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This study aimed to investigate how people manage their sexuality when practicing naturism in the United Kingdom (UK). Thirty-nine self-identified naturists from across the UK were interviewed. Sexuality, when practicing naturism, was found often to be suppressed through the use of rules, geographical isolation and thoughts and behaviour. Some participants found ways of exploring and enjoying their sexuality by keeping feelings hidden and/or seeking out more sympathetic naturist environments. Naturist environments may offer a unique space in which to explore aspects of our sexuality that are currently pathologised, criminalised or commercialised. This has important implications for sexual health policy and promotion.

The receptor tyrosine kinase ErbB2 (HER2/neu) is overexpressed in ˜30% of breast cancers and is associated with poor prognosis and an increased likelihood of metastasis. Clinical treatments such as trastuzumab are effective in less than 35% of women diagnosed as ErbB2-positive, highlighting the necessity of searching for novel targets and alternative therapies. Herein, a proteomic screening strategy combining quantitative-based gel electrophoresis and MS was used to compare the protein expression of 48 normal human breast and tumour tissues differing in ErbB2 expression and lymph node status. The aim was to identify proteins associated with the aggressive phenotype of ErbB2-positive breast cancer which could be potential biomarkers of the disease as well as therapy targets. In total, 177 protein isoforms (107 gene products) differentially expressed between tissue groups were identified. Immunohistochemical staining of a tissue-microarray was used for validation of selected protein candidates. We found that expression of HSP90α, laminin and GSTP1 significantly correlated with ErbB2 expression, while others such as AGR2, NM23H1 and Annexin 2 were overexpressed in greater than 40% of tumours. Finally, knocking-down the expression by RNA interference of three candidates, AGR2, Transgelin2 and NM23H1 resulted in an enhanced invasive capacity of MDA-MB435 cells. These data support the involvement of these targets in tumour progression and identify them as novel biomarkers of the disease., (Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The role of donor lymphocyte infusion (DLI) in the management of lymphoid malignancies after allogeneic stem cell transplantation (SCT) has not been clearly characterized. There is emerging evidence pointing to the effectiveness of this approach, particularly in patients with low-grade disease, although to date this has been reported only in small numbers of patients, and thus the utility of this treatment remains uncertain. A total of 28 patients with low-grade lymphoid malignancies previously treated with allogeneic SCT received a total of 68 infusions of donor lymphocytes. The diagnoses were indolent non-Hodgkin lymphoma (NHL; n = 23) and transformed NHL (n = 5), and the indications for DLI were progressive disease with or without mixed chimerism (MC) (n = 17) and persistent MC alone (n = 11). Escalating doses of cells were administered in the absence of graft-versus-host disease (GVHD) or continued disease progression, until stable full donor chimerism or disease response were achieved. The cumulative response rates after DLI to treat progressive disease and persistent MC were 76.5% and 91.6%, respectively. The major toxicity resulting from the use of donor lymphocytes was GVHD. The cumulative incidence of acute grade II-IV disease was 15%, and that of extensive chronic disease was 31%; there were no deaths resulting from GVHD. Seven patients had graft-versus-lymphoma responses without significant GVHD. These data support the existence of a clinically significant graft-versus-tumor effect in indolent NHL and suggest that this is an effective treatment for progressive disease after allogeneic SCT.

Setting: Patient support organisation (Myeloma UK) and Hospital Myeloma Clinic., Type of Study: Case review of two patients, one whose treatment is funded by a private insurance company in the UK, and the other who is funded by the National Health Service (NHS) and questionnaire survey of 51 haematologists from Myeloma UK database., Results: The treatment options available for private patients with myeloma in the UK are broader and more in line with national and international practice than are options available to UK NHS patients. 22/41 (54%) of respondents had received refusals to fund bortezomib by NHS funding agencies; all the rejections had been from Primary Care Trusts in England, which are governed by guidance issued from a different regulator than the other UK countries and subject to divergent local funding arrangements; 19/46 (41%) felt that it was currently (May 2007) more difficult to obtain funding approval for one treatment, bortezomib, than in September 2006, when it received a negative recommendation from the National Institute for health and Clinical Excellence and 15/17 doctors who prescribe on the NHS and privately felt it was easier to obtain bortezomib for a private patient than an NHS patient in the UK., Conclusion: The current funding arrangements for new drugs to treat myeloma in the UK are inequitable and do not lend themselves to achieve the best possible outcome for patients.

The objective of this study was to establish if diabetes in the presence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in the amounts of 8-epi-PGF2alpha (IP) and its metabolites including 2, 3-dinor-8-epi-PGF2alpha (dinor-IP) and 2, 3-dinor-5, 6 dihydro-8-epi-PGF2alpha (dinor-dihydro-IP) in urine. Mass spectrometric separation showed that excretion of IP was similar in the PN + /CAN- and PN+/CAN+ groups but higher than in the PN-/CAN- group (n = 103, 22 and 60, respectively; P < 0.05). By contrast, excretion of dinor-IP or dinor-dihydro-IP were similar in the PN-/CAN- and PN+/CAN- groups but higher than in PN+/CAN+ group. Correlations were obtained between IP and dinor-IP or dinor-dihydro-IP (r = 0.30; P < 0.001 and r = 0.31; P < 0.001, respectively). A significant association was also observed between dinor-IP and dinor-dihydro-IP (r = 0.48; P < 0.001). In conclusion, these biomarkers should prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of diabetic complications.

Background and Objectives: Total antioxidant capacity (TAC) reflects the capacity of plasma, or other body fluid, to resist oxidation. The aim of the present study was to assess the prognostic value of Pholasin as a probe for the determination of plasma TAC., Design and Methods: Plasma samples either oxidised using the free radical generator 2'-azobis-(2-amidinopropane) hydrochloride (AAPH) at 60 degrees C for 180 min or obtained from diabetic (type 1 and type 2) patients (n = 61 and 124, respectively) with or without polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) and control subjects (n = 70) were analysed for TAC status. TAC was assessed using two versions of Analysis By Emitted Light (ABEL) tests including quenching of Pholasin chemiluminescence (QPC) with peroxynitrite (ONOO(-)-QPC) and with superoxide anion (O2(-)-QPC)., Results: The utilisation of AAPH to induce peroxyl radical mediated plasma oxidation produced a significant decrease in TAC as assessed by ONOO(-)-QPC and O2(-)-QPC assays in a time-dependent manner. Type 1 and type 2 diabetic patients without PN and/or CAN had lower TAC (ONOO(-)-QPC and O2(-)-QPC) than in control subjects. Further alterations in TAC were noted in the presence of PN and/or CAN. Correlations were found between TAC (ONOO(-)-QPC and O2(-)-QPC) values on duration of diabetes and neurological impairment score-lower limb (NIS-LL) in type 1 diabetic patients., Conclusions: This study has established that the ONOO(-)-QPC and O2(-)-QPC versions of the ABEL test fulfil the criteria in terms of simplicity, sensitivity and reliability for the measurement of plasma TAC. These biomarkers may prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of complications in clinical conditions associated with oxidative stress.

Substantial challenges remain in our understanding of fibrotic lung diseases. Nowhere is this more true than in the elucidation and verification of the pathogenetic basis upon which they develop. Scientific progress, most recently in the field of experimental therapy, has relied closely on interpreting data derived from animal modeling. Such models are used to identify the cellular interactions and molecular pathways involved in lung tissue repair and fibrosis. Over the coming years, the significance of new discoveries will continue to be evaluated using the in vivo analysis of animal models substituting for patients with actual pulmonary fibrosis. The commonest strategy to induce experimental pulmonary fibrosis is by directly administering a profibrotic agent to either wild-type animals or those that bear a specific genetic modification. The creation of new models has been greatly enhanced by the availability of stem cell lines and methods for introducing genetic mutations into these cells. Despite an increasing choice of models, there are still good reasons to continue adapting and using one of its earliest examples, the bleomycin model, in post-genomic pulmonary fibrosis research. A brief review of the exacting requirements of such research will place the strengths of this particular model in perspective.

Increased circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) are seen in several pathological conditions associated with vascular disease. TNF-alpha induces the synthesis of endothelin-1 (ET-1), a potent vasoconstictor, by the endothelium. However, there is profound vasodilatation in sepsis, where circulating levels of both ET-1 and TNF-alpha are elevated. The details of the interaction between ET-1 and TNF-alpha and the predominant resulting haemodynamic effect in healthy humans are unclear. The aim of the present study was to determine the effects of intra-arterial TNF-alpha on ET-1 spillover, vascular tone and endothelial function in the healthy human forearm. Brachial arterial and deep venous blood samples, forearm plasma flow measurements and blood flow responses to acetylcholine and sodium nitroprusside were obtained in six healthy subjects before and during a 6 h infusion of TNF-alpha into the brachial artery. Forearm blood flow was significantly greater than baseline during exposure to TNF-alpha [median (lower quartile, upper quartile): baseline, 2.6 (2.1, 2.8) ml.min(-1).100 ml(-1); TNF-alpha, 4.6 (4.5, 5.1) ml.min(-1).100 ml(-1); P <0.05]. The rate of release of ET-1 was significantly greater than baseline after 30 and 260 min of TNF-alpha infusion [median (lower quartile, upper quartile): baseline, 0.8 (0.6, 1.1) pg.min(-1).100 ml(-1); 30 min, 2.4 (1.9, 3.2) pg.min(-1).100 ml(-1); 260 min, 4.1 (3.1, 4.2) pg.min(-1).100 ml(-1); P <0.05]. The vasodilatory response to acetylcholine was diminished during TNF-alpha infusion, whereas the response to sodium nitroprusside remained unchanged. We thus demonstrate for the first time that local TNF-alpha increases ET-1 spillover from the human forearm and impairs endothelium-dependent vasodilatation. In spite of this action, TNF-alpha has a vasodilatory effect, resulting in an increase in forearm blood flow.

Unlabelled: Hextend is a new plasma volume expander containing 6% hydroxyethyl starch (HES) in a physiologically balanced medium of electrolytes, glucose, and lactate (weight average, molecular weight 670 kDa, molar substitution 0.75). This open-label study was designed to investigate the pharmacokinetic and pharmacodynamic profiles of Hextend in 21 healthy volunteers. We infused Hextend 10 ml/kg IV over 20 min and determined serum concentrations of HES at selected intervals over a 7-day period. Serum concentration-time curves indicated mixed pharmacokinetic behavior reflecting a two-compartment model in most subjects. The median serum half-life over 7 days was 38.2 h. The balanced formulation of the suspension medium did not seem to affect distribution, metabolism, or excretion of Hextend when compared with similar HES. Pharmacodynamic analysis demonstrated decreases in some plasma components compatible with the infusion of that volume of fluid and the duration of plasma volume expansion. Other plasma components remained unchanged, reflecting the benefit of a balanced electrolyte solution. Hemodilution was observed for 24--48 h after short-term infusion of Hextend. Some hemostatic indices showed moderate changes, and serum amylase demonstrated a temporary increase. Our study suggested that Hextend has pharmacokinetic and pharmacodynamic profiles that are similar to those of other HES., Implications: Hextend is a new plasma volume expander containing 6% hydroxyethyl starch in a physiologically balanced medium. This open-label volunteer study demonstrated that it has pharmacokinetic and pharmacodynamic profiles similar to those of established HES.

Background: Identification of HLA class I-restricted CMV epitopes, and the subsequent synthesis of HLA class I-peptide tetrameric complexes, have provided investigators with an important tool for visualising and quantifying the precise in vivo CTL response to CMV reactivation following stem cell transplantation. In conjunction with PCR-monitoring of the viral load, the magnitude and dynamic of the host's specific CD8(+) T cell response to viral replication can be studied., Methods: CMV peptide epitopes can be identified be searching the CMV-pp65 antigen for HLA class I allele binding motifs, by testing their binding affinity and ability to generate CTLs, and by screening for CTL responses in as many individuals as possible to assess their general applicability for monitoring large number of patients. HLA tetramers are synthesized by refolding recombinant class I heavy chains and beta(2)m with CMV-pp65(495-503) peptide. After biotinylation and tetramerisation to PE-conjugated streptavidin, they are used to stain CD8(+) T cells taken from patients at different time points after SCT., Results: The T-cell mediated immune response is mainly directed against epitopes derived from the CMV tegument protein pp65. CMV-specific CTL's confer protection against CMV reactivation above a threshold level of 10(7) to 2 x 10(7)/L. CMV reactivation is required to stimulate CTL responses. Transfer of CMV immunity from seropositive donors is associated with better outcome and steroids suppress the Ag-specific immune response., Discussion: Initial studies with CMV-specific HLA class I tetramers have helped to define the nature of anti-CMV T cell response in SCT patients and to determine a threshold CTL level required for controlling CMV reactivation. Monitoring patients with HLA-tetramers should therefore allow clinicians to predict and assess the risk of reactivation and to balance the risks and benefits of early anti-viral treatment, thereby avoiding the hazards of anti-viral prophylaxis. HLA-tetramers can also be used to isolate antigen-specific cells for further in vitro expansion and transfer to patients for antiviral immunotherapy. The threshold level determined from patient monitoring can be used as a guide for estimating an effective target cell dose.

Assessment of clinical skills in addition to factual knowledge has become part of the examination system in both undergraduate and postgraduate examinations. There is an increasing interest in the concept of competence and how it can be measured, particularly for the process of revalidation of practitioners. The Objective Structured Clinical Examination (OSCE) has been introduced for the assessment of clinical skills into postgraduate anaesthetic examinations in the United Kingdom. As with any examination, the issues regarding setting a standard are under continual review. The application of this exam format to the measurement of competency as well as skills has been the subject of scrutiny during the period reviewed. The literature suggests that competence is a much more complex construct than skill and that OSCE exams will be a contributory part but more work is required to establish assessment methods which will produce a global rating of competence. The role of the OSCE format in education as well as assessment has been examined and it is suggested that formative assessment can be made, and peer review learning brought about using an OSCE performed in teams.

In the industrialised world, type 1 diabetes rarely results in death from ketoacidosis. The same is not true in many countries in the developing world where insulin availability is intermittent, and insulin may not even be included on national formularies of essential drugs. The life expectancy for a newly diagnosed patient with type 1 diabetes in some parts of Africa may be as short as 1 year. The World Bank has identified 40 highly indebted poor countries (HIPCs) whose national debt substantially exceeds any possibility of repayment without heavy impact on health and social programmes. Incidence and prognosis of type 1 diabetes in HIPCs are lower than in most industrialised countries, and 0.48% of the world's current use of insulin is estimated to be sufficient to treat all type 1 diabetic patients in these countries. A proposal is made for the major insulin manufacturers to donate insulin, at an estimated cost of US$3-5 million per year, as part of a distribution and education initiative for type 1 diabetic patients in the HIPCs. No type 1 diabetic patient in the world's poorest countries need then die because they, or their government, cannot afford insulin.

In the UK there are numerous schemes whereby general practitioners can prescribe exercise programmes, usually based in leisure centres. Of the factors that discourage adherence to such programmes in the USA, cost has proved important. We collected demographic and questionnaire data from 152 inner-London patients (108 women, 44 men) before they started an exercise programme on a National Health Service prescription, and analysed the results according to whether they dropped out of the programme (78%) or not. Use of logistic regression revealed only one previous barrier to exercise, 'not knowing about local exercise facilities', as a significant positive determinant of adherence (adjusted odds ratio 3.51, 95% confidence interval, 1.04 to 11.86). For 'lack of money' patients were more likely to drop out of the programme (adjusted odds ratio 0.25, 95% CI 0.07-0.85). The very low cost of participation in this scheme, did not encourage adherence, particularly by those who had cited 'lack of money' as a previous barrier. The case of making prescribed exercise free or even low-cost remains unproven.

Colorectal cancer is a common malignancy which is occurring with increasing incidence in the elderly. As the age of the population increases so the importance of this malignancy will gradually increase. In addition a high proportion of elderly patients present with intestinal obstruction secondary to colorectal cancer and therefore the management of intestinal obstruction in the elderly becomes an important surgical consideration. This review discusses the management of colorectal cancer in patients over the age of 75 in both the elective and emergency situations with particular reference to screening, surgical management and the use of adjuvant therapy.

Background: The London Academic Training Scheme (LATS) provides a 1-year training programme in research methods and teaching for GPs who have recently finished vocational training. This paper describes an adult educational approach to learning about research methods through teaching as part of the LATS trainees' weekly academic programme., Objective: We aimed to provide and evaluate a course exploring research methodologies used in primary care by a three-step approach to learning, with trainees taking the main role as teachers., Method: Trainees on the LATS programme met for one afternoon each week for one term. During alternate sessions a pair of trainees would deliver a whole afternoon's seminar on one aspect of primary care research methodology. The teaching of each session was evaluated by the whole group, by academic supervisors and by experts., Results: Sessions were scored by participants for content, style of presentation, educational value and enjoyment on a seven-point rating scale where 1 = no value, 4 = neutral and 7 = very valuable. All sessions scored above 4 and usually above 5 for each aspect. Open comments collected showed that trainees greatly appreciated this self-directed approach to learning and teaching., Conclusion: The active involvement of learners as teachers is a practical and rewarding means of using adult educational principles in providing an academic programme.