US Army basic combat training alters the relationship between body mass index and per cent body fat.

INTRODUCTION/BACKGROUND: As a proxy for adiposity, body mass index (BMI) provides a practical public health metric to counter obesity-related disease trends. On an individual basis, BMI cannot distinguish fat and lean components of body composition. Further, the relationship between BMI and body composition may be altered in response to physical training. We investigated this dynamic relationship by examining the effect of US Army basic combat training (BCT) on the association between BMI and per cent body fat (%BF). METHODS: BMI and %BF were measured at the beginning (week 1) and end (week 9) of BCT in female (n=504) and male (n=965) trainees. Height and weight were obtained for BMI, and body composition was obtained by dual X-ray absorptiometry. Sensitivity and specificity of BMI-based classification were determined at two BMI thresholds (25 kg/m2 and 27.5 kg/m2). RESULTS: A progressive age-related increase in fat-free mass index (FFMI) was observed, with an inflection point at age 21 years. In soldiers aged 21+, BMI of 25.0 kg/m2 predicted 33% and 29% BF in women and 23% and 20% BF in men and BMI of 27.5 kg/m2 predicted 35% and 31% BF in women and 26% and 22% BF in men, at the start and end of BCT, respectively. Sensitivity and specificity of BMI-based classification of %BF were poor. Soldiers below BMI of 20 kg/m2 had normal instead of markedly reduced %BF, reflecting especially low FFMI. CONCLUSIONS: BCT alters the BMI-%BF relationship, with lower %BF at a given BMI by the end of BCT compared with the beginning, highlighting the unreliability of BMI to try to estimate body composition. The specific BMI threshold of 25.0 kg/m2, defined as 'overweight', is an out-of-date metric for health and performance outcomes. To the extent that %BF reflects physical readiness, these data provide evidence of a fit and capable military force at BMI greater than 25.0 kg/m2.

Increasing Symptoms in Irritable Bowel Symptoms With Ingestion of Galacto-Oligosaccharides Are Mitigated by α-Galactosidase Treatment.

OBJECTIVES: Galacto-oligosaccharides (GOS) are dietary FODMAPs (fermentable carbohydrates) associated with triggering gastrointestinal symptoms in patients with irritable bowel syndrome (IBS). This randomized, double-blind, placebo-controlled, cross-over trial aimed to assess whether oral α-galactosidase co-ingestion with foods high in GOS and low in other FODMAPs would reduce symptoms. METHODS: Patients meeting the Rome III criteria for IBS who were hydrogen-producers on breath testing were recruited. Participants were treated with full-dose (300 GALU (galactosidic units) α-galactosidase) and half-dose enzyme (150 GALU α-galactosidase), and placebo (glucose) in a random order with ≤14 days washout between arms. Following a 3-day low FODMAP run-in period, participants consumed provided diets high in GOS for a further 3-days. Gastrointestinal symptoms were measured daily using a 100 mm visual-analogue-scale, and breath samples taken hourly on the second last day with hydrogen content analysed as area-under-the-curve. RESULTS: Thirty-one patients with IBS (20 IBS-D, 4 IBS-C, 7 IBS-M) completed the study. The addition of high GOS foods resulted in a significant increase in overall symptoms with 21 patients exhibiting GOS-sensitivity (>10 mm increase for overall symptoms). Of those, full-dose enzyme reduced overall symptoms (median 24. 5(IQR 17.5-35.8) vs. 5.5(1.5-15.0) mm; P=0.006) and bloating (20.5(9.5-42.0) vs. 6.5(2.0-15.8); P=0.017). Breath hydrogen production was minimal with no differences seen between placebo and full-dose (P=0.597). CONCLUSIONS: Oral α-galactosidase taken with high GOS foods provides a clinically significant reduction in symptoms in GOS-sensitive individuals with IBS. This strategy can be translated into practice to improve tolerance to high GOS foods as an adjunct therapy to the low FODMAP diet.

Phosphorylation of zinc channel ZIP7 drives MAPK, PI3K and mTOR growth and proliferation signalling.

Zinc is an essential trace element participating in diverse biological processes. Cellular zinc levels are strictly controlled by two families of transport proteins: ZIP channels (SLC39A) and ZnT transporters (SLC30A). ZIP channels increase cytosolic zinc levels by importing zinc into cells or releasing zinc from intracellular stores such as the ER. Among all the 14 human members of the ZIP family, ZIP7 is a gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation on residues S275 and S276, resulting in activation of multiple downstream pathways. Employing site-directed mutagenesis, we investigated the importance of these individual serine residues as well as other predicted phosphorylation sites on ZIP7, showing that all four sites are required for maximal ZIP7 activation. Using phosphor-protein arrays, we also discovered the major signalling pathways that were activated as a direct result of ZIP7-mediated zinc release from intracellular stores. These data reveal the role of ZIP7-mediated zinc release from intracellular stores in driving major pathways, such as MAPK, mTOR and PI3K-AKT, involved in providing cell survival and proliferation and often over activated in cancer.

Patients' practices and experiences of using nebuliser therapy in the management of COPD at home.

BACKGROUND AND AIM: How patients use their nebulisers at home is vital to ensure effective treatment and optimal health outcomes for patients with chronic obstructive pulmonary disease (COPD). The aim of the study was to identify the practicalities and problems associated with nebuliser use by patients with COPD at home, which may impact on the safety and effectiveness of therapy. DESIGN AND SETTING: A cross-sectional descriptive study in which participants were recruited from two levels of care: primary care, involving 38 GP practices in North West London, and intermediate care with a major acute hospital. METHOD: In-depth interviews were conducted with a representative sample of 50 patients with COPD using nebulisers in their home, recruited from general practice populations and at hospital discharge. A checklist was used to record activities and patients demonstrated use of their nebuliser. Qualitative procedures were employed to identify the range of problems experienced with nebuliser use. RESULTS: A wide range of practical issues was identified at all stages: problems prior to nebulisation: setting up equipment, lack of instructions, manual dexterity and time required. Problems during medication administration: inhalation technique, duration of nebulisation and understanding how to achieve optimal efficacy. Problems post-administration: inadequate cleaning of nebuliser components, access to accessories and use of damaged parts or self-repairs. Other problems included noise, weight and non-portability of equipment. CONCLUSIONS: Patients with COPD using nebulisers at home experienced problems with all aspects, many of which may be anticipated to compromise clinical outcomes. Healthcare providers should be aware of these problems to effectively support patients with COPD with the use of their nebulisers at home.

Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation.

A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum--including the nucleus accumbens (NAc)--impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc.

Experiences of children/young people and their parents, using insulin pump therapy for the management of type 1 diabetes: qualitative review.

WHAT IS KNOWN AND OBJECTIVE: Advances in medical technology have made insulin pumps an attractive treatment option for patients with type 1 diabetes and in particular for children and young people. Previous studies have accounted the experiences and views of children/young people and their parents for the use of the injection therapy, but very few have focused on the use of insulin pumps. The objective of this review was to identify studies that explore the experiences of children/young people and their parents on the transition from injections to insulin pump therapy, in the context of their social life. METHODS: A systematic literature search was conducted, and six studies meeting the inclusion and exclusion criteria were identified. RESULTS: Views and perspectives from the studies identified mainly focused on: introduction to the pump; reasons for the transition to pump therapy; advantages and disadvantages of this treatment option; and impact on quality of life (QoL). Parents and/or children reported that they learned about pump therapy either formally from a healthcare professional or informally from a friend or the internet. Many reasons were identified for the transition, the most important being the pursuit of stable and controlled blood sugar levels and the desire for a more flexible lifestyle. Participants highlighted the advantages of insulin pumps in terms of improved diabetes control. Moreover, there was a positive impact on the QoL, as insulin pumps provided children greater flexibility in lifestyles especially with regards to meals and socialization. In contrast, psychosocial issues such as pump visibility and physical restrictions were highlighted as disadvantages. Issues such as day-to-day management were also discussed. WHAT IS NEW AND CONCLUSION: Exploring children/young people's perspectives on the use of pump therapy for managing their diabetes, and parental reflections in caring for those children is important as it provides evidence informing policy for the wider implementation of this technology in the management of diabetes in children. However, the review revealed that there is a scarcity of data in this area and that further research is needed.

Insulin pumps: from inception to the present and toward the future.

As an alternative to the usual insulin injections, insulin pumps have been introduced as an advanced method of insulin delivery for managing type 1 diabetes mellitus patients. This review documents the history of insulin pump development and the production of 'smart pumps' that offer patients greater dosing accuracy, flexibility, and ease of use. This has resulted in an increase in the number of insulin pump users around the world. This paper also provides a comprehensive survey of the pumps currently available on the market and their specifications. Unique features of each product and the drawbacks are addressed in the review. The future direction of insulin pump development is targeted toward closing the loop, to allow feedback control between an insulin pump and a glucose sensor, and hence finer adjustment of insulin delivery rates as required.

Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation.

Zinc, which is essential for many cellular processes, is controlled by zinc transporters and through buffering by metallothioneins and glutathione. Although zinc is increasingly implicated in disease states, little is known about how zinc regulates cellular biochemical pathways. Recent seminal articles have revealed discrete zinc-trafficking pathways that are linked to signalling cascades, particularly those involving protein phosphatase inhibition and downstream activation of mitogen-activated protein kinases and tyrosine kinases. Here, we discuss the mechanisms of cellular zinc homeostasis, and we propose an important role for the zinc transporter solute carrier family 39, member 7 (SLC39A7; commonly referred to as ZIP7). ZIP7 releases zinc from the endoplasmic reticulum and might be required for tyrosine kinase activation. These observations position ZIP7 at a critical node in zinc-mediated tyrosine kinase signalling and suggest that this protein might form a novel target for diseases such as cancer where prevention of tyrosine kinase activation would be therapeutically advantageous.

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells.

Acquired resistance to endocrine therapies presents a major obstacle to the successful treatment of breast cancer patients. Previously, we have shown that acquisition of resistance to tamoxifen in breast cancer cells is accompanied by an elevation in Src kinase activity which promotes an aggressive, invasive phenotype in vitro. Here, we have explored the potential therapeutic effects of combining Src inhibition with anti-oestrogen treatment on the development of endocrine insensitivity in breast cancer cells. Treatment of MCF7 and T47D cells with tamoxifen alone resulted in an initial growth inhibitory phase followed by the eventual development of tamoxifen resistance together with an elevation of Src kinase activity, which was central to their increased invasive capacity. Chronic exposure of both cell types to the Src inhibitor, AZD0530, as a monotherapy resulted in outgrowth of AZD0530-resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasive nature. Treatment of both MCF7 and T47D cells with AZD0530 in combination with tamoxifen resulted in a reduction of Src activity together with inhibition of focal adhesion kinase phosphorylation and a complete abrogation of their in vitro invasive behaviour. Furthermore, combination therapy significantly suppressed expression of cyclinD1 and c-myc and prevented cell proliferation and the subsequent emergence of a resistant phenotype, with total cell loss occurring by 12 weeks. These data demonstrate that pharmacological targeting of Src kinase, in conjunction with antihormone therapies, effectively prevents antihormone resistance in breast cancer cells in vitro and suggests a potential novel therapeutic benefit of Src kinase inhibitors clinically.

Medicines for chronic illness at school: experiences and concerns of young people and their parents.

BACKGROUND AND OBJECTIVE: Access to medicines by young people with chronic conditions during the school day and suitable environments and support in the administration of a range of dosage forms may be required for optimal clinical management. Whilst Government policy emphasizes that children and young people with chronic illness should be able to lead as normal lives as possible, there is only limited evidence on the experiences and concerns of young people and their parents regarding the use of medicines at school and the impact on school life. The objective of this study was to examine the experiences and concerns of young people with chronic conditions, and their parents/carers, in managing medication at school. METHODS: Data were gathered in audio-recorded face-to-face semi-structured interviews with 27 young people (5-18 years) and their parents attending out-patient clinics at a major London teaching hospital. Open-ended questions provided an opportunity for participants to describe experiences and views in the context of their activities, priorities and concerns and enabled a qualitative analysis. RESULTS AND DISCUSSION: The findings indicated that storage and access of medicines did not present major problems for young people receiving regular medication. However, those receiving medication on a 'when required' basis reported barriers to access. The most common concern regarding taking medication was lack of privacy, which sometimes led to non-adherence. Adverse effects of medication were highlighted as a cause of both non-adherence and poorer school performance. Extracurricular activities such as school trips were not viewed as presenting a problem by those who were interviewed. However, this was often because young people and their families devised their own strategies regarding the use of medicines that did not depend on the input of staff. There was wide variation in responses about the support young people received from school staff, with evidence of helpful and unhelpful practice. The potential benefits of liaison between schools and health professionals to assist schools in their support of students with their medicines were highlighted. CONCLUSION: This study has identified medication-related issues from the perspective of young people and their parents, indicating ways in which their needs might be served more sensitively and effectively.

The inflammatory effect of cardiopulmonary bypass on leukocyte extravasation in vivo.

OBJECTIVE: Extravascular trafficking of leukocytes into organs is thought to play a major role in the pathophysiologic mechanisms of the inflammatory response to cardiopulmonary bypass, yet leukocyte extravasation is difficult to study clinically. Here we have tested the hypothesis that leukocyte emigration into skin blisters can provide a way to monitor the inflammatory effect of cardiopulmonary bypass that allows testing of anti-inflammatory interventions (exemplified by aprotinin). METHODS: Patients undergoing primary elective coronary artery bypass grafting (n = 14) were randomized into 2 equal groups to receive saline infusion during cardiopulmonary bypass (control group) or high-dose aprotinin. Experimental skin blisters (in duplicate) were induced on the forearm by means of topical application of the vesicant cantharidin, and blister fluid was sampled at 5 hours postoperatively. Inflammatory leukocyte subsets in blister fluid were analyzed by means of flow cytometry by using expression of CD11b and CD62L as a phenotypic marker of activation. RESULTS: In the control group of patients, cardiopulmonary bypass surgery triggered a 381% increase in leukocyte extravasation into the skin compared with reference blisters carried out before surgical intervention, with neutrophil (P = .014), monocyte (P = .014), and eosinophil (P = .009) levels all statistically significantly increased. In the aprotinin group there was no statistically significant increase during cardiopulmonary bypass surgery in any inflammatory leukocyte subset. The activation phenotype of extravascular leukocytes was not significantly altered between surgical groups. CONCLUSIONS: This study introduces the cantharidin blister technique as a powerful new research tool for analyzing the inflammatory effect of cardiopulmonary bypass in vivo. It has provided detailed molecular insight into the extravascular leukocyte population during cardiopulmonary bypass. Although aprotinin blocked cardiopulmonary bypass-dependent extravasation of leukocytes, there was no change in their CD11b/CD62L activation status. The cantharidin skin test thus represents a novel research tool for evaluating future anti-inflammatory interventions in cardiothoracic surgery.

Prospective audit of colonoscopy quality in Kent and Medway, UK.

AIM: To compare the quality of colonoscopy in the Kent and Medway Strategic Health Authority with national standards and previous audits. METHOD: A prospective 12-month audit of colonoscopy quality as assessed by number of procedures performed, total colonoscopy rates, sedation usage, and complications. Data were collected by 7 endoscopy units on 5905 colonoscopies performed by 62 colonoscopists. The endoscopy unit nurses, as opposed to the colonoscopists, verified that colonoscopy was total. RESULTS: Seven doctors stopped performing colonoscopy during the study period. Thirty-nine of 55 colonoscopists (71 %) achieved total colonoscopy in at least 90 % of cases; 12 (22 %) completed colonoscopy in 80 - 89 % of their cases and 4 (7 %) in 79 % or less of their cases. Seventy-nine percent of colonoscopists used sedation in accordance with British Society of Gastroenterology (BSG) guidelines. Only 22 of 55 (40 %) of colonoscopists performed more than 100 colonoscopies during the 12-month audit period. Reported complications were below expected levels. CONCLUSION: In our study almost one-third of colonoscopists did not achieve colonoscopy completion rates of at least 90%, and less than half performed more than 100 colonoscopies during the 12 month study. Adherence to quality standards appears to be inadequate.

Influence of socioeconomic status on survival after primary aortic or mitral valve replacement.

OBJECTIVES: We sought to evaluate whether socioeconomic status influences outcome after first-time single aortic or mitral valve replacement. SETTING: National Heart Valve registry. DESIGN AND PATIENTS: Between 1 January 1986 and 31 December 2001, 51 844 consecutive patients who underwent primary aortic or mitral valve replacement were registered on the United Kingdom (UK) Heart Valve Registry. Data included age, gender, valve position, type of valve implant, postcode, follow-up time, date and cause of death. The Carstairs deprivation score (1991 Census data for the UK) was used to stratify cases by level of social deprivation according to postcodes. RESULTS: Both 30-day and 1-year survival/mortality rates were similar across all socioeconomic levels. However, long-term survival rate (up to 15 years) was significantly higher in the least deprived socioeconomic level than in the two most deprived levels. There was an 18% lower survival rate amongst women in the most deprived levels (35.9%, 95% CI: 32.4 to 39.4) versus the least deprived level (43.7%, 95% CI: 38.1 to 49.2, p<0.004). In men, survival in the most deprived levels (39.5%, 95% CI: 36.4 to 42.5) was 7% lower than in the least deprived level (42.7%, 95% CI: 37.7 to 47.7, p<0.005). Biological valve, mitral position, female gender, and low socioeconomic status were all associated with long-term mortality. CONCLUSIONS: A disadvantaged social background has a negative influence on long-term survival after aortic or mitral valve replacement, especially among women.

Growth factor signalling in endocrine and anti-growth factor resistant breast cancer.

Growth factors provide powerful mitogenic and survival signals to breast cancer cells and it is therefore not surprising that they are able to subvert inhibitory responses to anti-hormonal drugs. In this review we discuss several mechanisms by which this may be achieved and expand our observations to encompass recently emerging anti-growth factor treatments. The information presented is underpinned by inhibitor studies that show the targeting of such mechanisms in advance of anti-hormone or anti-growth factor resistance development is able to substantially delay this event, thus pointing the way forward to intelligent combination therapies relevant to the future management of breast cancer.