An initial evaluation of a family-based approach to weight management in adolescents attending a community weight management group.

BACKGROUND: Family-based approaches are recommended for the prevention and management of childhood obesity. Given the large numbers of obese children, scalable practical solutions are required. The present study evaluated a family-based national programme that aimed to empower adolescents to adopt healthier lifestyles. METHODS: Group facilitators supporting more than six young members (11-15 years) participated in the study. A questionnaire was designed to determine the characteristics of the adult attending with the adolescent, any health professional recommendations given and the young member's integration within traditional adult weight management groups. Data on measured height and weight [and calculated body mass index (BMI)], sex and attendance were collated from member's records. RESULTS: Questionnaires were completed by 22 facilitators (15% response rate), representing data for 128 young members with complete weight data available for 106. All members had a joining BMI > 91st centile, with 68% >98th centile. The mean (SD) number of weeks attended was 12.5 (8.1), with 19% (20) having attended for more than 20 weeks with 62% still attending. A mean (SD) BMI Z-score change of 2.49 (0.72) to 2.27 (0.74) was achieved (P < 0.001). The relationship of the adult supporter to the young member was varied, with 62% either already members or joining alongside their daughter/son. Limited guidance was provided by health professionals before or during attendance. Facilitators were comfortable about the age mix within groups. CONCLUSIONS: The community weight management organisation studied takes a family-based approach and successfully supports young members to manage their weight.

Weight, body mass index and behaviour change in a commercially run lifestyle programme for young people.

BACKGROUND: There are few practical, scalable, community-based solutions that provide ongoing support to combat the recent rapid rise in obesity in young people. A commercial weight management organisation (CWMO) has developed a tailored version of its programme for young people. The present study assessed the programme's impact on self-reported body weight, body mass index (BMI; kg m(-2) ) and health-related behaviour changes in participating young people. METHODS: Seventy-nine current young members completed a web-based questionnaire on age, height, weight and self-reported eating and activity behaviours for when they joined the programme and at the time of survey. Inclusion criteria were age 11-15 years old and membership for at least 1 month. Subjects completed the questionnaire online via the CWMO website. This was a retrospective observational study without a control group. All data were self-reported. RESULTS: Mean (SD) age was 13.4 (1.4) years and start weight was 78.5 (16.7) kg; 67% were >99th centile for BMI. Mean (SD) attendance was 23 (19) weeks; weight change was -5.0 (4.5) kg; BMI change was -2.5 (2.0) kg m(-2) ; and BMI Z-score change was -0.5 (0.4) (all P < 0.001). Height increased by 0.01 (0.03) m (P < 0.01); however, height Z-score remained unchanged. Regression analysis showed that BMI Z-score change was related to increased fruit and vegetable intake (P = 0.012), as well as a decrease in avoidance of moderate and intense activity (both P < 0.003). CONCLUSIONS: This programme for overweight and obese young people helped implement behaviour and lifestyle changes that were associated with significant reductions in self-reported weight and BMI Z-score, without compromising growth in height.

Attendance and weight outcomes in 4754 adults referred over 6 months to a primary care/commercial weight management partnership scheme.

WHAT IS ALREADY KNOWN ON THIS SUBJECT: • There is growing evidence of the effectiveness of commercial weight management programmes in the community. A recent randomized controlled trial has shown commercial providers to be more effective than NHS providers for weight management solutions in primary care. Some commercial weight management providers have established national slimming on referral schemes for weight management, which result on average in weight losses of 4-5% over a 12-week referral period. A recent randomized controlled trial of a similar scheme over 12 months yielded similar weight loses. Another RCT comparing commercial providers over 6 months showed average weight losses of ∼6.6% across providers. WHAT THIS STUDY ADDS: • The present study shows that when local primary care practitioners target resources to where they, as health professionals, felt they would have the most beneficial effect in their local communities, greater weight losses can be achieved. • Different NHS Trusts extended 12-week referrals by an additional 12 weeks in a total of 4754 patients. • Mean weight losses of 8.6% were achieved suggesting that local targeting of primary care resources can maximize returns for NHS investments in commissioning the services of commercial weight management organizations. SUMMARY: This project audited attendance and weight loss in a primary care/commercial weight management partnership scheme in patients who participated over 6 months. 4754 adult patients (575 men, 4179 women) were referred to Slimming World for 24 weekly sessions. Data were analysed using individual weekly weight records. Mean (standard deviation, SD) body mass index (BMI) change was -3.3 kg m(-2) (2.2), weight change -8.9 kg (6.0), percent weight change -8.6% (5.3) and number of sessions attended 21.3 (3.2) of 24. For patients attending at least 20 of 24 sessions (n = 3626 or 76.3%), mean (SD) BMI change was -3.6 kg m(-2) (2.2), weight change -9.6 kg (6.1), percent weight change -9.3% (5.3). Weight loss was greater in men than women (P < 0.001). 74.5% of all patients enrolled, and 79.3% of patients attending 20 or more sessions achieved at least 5% weight loss. 37.3% of the whole population lost ≥10% of their weight. Weight gain was prevented in 96.3% of all patients referred. Referral to a commercial organization for community-based lifestyle intervention is a practical option for longer-term National Health Service weight management strategies.

Influence of Slimming World's lifestyle programme on diet, activity behaviour and health of participants and their families.

BACKGROUND: Understanding the impact of commercial weight management programmes on behaviour change is an area that requires greater evidence. The present study investigated the impact of a commercial weight management organisation's diet and activity programmes on the lifestyles of those accessing the services and their families. METHODS: This survey was based on self-reports from a group of people involved in their own weight control. A questionnaire consisting of multiple choice and open-ended questions regarding diet, activity patterns and health was distributed in a commercial slimming organisation's magazine and was available on the website for a 4 week period. Two thousand eight hundred and twelve respondents were analysed, including the organisation's members (53%) and nonmembers (47%). RESULTS: Those following the dietary programme reported significant changes towards healthier food choices in line with current guidelines (P < 0.01). Over 80% reported an improvement in their own health and over 26% reported an improvement in their partner's or family's health (P < 0.01). Respondents reported increasing physical activity after being made aware of the organisation's activity programme (P < 0.001). Members were more likely to have become more active than nonmembers (P = 0.011). The longer respondents had been members, the more likely they were to report an increased participation in physical activity (P = 0.02). Half of those reporting increased activity indicated that their partner or whole family had also increased their activity levels. CONCLUSIONS: The commercial slimming organisation's programme appeared to be having a beneficial impact on the diet and activity behaviours of those accessing the service. Group members were more likely to make positive behaviour changes and health improvements tended to increase with the duration of membership. The improvements observed with respect to both diet and activity levels also reached the wider family network.

The impact of anaemia on outcome in cancer.

Anaemia is not an inconsequential side effect of cancer and its treatment should not be ignored. Current practice for anaemia management varies and its role in influencing outcome in cancer patients is under recognized. As a common complication of cancer, anaemia is prevalent in virtually all tumour types to varying degrees. Predictive factors for anaemia include baseline haemoglobin concentration, decrease in haemoglobin concentration within the first month of treatment, tumour type, duration of treatment and prior blood transfusions. Interest in the prognostic significance of anaemia in cancer patients has generated extensive clinical research. Data is now published in a wide range of tumour types confirming that anaemia is a negative prognostic indicator of outcome (e.g. survival, disease-free recurrence and local relapse), with the strongest association in patients receiving radiotherapy. The association has also been documented in patients undergoing chemotherapy and chemoradiation. A retrospective meta-analysis has shown an overall 65% increased risk of death associated with anaemia in cancer patients. The impact of anaemia as an independent prognostic factor for outcome may be mediated by several factors, however the emerging consensus is on the central role of tumour hypoxia. It has been nearly 50 years since R. Thomlinson and L. Gray (British Journal of Cancer 1955, 9: 539) first documented the existence of hypoxia in tumours and it is now well accepted that tumour hypoxia protects tumour cells from therapeutic damage directly by reducing the availability of oxygen-free radicals which are necessary for optimal impact of radiotherapy, certain chemotherapeutic agents and photodynamic therapy. The indirect effects include the impact of hypoxia on gene expression, which affects genetic stability, proliferation kinetics and cellular metabolism. There has been an emergence of preclinical and circumstantial data over recent years that are suggestive of the ability to correct the negative effect of anaemia on outcome by the use of repeated blood transfusions or recombinant human erythropoietin. This has led to some attempts to measure the impact on survival in cancer patients of treating anaemia, but early attempts have served to underline the complexity of the relationship and have produced unexpected results.

C-kit mutation screening in patients with acute myeloid leukaemia: adaptation of a Giemsa-stained bone-marrow smear DNA extraction technique.

The scarcity of viable tissue samples for leukaemia research is widely recognised and currently restrictive. Archival bone-marrow smears present a valuable resource that can be exploited easily for mutational analysis. Here, a modified technique to extract DNA is described, and used subsequently for mutation/polymorphism screening of the stem-cell factor receptor proto-oncogene c-kit in 23 patients with acute myeloid leukaemia (AML). The selected method was straightforward and used bone-marrow material scraped from periodic acid-Schiff, sudan black B and May-Grünwald/Giemsa-stained preparations, and treated initially with proteinase K prepared in digestion buffer to digest all proteinaceous matter. Following incubation, saturated sodium chloride was added and DNA extracted from the supernatant by phenol/chloroform/isoamyl alcohol treatment. Retrieved DNA was precipitated with ethanol at -20 degrees C overnight, washed with 95% ethanol, air-dried, resuspended using purite water and stored at -20 degrees C prior to use in mutational analysis. The extraction method described was compared with a commercial reagent for combined DNA, RNA and protein isolation using cryopreserved cells from 20 patients with AML. The quality of extracted DNA isolated by the two methods was comparable by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) techniques. Bone-marrow biopsies are performed regularly on each AML patient to monitor the disease; therefore, an extraction method using this resource could liberate a valuable source of DNA for study (e.g. molecular investigations, including mutation/polymorphism screening etc.). This would allow fresh and programme-frozen cells to be reserved for those investigations requiring intact, viable cells. The use of archived bone-marrow smears would permit vast increase in the scope for retrospective testing and large-scale analyses.

Stem cell factor: biology and relevance to clinical practice.

The type III tyrosine kinase receptor c-KIT and its ligand stem cell factor (SCF; also known as KIT ligand, mast cell growth factor and steel factor) are closely involved in the regulation of a wide range of tissues at different stages of life. This review provides an outline of the discovery, structure and expression of SCF and c-KIT but concentrates on their respective roles in the regulation of human haemopoiesis and how this knowledge might be exploited in the clinical setting.

Characterization and purification of the vitamin K1 2,3 epoxide reductases system from rat liver.

The enzyme vitamin K1 2,3 epoxide reductase is responsible for converting vitamin K1 2,3 epoxide to vitamin K1 quinone thus completing the vitamin K cycle. The enzyme is also the target of inhibition by the oral anticoagulant, R,S-warfarin. Purification of this protein would enable the interaction of the inhibitor with its target to be elucidated. To date a single protein possessing vitamin K1 2,3 epoxide reductase activity and binding R,S-warfarin has yet to be purified to homogeneity, but recent studies have indicated that the enzyme is in fact at least two interacting proteins. We report on the attempted purification of the vitamin K1 2,3 epoxide reductase complex from rat liver microsomes by ion exchange and size exclusion chromatography techniques. The intact system consisted of a warfarin-binding factor, which possessed no vitamin K1 2,3 epoxide reductase activity and a catalytic protein. This catalytic protein was purified 327-fold and was insensitive to R,S-warfarin inhibition at concentrations up to 5 mM. The addition of the S-200 size exclusion chromatography fraction containing the inhibitor-binding factor resulted in the return of R,S-warfarin inhibition. Thus, to function normally, the rat liver endoplasmic reticulum vitamin K1 2,3 epoxide reductase system requires the association of two components, one with catalytic activity for the conversion of the epoxide to the quinone and the second, the inhibitor binding factor. This latter enzyme forms the thiol-disulphide redox centre that in the oxidized form binds R,S-warfarin.

Platelet activation via the collagen receptor GPVI is not altered in platelets from chronic myeloid leukaemia patients despite the presence of the constitutively phosphorylated adapter protein CrkL.

In this study, we show that the adapter proteins CrkL and Cbl undergo increases in tyrosine phosphorylation and form an intracellular complex in platelets stimulated with the snake venom toxin convulxin, a selective agonist at the collagen receptor glycoprotein VI (GPVI). Constitutive tyrosine phosphorylation of CrkL has previously been reported in platelets from chronic myeloid leukaemia (CML) patients. This was confirmed in the present study, and shown to result in a weak constitutive association of CrkL with Cbl and a number of other unidentified tyrosine-phosphorylated proteins. There was no further increase in phosphorylation of CrkL in CML platelets in response to GPVI activation, whereas phosphorylation of Cbl and its association with CrkL were potentiated. In addition, this was accompanied by a small increase in p42/ 44 mapkinase (MAPK) activity in CML platelets. The functional consequence of the presence of constitutively phosphorylated proteins in CML platelets was investigated by measurement of aminophospholipid exposure and alpha-granule secretion. This revealed little alteration in the concentration-response curves for either in CML platelets stimulated via GPVI, although maximal levels of P-selectin were depressed. Despite the minimal effect on platelet activation in CML patients, we cannot exclude a role for CrkL or Cbl in signal transduction pathways stimulated via GPVI.

Effects of antimicrobial drugs on human neutrophil-microbe interactions.

Antimicrobial drugs may influence neutrophil-microbe interactions in several ways, and, conversely, neutrophils may interfere with the action(s) of antimicrobial drugs. Here, evidence for the existence of such effects is evaluated and attention drawn to the problems of in vitro experimentation in this area. The review is restricted to those studies that used human neutrophils, clinically achievable drug concentrations, and were well designed. Even so, it is noted that little attempt has been made to investigate underlying mechanisms. The effects of drugs on microbes, which influence neutrophil-microbe interactions, such as concentration and the post-antibiotic effect, are considered. The penetration of antimicrobial drugs into neutrophils and subsequent intracellular activity is discussed and contrasted with observations obtained using macrophages. Overall, neutrophil-microbe interactions are complex and difficult to dissect, and carefully designed experiments using closely defined conditions are required if meaningful results are to be obtained.

Kinetic characteristics of de novo and secondary AML cells influence their response to haemopoietic growth factor (HGF) priming and correlate with clinical outcome.

This study has assessed the effect of in vitro haemopoietic growth factor (HGF) priming on the S phase activity of cells from patients with de novo AML and AML secondary to MDS. The occurrence of receptors for G-CSF, GM-CSF, IL-3 and SCF on marrow cells was assessed using immunofluorescent ligand binding assays. Additionally, patients responses to first phase induction chemotherapy was recorded to examine whether in vitro kinetic data might correlate with clinical outcome. All kinetic and receptor assays were performed in normal marrow cells to ascertain their response to priming. Incubation of AML cells in serum free medium (SFM) +/- G + GM-CSF, IL-3, SCF, G + GM-CSF + SCF or IL-3 + SCF prior to S phase assessment revealed that priming permutations inclusive of SCF were most effective but also that the baseline level of S phase activity with SFM alone influenced the subsequent response to priming. Regardless of AML group, samples with low baseline S phase activity (< 10%) were significantly more responsive than those with high (> 10%) SFM S phase levels. However there was no corresponding difference in the percentages of cells bearing receptors. In both AML groups, low baseline S phase activity was observed more frequently in samples from patients who achieved CR. Normal samples possessed receptors for all HGFs and were responsive to all priming permutations except SCF alone. This study raises four points: (a) it may be prudent to reserve the use of priming HGFs for those patients with low baseline S phase activity whose cells respond in vitro and to use SCF in these priming cocktails; (b) the presence of receptors capable of ligand binding in AML samples did not guarantee kinetic response; (c) normal progenitors were responsive to priming which may have implications for haemopoietic reconstitution post therapy; and (d) the kinetic characteristics of AML progenitors may influence clinical outcome regardless of whether treatment includes HGFs.

Lymphocyte content of amyloid precursor protein is increased in Down's syndrome and aging.

We quantified cellular amyloid precursor protein (APP) in ethanol-permeabilized peripheral lymphocytes from 13 subjects with Alzheimer's disease (AD), 11 subjects with Down's syndrome (DS), and 13 healthy elderly and 31 healthy young controls. APP content was analyzed by indirect immunofluorescence and flow cytometry, using the 22C11 monoclonal antibody (mAb) directed against an N-terminal domain of APP. Authenticity of 22C11 APP signal was confirmed by immunoblotting and flow cytometry studies with the mAb 6E10, directed against the A beta domain of APP. Consistent with gene dosage, patients with DS had 1.51-fold higher lymphocyte APP signal than age-matched normal young subjects (corrected p < 0.05). Both AD patients and elderly control groups had significantly increased lymphocyte APP signal compared to young controls (either comparison corrected p < 0.01). Indeed, increasing age in non-DS subjects was significantly correlated with lymphocyte APP (r = 0.508, p < 0.0001), such that APP immunoreactivity more than doubled from 20 to 80 years. Lymphocyte APP was nonsignificantly higher in AD vs. aged controls in this small sample. Increased cellular APP content in DS and aging may correspond to generalized alterations in expression or processing of this molecule, and suggests a novel determinant for the timing of AD onset.

Haemopoietic growth factors, the cell cycle of acute myeloblastic leukaemia progenitors and sensitivity to cytosine arabinoside.

We describe an 'in vitro' model which permits assessment of acute myeloblastic leukaemia (AML) progenitor cells' response to Ara-C alone and in conjunction with recombinant human (rh) cytokines by evaluating cell cycle characteristics of purified AML blast progenitors and their chemosensitivity in clonogenic culture before and after cytokine priming. Parallel investigation of Ara-C/cytokine treatment on normal CFU-GM progenitors was included as these cells are important for post-therapeutic reconstitution of haemopoiesis. Kinetic and clonogenic findings for AML marrows were extremely variable with G+GM-CSF or IL-3 priming. However, inclusion of rhSCF and resultant synergism with the other cytokines, introduced a pronounced element of consistency in AML results. Normal CFU-GM responded to rhG+GM-CSF or IL-3 with increased kinetic activity and sensitivity to Ara-C. rhSCF synergised strongly with the other factors, causing increased cell cycling and attainment of maximal chemosensitivity 'in vitro'. No correlation was evident between 'in vitro' findings for AML samples, patient FAB types or clinical outcome. This study highlights the fact that both normal and AML cells can be targeted by rh cytokines, particularly when rhSCF is included in priming cocktails.

The effect of haemopoietic growth factors on the cell cycle of AML progenitors and their sensitivity to cytosine arabinoside in vitro.

This study examines the effect of pretreatment in liquid culture of acute myeloid leukaemic (AML) progenitors with recombinant human IL-3 or G and GM-CSF. Prior to and following cytokine priming, the sensitivity of cells to cytosine arabinoside (Ara-C) at concentrations ranging from 10(-12) to 10(-4) M was assessed in clonogenic culture. In addition, the initial percentage of AML cells in S phase was assessed and their subsequent kinetic response to cytokine treatment evaluated by FACScan analysis. Light-density marrow cells (LDMCs) from 19 AML patients were initially T-cell and monocyte depleted in order to remove potential sources of endogenous cytokine production prior to in vitro investigation. LDMCs were incubated in liquid phase for 7 d in a chemically defined complete medium with or without cytokines. Clonogenic data from fresh AML LDMCs not pretreated with growth factors demonstrated a heterogenous response to Ara-C. In only 4/15 marrows tested clonogenically was there any improvement in sensitivity to Ara-C following cytokine priming. S-phase data on all 19 marrows were similarly variable either before or after cytokine preincubation. There was no discernible correlation between clonogenic and kinetic data, nor could any relationship be established between in vitro findings and the FAB subtypes of patients or clinical outcomes. In summary, it would appear that the cell-cycle status of AML cells is likely to be only one of many contributory factors governing the sensitivity of AML progenitors to Ara-C. The clinical response of AML patients to cytokine therapy in association with cell-cycle-specific cytotoxic agents may therefore be variable and unpredictable.

Phagocytic NADPH oxidase and its role in chronic granulomatous disease.

Chronic granulomatous disease is an inherited disease manifest as recurrent bacterial and fungal infections. Although extremely rare, in the absence of long-term treatment it can be lead to death at an early age. Even though the disease was first described almost 40 years ago it is only recently that the enzymatic defects which cause the disease have been well characterised, allowing an instructive classification of the disorder and paving the way for advances in gene therapy as a lasting cure.

In-vitro effects of liposome-encapsulated amphotericin B (AmBisome) and amphotericin B-deoxycholate (Fungizone) on the phagocytic and candidacidal function of human polymorphonuclear leucocytes.

Liposomal amphotericin B (AmBisome), at concentrations > or = 20 mg/L, and amphotericin B-deoxycholate (DC) (Fungizone), at concentrations > or = 1 mg/L, both caused a significant reduction in neutrophil uptake of Candida albicans blastospores following simultaneous addition of the drug with the blastospores. The reduction in uptake was seen also in tests in which blastospores were pre-treated with the drugs for 60 min, but was not detected in tests in which neutrophils were pre-treated for 60 min. Neither formulation affected neutrophil killing of C. albicans blastospores following simultaneous addition of the drug with the blastospores. However, previous treatment of the neutrophils with either formulation at a concentration of 20 mg/L led to enhanced killing of ingested blastospores. The results suggest that much higher concentrations of liposomal amphotericin B (AmBisome) are required to produce deleterious effects on neutrophil phagocytic function than with the conventional formulation of the drug.