted a cross-sectional case-finding study in the UK (March 2013 to June 2015), which recruited participants mainly through primary care settings. Data were obtained from medical records and during home visits. RESULTS: Of the 325 referrals, 147 eligible individuals participated. The participants' mean (sd) HbA1c concentration was 55 (15) mmol/mol [7.1 (1.4)%] and the mean (sd) BMI was 32.9 (7.9) kg/m2 , with 20% of participants having a BMI >40 kg/m2 . Self-reported frequency of physical activity was low and 79% of participants reported comorbidity, for example, cardiovascular disease, in addition to Type 2 diabetes. The majority of participants (88%) had a formal or informal supporter involved in their diabetes care, but level and consistency of support varied greatly. Post hoc exploratory analyses showed a significant association between BMI and self-reported mood, satisfaction with diet and weight. CONCLUSIONS: We found high obesity and low physical activity levels in people with intellectual disability and Type 2 diabetes. Glycaemic control was no worse than in the general Type 2 diabetes population. Increased risk of morbidity in this population is less likely to be attributable to poor glycaemic control and is probably related, at least in part, to greater prevalence of obesity and inactivity. More research, focused on weight management and increasing activity in this population, is warranted.

Hydrodehalogenation of alkyl iodides with base-mediated hydrogenation and catalytic transfer hydrogenation: application to the asymmetric synthesis of N-protected α-methylamines.

We report a very mild synthesis of N-protected α-methylamines from the corresponding amino acids. Carboxyl groups of amino acids are reduced to iodomethyl groups via hydroxymethyl intermediates. Reductive deiodination to methyl groups is achieved by hydrogenation or catalytic transfer hydrogenation under alkaline conditions. Basic hydrodehalogenation is selective for the iodomethyl group over hydrogenolysis-labile protecting groups, such as benzyloxycarbonyl, benzyl ester, benzyl ether, and 9-fluorenyloxymethyl, thus allowing the conversion of virtually any protected amino acid into the corresponding N-protected α-methylamine.

Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3.

Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure-activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the ß-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing ß-methylcinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5-1 µM in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production.

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity.

Conformationally constrained peptidomimetic inhibitors of signal transducer and activator of transcription. 3: Evaluation and molecular modeling.

Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH(2), were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21), which had an IC(50) of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK), and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic.

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dDelta12,14,PGJ2.

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in older adults, remains largely incurable and novel treatments are urgently required. We previously reported powerful pro-apoptotic actions of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against Burkitts lymphoma cells. Here, we demonstrate that BEZ and MPA individually, and more potently when combined (BEZ+MPA), induce apoptosis of unsorted and CD19(+ve)-selected CLL cells and abrogate the pro-proliferative activity of CD40(L). This action was tumor cell specific, as the drugs had little impact on normal donor cells. The antiproliferative actions of BEZ+MPA were associated with the generation of reactive oxygen species (ROS), and the proapoptotic actions were associated with the generation of both ROS and mitochondrial superoxide (MSO). BEZ increased prostaglandin D(2) (PGD(2)) synthesis by CLL cells, and treatment with PGD(2) and its antineoplastic derivative 15dDelta(12,14,)PGJ(2) recapitulated BEZ-induced antiproliferative and proapoptotic actions. The PGD(2) receptor antagonist, BW868C, did not block BEZ or PGD(2) activity against CLL cells. The potency of BEZ+MPA against CLL cells mirrored that of chlorambucil, and BEZ+MPA combined with chlorambucil was more potent than either treatment alone. Given the known safety profiles of BEZ and MPA, our data warrant further investigation of their potential as novel therapy for CLL.

The unhealthy lifestyle of people with schizophrenia.

BACKGROUND: Schizophrenia has a high natural mortality of a largely environmental aetiology. There is, however, little research about possible risk factors. This study measured the diet, cigarette and alcohol use, exercise and obesity of a cohort of people with schizophrenia and compared results to general population rates. METHODS: Semi-structured interview using validated research instruments on 102 middle-aged subjects with a diagnosis of schizophrenia, living in the community. Results were compared to general population norms using standard statistical tests. RESULTS: The subjects ate a diet higher in fat and lower in fibre than the general population. They look little exercise but were not significantly more obese. They smoked heavily but drank less alcohol. Most differences remained significant after controlling for social class. CONCLUSIONS: People with schizophrenia have an unhealthy lifestyle, which probably contributes to the excess mortality of the disease. They are therefore an appropriate target group for health promotion interventions.

Seasonal affective disorder: its recognition and treatment.

This article provides an introduction to seasonal affective disorder (SAD) and outlines various therapies, including phototherapy (light therapy), used in its treatment. SAD, colloquially termed 'winter blues', is a common condition that is thought to be caused by reduced levels of daylight in winter. During this period sufferers generally feel low and may experience clinical depression. The Department of Psychiatry at the University of Southampton has an established SAD service as part of its mood disorders clinic, which was developed from a research-based clinical investigation unit set up in the early 1990s. SAD is described as a mood disorder with a seasonal pattern and has a greater prevalence in countries with greater northern latitude. The aetiology of SAD is unclear, although the most promising theory suggests the role of the neurotransmitter serotonin. SAD is difficult to treat with conventional antidepressants although there is evidence that serotonin selective reuptake inhibitors may be useful for some patients. Phototherapy (light therapy) has been used successfully by many patients although it remains controversial and difficult to obtain on the NHS.

Role of dopamine in schizophrenia and Parkinson's disease.

The neurotransmitter dopamine (DA) and the dopaminergic neurones play an important role in schizophrenia and Parkinson's disease (PD). A decrease in DA in the substantia nigra of the brain has been implicated as the cause of PD. By contrast, it is argued that a functional excess of DA or oversensitivity of certain DA receptors is one of the causal factors in schizophrenia. These factors are reflected in the treatment of both conditions; drugs aimed at increasing DA are prescribed to patients with Parkinson's disease, while most antipsychotic drugs block and reduce the effects of DA. In schizophrenia the antipsychotic effects of traditional 'neuroleptic' drugs such as chlorpromazine are highly correlated with their ability to block DA receptors and reduce the effects of DA. This article examines the role of DA in these two conditions.

People with schizophrenia and their families. Fifteen-year outcome.

BACKGROUND: This paper presents 15-year outcome data on place of residence, clinical and social morbidity and carer distress in a cohort of 179 people with schizophrenia who were living with their families in 1981-1982. METHOD: Data on morbidity and carer distress were derived from replicated patient and informant interviews using standardised research instruments. Details of residence came from patient and informant interviews corroborated by case note information. RESULTS: Thirty-nine (22%) of the original 179 patients were dead and six (3%) lost to follow-up. Of the remaining 134 patients, 74 (55%) still lived with their families, 31 (23%) lived in institutional accommodation, 26 (19%) lived alone and 3 (2%) were homeless. There was little change in the level of clinical or social morbidity or carer distress. CONCLUSIONS: These findings suggest that most people with schizophrenia who live with their families remain significantly disabled by their illness, while their carers suffer ongoing distress. Mental health services should seek to support families who want to care for relatives with schizophrenia. Appropriate alternative accommodation must be provided when family care is not possible.

Do not resuscitate: an ethical dilemma for the decision-maker.

Since its introduction in the 1960s, cardiopulmonary resuscitation (CPR) has been universally available to all hospital patients unless the consultant in charge has specified a 'do not resuscitate' (DNR) order. The public perception of CPR has tended to be one of overoptimism, but this is not matched by the low survival to discharge ratio of approximately 1:10. In addition, there is the risk of prolonging suffering, compared with the quick and relatively painfree alternative offered by cardiac arrest. Decisions about resuscitation pose many ethical dilemmas for those involved and should take into consideration the patient's wishes, prognosis and quality of life.

The side effect burden associated with drug treatment of panic disorder.

This article reviews the incidences of side effects in placebo-controlled clinical trials of drug therapy in patients with panic disorder. We performed a MEDLINE search for placebo-controlled studies in panic disorder that reported the incidences of side effects, published in English language, peer-reviewed journals between 1992 and 1997. We discuss the side effects experienced by patients receiving tricyclic antidepressants, serotonin selective reuptake inhibitors, and benzodiazepines, the drug classes most commonly prescribed for the treatment of panic disorder. Available evidence suggests that, with respect to tolerability, serotonin selective reuptake inhibitors are the most favorable treatment choice for patients with panic disorder.

Effects of antidepressant drugs on sexual function.

Adequate sexual expression is an essential part of human relationships, enhancing quality of life and providing a sense of physical, psychological and social well-being. Unfortunately, depression is associated with impairments of sexual function and satisfaction. These problems can worsen a quality of life that is already reduced by the effects of depressive illness. The existing antidepressant drugs are far from ideal, most having adverse effects on sexual function. Unfortunately, the exact incidence of sexual dysfunction during treatment with many antidepressants is not known. Disturbances of sexual interest and performance will only be detected in a reliable fashion when systematic enquiries are made during the course of the standard clinical interview. Growing awareness of the adverse effects of many antidepressants on sexual function has led to some re-evaluation of the earlier claims for the good tolerability of many of the newer drugs. There is a clear need for further well-designed controlled studies of the effects of antidepressants on sexual function, so that this aspect of the tolerability of differing drugs can be assessed more reliably. (IntJ Psych Clin Pract 1997; 1: 47-58).

The role of cigarettes and nicotine in the onset and treatment of ulcerative colitis.

Epidemiological evidence suggests that ulcerative colitis is a disease of nonsmokers, while Crohn's disease is a disease of smokers. The relative risk of developing ulcerative colitis is not only greater in nonsmokers, in addition there appears to be a rebound effect in smokers who quit, with the heaviest (ex-)smokers increasing their relative risk of the disease the most. This factor poses an ethical dilemma for health professionals giving advice on stopping smoking, which may thus have a serious detrimental effect on the health of some patients. Nicotine is believed to be the pharmacological ingredient of tobacco that is responsible for this beneficial effect and several clinical trials using nicotine have demonstrated it to be an effective therapeutic agent in the treatment of ulcerative colitis. Although the aetiology of ulcerative colitis is unclear, current research using nicotine-based products has produced some interesting clues, together with the possibility of some form of therapeutic treatment based on nicotine administration.

Does nicotine have beneficial effects in the treatment of certain diseases?

Although tobacco smoking has long been associated with diseases of the lungs and cardiovascular system, numerous studies have demonstrated a negative association between tobacco smoking and ulcerative colitis, and the neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). The evidence suggests that nicotine--the main pharmacologically active ingredient of tobacco--appears to be responsible for this effect. Pure nicotine has no known carcinogenic properties and can be administered in numerous ways including transdermal patches and tablets. As a therapeutic agent, its association with tobacco can be likened to morphine and opium smoking. There is ample clinical evidence to suggest that nicotine could be beneficial in the treatment of some patients with diseases. Pharmacologically, nicotine acts on cholinergic (nicotinic-specific) receptors which are depleted in AD and PD. Nicotinic receptors also interact closely with several neurotransmitters including dopamine, which is implicated in both PD and Gilles de la Tourettes's syndrome. There is no doubt that tobacco smoking can be harmful and no-one should be encouraged to smoke. However, although nicotine has many harmful side-effects, it may have therapeutic value or at the very least be a useful tool for future drug development.

Quitting smoking could increase your risk of surgery for ulcerative colitis!

There is ample evidence to demonstrate that ulcerative colitis is a disease of non-smokers and ex-smokers. Cigarette smoking appears to convey some protection against the disease and can induce a remission in ex-smokers who recommence while they are in a relapse. Nicotine is believed to be the pharmacological agent responsible for this effect, although its mode of action remains a puzzle.