Mapping genes for phosphorus utilization and correlated traits using a 4k SNP linkage map in Japanese quail (Coturnix japonica).

A large F2 cross with 920 Japanese quail was used to map QTL for phosphorus utilization, calcium utilization, feed per gain and body weight gain. In addition, four bone ash traits were included, because it is known that they are genetically correlated with the focal trait of phosphorus utilization. Trait recording was done at the juvenile stage of the birds. The individuals were genotyped genome-wide for about 4k SNPs and a linkage map constructed, which agreed well with the reference genome. QTL linkage mapping was performed using multimarker regression analysis in a line cross model. Single marker association mapping was done within the mapped QTL regions. The results revealed several genome-wide significant QTL. For the focal trait phosphorus utilization, a QTL on chromosome CJA3 could be detected by linkage mapping, which was substantiated by the results of the SNP association mapping. Four candidate genes were identified for this QTL, which should be investigated in future functional studies. Some overlap of QTL regions for different traits was detected, which is in agreement with the corresponding genetic correlations. It seems that all traits investigated are polygenic in nature with some significant QTL and probably many other small-effect QTL that were not detectable in this study.

Population Pharmacokinetics and Pharmacodynamics of Ciprofloxacin Prophylaxis in Pediatric Acute Lymphoblastic Leukemia Patients.

BACKGROUND: Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guidelines concerning prophylactic dose. AIMS: To determine the pharmacokinetics and pharmacodynamics (PKPD) of ciprofloxacin prophylaxis in a pediatric ALL population. The effect of patient characteristics and antileukemic treatment on ciprofloxacin exposure, the area under the concentration time curve over minimal inhibitory concentration (AUC24/MIC) ratios, and emergence of resistance were studied. METHODS: A total of 615 samples from 129 children (0-18 years) with ALL were collected in a multicenter prospective study. A population pharmacokinetic model was developed. Microbiological cultures were collected prior to and during prophylaxis. An AUC24/MIC of ≥125 was defined as target ratio. RESULTS: A 1-compartment model with zero-order absorption and allometric scaling best described the data. No significant (P < .01) covariates remained after backward elimination and no effect of asparaginase or azoles were found. Ciprofloxacin AUC24 was 16.9 mg*h/L in the prednisone prophase versus 29.3 mg*h/L with concomitant chemotherapy. Overall, 100%, 81%, and 18% of patients at, respectively, MIC of 0.063, 0.125, and 0.25 mg/L achieved AUC24/MIC ≥ 125. In 13% of the patients, resistant bacteria were found during prophylactic treatment. CONCLUSION: Ciprofloxacin exposure shows an almost 2-fold change throughout the treatment of pediatric ALL. Depending on the appropriateness of 125 as target ratio, therapeutic drug monitoring or dose adjustments might be indicated for less susceptible bacteria starting from ≥ 0.125 mg/L to prevent the emergence of resistance and reach required targets for efficacy.

Modifiable factors related to life-space mobility in community-dwelling older adults: results from the Canadian Longitudinal Study on Aging.

BACKGROUND: The most common methods for measuring mobility in older adulthood include performance-based tests, such as the Timed-Up-and-Go and gait speed. While these measures have strong predictive validity for adverse outcomes, they are limited to assessing what older adults do in standardized settings, rather than what they do in their daily life. Life-space mobility, which is the ability to move within environments that expand from one's home to the greater community, has been proposed as a more comprehensive measure of mobility. The aim of this study was to determine the association between modifiable factors and life-space mobility in older adults enrolled in the Canadian Longitudinal Study on Aging (CLSA). METHODS: Life-space mobility was measured using the Life Space Index (LSI). Explanatory factors included physical, psychosocial and cognitive determinants, as well as pain, fatigue, driving status, nutrition, body mass index, smoking status, and vision. To estimate the association between the LSI and explanatory variables, univariate and multivariable ordinary least squares regression analyses were performed. RESULTS: All adults 65 years and older (n = 12,646) were included in the analysis. Fifty percent were women and the mean age was 73.0 (SD5.7). The mean LSI score was 80.5, indicating that, on average, the sample was able to move outside of their neighborhood independently. All explanatory variables were significantly associated with the LSI except for balance and memory. The top 3 variables that explained the most variation in the LSI were driving, social support and walking speed. CONCLUSION: To our knowledge, this was the first study to examine the association between life-space mobility and a comprehensive set of modifiable factors that were selected based on a theoretical framework and existing research evidence. This study had two important messages. First, driving, social support and walking speed emerged as the most significant correlates of life-space mobility in older adults. Second, life-space mobility is multifactorial and interventions that are pragmatic in their design and testing are needed that consider the complexity involved. A multi-disciplinary approach to examining life-space mobility in older adults is needed to optimize opportunities for healthy aging and develop strategies that support mobility in older adulthood.

Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals.

BACKGROUND & AIMS: 3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB. METHODS AND RESULTS: We analyzed plasma and urine in 109 overweight to obese individuals before and after six months on hypocaloric diets reduced in either carbohydrates or fat. We calculated the homeostasis model assessment index (HOMA-IR) and whole body insulin sensitivity from oral glucose tolerance tests and measured intramyocellular fat by magnetic resonance spectroscopy. BCAAs and 3-HIB plasma concentrations were inversely related to insulin sensitivity but not to intramyocellular fat content at baseline. With 7.4 ± 4.5% weight loss mean BCAA and 3-HIB plasma concentrations did not change, irrespective of dietary macronutrient content. Individual changes in 3-HIB with 6-month diet but not BCAAs were correlated to the change in whole body insulin sensitivity and HOMA-IR independently of BMI changes. CONCLUSIONS: 3-HIB relates to insulin sensitivity but is not associated with intramyocellular fat content in overweight to obese individuals. Moreover, changes in 3-HIB rather than changes in BCAAs are associated with metabolic improvements with weight loss. Registration number for clinical trials: ClinicalTrials.gov Identifier: NCT00956566.

What are the differences among occupational groups related to their palliative care-specific educational needs and intensity of interprofessional collaboration in long-term care homes?

BACKGROUND: The purpose of this study was to compare the differences across occupational groups related to their end-of-life care-specific educational needs and reported intensity of interprofessional collaboration in long-term care (LTC) homes. METHODS: A cross-sectional survey, based on two questionnaires, was administered at four LTC homes in Ontario, Canada using a modified Dilman's approach. The first questionnaire, End of Life Professional Caregiver Survey, included three domains: patients and family-centered communication, cultural and ethical values, effective care delivery. The Intensity of Interprofessional Collaboration Scale included two subscales: care sharing activities, and interprofessional coordination. In total, 697 LTC staff were given surveys, including personal support workers, support staff (housekeeping, kitchen, recreation, laundry, dietician aids, office staff), and registered staff (licensed nurses, physiotherapists, social workers, pharmacists, physicians). RESULTS: A total of 317 participants completed the survey (126 personal support workers, 109 support staff, 82 registered staff) for a response rate of 45%. Significant differences emerged among occupational groups across all scales and subscales. Specifically, support staff rated their comfort of working with dying patients significantly lower than both nurses and PSWs. Support staff also reported significantly lower ratings of care sharing activities and interprofessional coordination compared to both registered staff and personal support workers. CONCLUSIONS: These study findings suggest there are differing educational needs and sense of interprofessional collaboration among LTC staff, specific to discipline group. Both the personal support workers and support staff groups appeared to have higher needs for education; support staff also reported higher needs related to integration on the interdisciplinary team. Efforts to build capacity within support staff related to working with dying residents and their families are needed. Optimal palliative care may require resources to increase the availability of support for all staff involved in the care of patients.

[Significance of Thoracic Surgery for Treatment of Pleural Empyema in Childhood and Adolescence]. / Stellenwert der Thoraxchirurgie im Gesamtkonzept der Behandlung von Pleuraempyemen bei Kindern.

BACKGROUND: There still is controversy about surgical treatment of pleural empyema in children. PATIENTS AND METHODS: Retrospective analysis of treatment strategy, focussing on indication for surgery and outcome of children treated in 2 centres for pleural complications due to primary pneumonia from January 1(st) 2008 to December 31(st) 2012. RESULTS were compared to studies published within the last 10 years. RESULTS: 1 451 children with pneumonia were treated during the 5 year period. 187 (average age 6.1 years, sex: 86/101 f/m) developed a pleural effusion. THERAPY: pleural punction in 22 children, chest tube in 78 and operation in 37 children. In 9 cases microorganisms were identified. 34 children were operated for empyema stage II, only 3 for stage III. 3 children were operated due to septicaemia not responding to antibiotics. Time from admission to operation (including referring hospital):14.5 days. Time from operation to discharge: 12,5 days. All children but one were operated by thoracoscopy. COMPLICATIONS: 1 bronchopleural fistula, 1 delayed healing of the wound. All children survived and fully recovered mean (observation period 28 months postoperatively). SUMMARY: In experienced hands thoracic surgery yields excellent results for children suffering from pleural empyema stage II and III. Recent randomised prospective trials comparing fibrinolysis with VATS do not convince regarding the treatment protocols of their surgical arms. Fibrinolysis is nevertheless a valuable treatment in early stage II empyema, especially if thoracic surgical experience is not available. However, the further advanced the empyema presents, the sooner surgical experience should be gathered.

[Treatment Strategies for Septic Arthritis of the Sternoclavicular Joint]. / Behandlungsstrategie der septischen Arthritiden des Sternoklavikulargelenks.

Septic arthritis of the sternoclavicular joint (SCJ) is a relatively rare disease. Due to serious complications including mediastinitis and generalised sepsis early diagnosis and rapid onset of treatment are mandatory. The disease often affects immunocompromised patients, diabetics, or patients with other infectious diseases. The therapeutic options range from administration of antibiotics to extended surgery including reconstructive procedures. Apart from rare situations where conservative treatment with antibiotics is sufficient, joint resection followed by plastic surgical procedures are required. We present a retrospective analysis with data from two hospitals. From January 2008 to December 2012 23 patients with radiographically confirmed septic arthritis of various aetiology were included. Fourteen (60.8 %) male, nine (39.2 %) female patients with an average age of 60.3 ± 14.2 years (range: 23-88 years) with septic arthritis of the SCJ were treated. Seven (30.4 %) patients suffered from Diabetes mellitus, nine (39.1 %) had underlying diseases with a compromised immune system. In 14 (60.8 %) out of 23 patients a bacterial focus was detected. Only six (26 %) patients suffered from confined septic arthritis of the SCG, in 17 (73,9 %) patients osteomyelitis of the adjacent sternum, and the clavicle was present. In addition, 15 (65.2 %) patients already suffered from mediastinitis at the time of diagnosis, eight (35 %) patients even from septicaemia. In conclusion, septic arthritis requires an active surgical treatment. Limited incision of the joint and debridement alone is only successful at early stages of the disease. The treatment concept has to include the local joint and bone resection as well as complications like mediastinitis. After successful treatment of the infection, the defect of the chest wall requires secondary reconstructive surgery using a pedicled pectoralis muscle flap.

[Differential Treatment Strategy of Pleural Empyema in a Post-Pneumonectomy Cavity]. / Differenzierte Behandlungsstrategie des Pleuraempyems in der Postpneumonektomiehöhle.

INTRODUCTION: Pleural empyema in a post-pneumonectomy cavity (PEC) occurs with a frequency of 2% -15% and a mortality of more than 10%. It can occur with or without bronchopleural fistula (BPF). The treatment of empyema in the PEC requires a strict algorithm: drainage, bronchoscopy, closure of the fistula, thorough cleaning of the PEC, filling the cavity, thoracoplasty. METHODS: 39 cases with an empyema in the PEC were analysed retrospectively (men: n = 38; women: n = 1; mean age: 60.3 ±â€Š7.6 years). In 32 (82.1%) of the patients, a BPF was detected (right: n = 26, left: n = 6). The average length of stay in hospital was 125 days (22 - 293 days). Cleaning of the PEC was achieved in all surviving patients (n = 23, 65.1%). All patients (n = 39) underwent bronchoscopy with placement of a chest tube for drainage. The BPF was closed in three cases (7.7%) with a stent while in 12 cases (30.8%) a vascularized flap was used. In 14 patients (35.9%) the bronchial stump was either reclosed with sutures or resected. In three cases (7.7%) a re-anastomosis was performed. RESULTS: The PEC became sterile by regular flushing with antibiotic solution in three patients (7.7%). In 35.9% of the patients (n = 14), aggressive surgical debridement (Weder procedure) was necessary. A thoracic window was applied in 22 patients (56.4%), followed by negative pressure wound therapy (NPWT) and change of dressing every three to four days or a tamponade of the thoracic cavity with simple dressings. In 19 patients (48.7%) the thoracic cavity was sealed with an antibiotic solution. In 5 cases an Alexander thoracoplasty took place. CONCLUSIONS: Pleural empyema after pneumonectomy still poses a serious postoperative complication. A bronchopleural fistula is often detected. Thus, two problems arise at the same time ­ fistula and infection in the pleural cavity. Through a strict algorithm, both problems can be dealt with in stages. After sealing the fistula, the thoracic cavity is thoroughly cleaned and finally the thorax is closed. Only in a small number of patients (1.3%) in whom these measures remain ineffective (persistent MRSA, aspergillus colonization) should the cavity be obliterated by thoracoplasty.

Influence of dietary fat ingestion on asymmetrical dimethylarginine in lean and obese human subjects.

BACKGROUND AND AIMS: Asymmetrical dimethylarginine (ADMA) may contribute to hypertension and cardiovascular disease by decreasing NO formation. In diabetic patients, a high fat meal acutely increased plasma ADMA while impairing endothelial function. We hypothesized that chronic and acute increases in dietary fat intake augment ADMA also in lean and in obese subjects without diabetes. METHODS AND RESULTS: Seventeen lean and twelve obese volunteers were randomized to two weeks of isocaloric diets with approximately 20% or >40% calories from fat in a cross-over fashion. At the end of the high and low fat periods, volunteers received corresponding test meals. ADMA was measured by GC-MS/MS using a deuterated standard. Mean fasting plasma ADMA concentration was 0.52 (0.49-0.54; 95% CI) µmol/l in lean and 0.53 (0.50-0.55) µmol/l in obese subjects (p = 0.55). The two week high fat diet did not influence ADMA. Both test meals elicited a 6%increase in circulating ADMA in lean subjects. In obese subjects, plasma ADMA concentration did not change with the low fat meal, and decreased by approximately 4% with the high fat meal. CONCLUSION: Our findings challenge the idea that obesity and dietary fat intake have a major effect on plasma ADMA, at least in subjects without overt cardiovascular and metabolic disease. This finding is important with regard to dietary recommendations for weight loss. Overestimation of the influence of dietary fat intake and obesity on circulating ADMA in previous reports was most likely due to methodological issues concerning ADMA measurements.

Agouti-related protein in patients with acute and weight-restored anorexia nervosa.

BACKGROUND: An imbalance in appetite-regulating neuropeptides of the central nervous system has been associated with anorexia nervosa (AN), but the mechanisms of action are poorly understood. Agouti-related protein (AGRP), an orexigenic mediator of the hypothalamus, increases food intake and decreases energy expenditure in times of negative energy balance. The aim of the present study was to investigate AGRP in acute and fully weight-restored patients with AN, as well as during weight gain. METHOD: Plasma AGRP and leptin levels were assessed using an enzyme-linked immunosorbent assay kit in a total of 175 female participants, including 75 patients with acute AN, 37 weight-restored AN patients and 63 healthy controls. Of the patients with acute AN, 33 were reassessed after partial weight gain. RESULTS: In weight-restored AN patients plasma AGRP levels were similar to those in healthy controls, whereas in patients with acute AN, AGRP was elevated. AGRP was inversely correlated with indicators of undernutrition such as body mass index and plasma leptin. In addition, AGRP levels normalized during weight gain of longitudinally assessed AN patients. CONCLUSIONS: Our results underline the significance of undernutrition and hypoleptinemia for the interpretation of peripheral AGRP concentrations. This provides support for the hypothesis that abnormal AGRP plasma levels in AN patients reflect undernutrition, rather than disease-specific traits.

Pyuria is absent during urinary tract infections in neutropenic patients.

To investigate the diagnostic significance of a normal urine sediment in the work-up for fever of unknown origin in neutropenia. Urinary tract infection was defined as ≥10(5) urinary pathogens in the absence of another focus. Pyuria was found in only 1/23 neutropenic episodes compared to 21/31 in controls (P < 0.0001).

Measurable residual disease in pediatric acute myeloid leukemia: a systematic review.

Introduction: A systematic review was performed to assess the prognostic value of Measurable Residual Disease (MRD) during treatment, for relapse and overall survival in pediatric acute myeloid leukemia (AML).Areas covered: A systematic search of available literature was performed to identify original full-text articles concerning MRD as prognostic for relapse and survival in pediatric AML. Thirteen studies were included, and in all studies, MRD positivity during treatment was associated with worse clinical outcome. MRD positivity was significantly associated with a higher probability of relapse in eleven studies. However, MRD negativity does not exclude the possibility of relapse in pediatric AML, while positivity early during therapy does not exclude cure.Expert opinion: MRD positivity during treatment has emerged as the most powerful prognostic factor in pediatric AML concerning relapse and overall survival and is useful for risk-group adapted treatment. Future studies should identify the optimal time-point(s) for MRD measurements and the optimal technique, to further improve its prognostic significance.

The Effects of a Walking Intervention on Gait Parameters in Older Adults Residing in Long-Term Care: A Randomized Controlled Trial.

OBJECTIVES: We examined the effects of a walking intervention in older adults residing in long-term care (LTC) homes on gait velocity (primary outcome), and stride length, cadence and heel-to-heel base of support (secondary outcomes) compared to those in an interpersonal interaction control group and a care-as-usual control group at 16-weeks post-intervention. METHODS: These previously unpublished gait data were collected as part of a larger prospective, randomized, three group study. One hundred and sixty-eight participants residing in 12 LTC homes were randomized into: a) a walking group (n=57) - 1:1 supervised, individualized, progressive, 30 minutes, five times a week walking program for 16 weeks; b) an interpersonal interaction group (n=55) - stationary 1:1 conversation time with research personnel; and, c) a care-as-usual control group (n=56). Gait was assessed at baseline and 16-weeks post-intervention using the GAITRite® computerized system. One-way Analysis of Covariance (ANCOVA), controlling for age, sex, cognitive status and baseline gait parameter (velocity, stride length, cadence, heel-to-heel base of support) was used to examine differences among groups for velocity, stride length, cadence, and heel-to-heel base of support at 16-weeks post-intervention. RESULTS: Ninety-one participants with available data were included in this analysis: walking group (n=31/57, mean age=82.77±6.75 years); interpersonal interaction group (n=31/55, mean age=82.74±9.27 years); care-as-usual control group (n=29/56, mean age=85.40±8.78 years). ANCOVA showed a significant difference in the mean gait velocity at 16-weeks post-intervention [F(2, 84) =6.99, p=0.0006); η2 (95%CI)=0.16 (0.02, 0.27)]. Post hoc comparisons using Sidak test showed that the estimated marginal mean (EMM) for velocity for the walking group [EMM (SE), 0.51m/s (0.03)] was significantly higher compared to the interpersonal interaction group [EMM (SE), 0.38m/s (0.03); t(83)=3.15, p=0.007] and the care-as-usual control group [EMM (SE), 0.38m/s (0.03)]; t(83)=3.32, p=0.004]. No significant difference was observed between groups for stride length, cadence or heel-to-heel base of support. CONCLUSION: LTC residents with limited physical functioning showed significant improvement in gait velocity but not in stride length, cadence or heel-to-heel base of support after a 16-week walking intervention.

Safety and efficacy of a maternal vaccine for the passive protection of broiler chicks against necrotic enteritis.

Necrotic enteritis is a potentially fatal multifactorial disease of chickens, which under commercial conditions is often associated with increased levels of mortality and reduced bird performance. The safety and efficacy of a Clostridium perfringens type A alpha-toxoid (Netvax™) formulated as an oil emulsion was investigated, following maternal immunization of broiler breeder hens, housed under commercial conditions, by the intramuscular route. A total of 11,234 hens were vaccinated across two integrated poultry sites. The vaccine was safe with no systemic reactions or adverse effects on bird performance detected. Vaccination resulted in a significant increase in anti-alpha toxin antibody in the hen that was maintained throughout the study, and subsequently transferred to their progeny throughout the laying period via egg yolk. Chicks hatched from eggs produced from vaccinated hens were shown to have reduced mortality specifically related to progeny flocks where gross gut lesions associated with necrotic enteritis were observed in control chicks. Further, whilst C. perfringens was isolated from control chicks with necrotic enteritis lesions, no such isolations were made at these time points from chicks from vaccinated hens. These results indicate that, under commercial conditions, maternal vaccination with Netvax™ can help to control losses related to necrotic enteritis.

Clinical relevance of measuring colonic permeability.

BACKGROUND: Gastroduodenal and small intestinal permeability are increased in patients with Crohn's disease (CD) and intensive care patients. The relevance of colonic permeability has not yet been adequately investigated. The aim of this study was to investigate the clinical value of sucralose excretion as indicator for colonic permeability in these patient groups. DESIGN: After oral administration of four sugars and subsequent analysis of urinary excretion, gastroduodenal and intestinal permeability were calculated from saccharose excretion and lactulose/mannitol (L/M) ratio over 5 h, and sucralose excretion from 5 to 26 h in 100 healthy controls, 29 CD and 35 patients after coronary surgery (CABG). RESULTS: In controls, sucralose excretion was highly variable (0.67+/-0.92%) and not related to small intestinal permeability. In CD and CABG, L/M ratio was increased (0.054+/-0.060; 0.323+/-0.253 vs. 0.018+/-0.001 in controls). Sucralose excretion was increased in 77% of CABG but only in 7% of CD. There was an association between gastroduodenal and intestinal permeability in CD and CABG (r=0.72, and r=0.51), but sucralose excretion was not related to either one of these two parameters. Other than a weak association between sucralose and length of stay in intensive care in CABG patients (P=0.099), sucralose excretion was not related to clinical outcome. CONCLUSIONS: The proposed cut-off for normal sucralose excretion is 2.11%, but its high variability and lack of association to gastrointestinal permeability or clinical outcome leave it open, if it can provide information beyond established permeability tests.

Improved survival for children and young adolescents with acute myeloid leukemia: a Dutch study on incidence, survival and mortality.

Variation in survival of pediatric acute myeloid leukemia (pAML) over time and between Western European countries exists. The aim of the current study is to assess the progress made for the Dutch pAML population (0-17 years) during 1990-2015, based on trends in incidence, survival and mortality. Data from the population-based Netherlands Cancer Registry were merged with leukemia-related characteristics and treatment specifics from the Dutch Childhood Leukemia Study Group (Dutch Childhood Oncology Group (DCOG) from 2002 onwards). Mortality data (1980-2016) were obtained from the cause of death registry of Statistics Netherlands. Trend analyses were performed over time and by treatment protocol. Between 1990 and 2015, a total of 635 children aged 0-17 years were diagnosed with AML for an average of 25 patients (range 18-36) per year. There was a slight increase in the incidence at age 1-4 years (average annual percentage change (AAPC) of +2.2% per year (95% CI 0.8-3.5, p < 0.01)). Overall, the 5-year survival significantly improved over the past 26 years and nearly doubled from 40% in the early 1990s to 74% in 2010-2015. Multivariable analysis showed a 49% reduction in risk of death for pAML patients treated according to the latest DB-AML 01 protocol (p = 0.03). The continuing decrease of mortality (AAPC -2.8% per year (95% CI -4.1 to -1.5)) supports the conclusion of true progress against pAML in the Netherlands.

Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease.

BACKGROUND: Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood. OBJECTIVES: The objective was to systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, EMBASE (January 1980 to August 2007), LILACS (January 1982 to August 2007), MEDLINE (January 1966 to August 2007), Cochrane Central Register of Controlled Trials (CENTRAL), PEDro (January 1980 to August 2007), AMED (January 1985 to August 2007), HealthSTAR (January 1975 to August 2007), CINAHL (January 1982 to August 2007). We also searched Dissertation Abstracts, inspected the reference lists of all papers selected for review and contacted the authors with expertise in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible amyotrophic lateral sclerosis, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. The authors of the papers were contacted to obtain information not available in the published articles. MAIN RESULTS: We identified two randomised controlled trials that met our inclusion criteria. The first examined the effects of a twice-daily exercise program of moderate load, endurance exercise versus "usual activities" in 25 people with ALS. The second examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined, there was a significant weighted mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in the exercise compared with the control groups (3.21, 95% confidence interval 0.46 to 5.96) in favour of the exercise group. No statistically significant differences in quality of life, fatigue or muscle strength were found. AUTHORS' CONCLUSIONS: The only studies detected were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed.

Perspective of Family Members of Transitions to Alternative Levels of Care in Anglo-Saxon Countries.

This scoping review explores circumstances surrounding the decision about, and eventual experience of, transitioning older adults into alternative levels of housing (ALH), such as long-term care. This topic is examined from a family member perspective, given their exposure and involvement in the care of older adult relatives during this transitional period. The scoping review methodology is based on the framework of Arksey and O'Malley and subsequent recommendations from Levac, Colquhoun, and O'Brien. Approximately 470 articles were reviewed covering the period between 2000 and November 2014; 37 articles met inclusion criteria. A temporal organization of themes was used to describe the experiences of family members in the pretransition, active transition, and posttransition periods of moving older adult relatives into ALH. This paper highlights the transitional period as a time of crisis, with a lack of planning, support, and transparent discussion. This study identifies a need for future research on the potential benefits of family support groups, interim transitional housing options, different models of ALH, changing roles in the posttransition period, and the need for a comprehensive list of housing options for older adults. Results have the potential to inform policy/practice and improve the lives of older adults and their family.

RAS pathway mutations as a predictive biomarker for treatment adaptation in pediatric B-cell precursor acute lymphoblastic leukemia.

RAS pathway mutations have been linked to relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive data on the frequency and prognostic value of subclonal mutations in well-defined subgroups using highly sensitive and quantitative methods are lacking. Targeted deep sequencing of 13 RAS pathway genes was performed in 461 pediatric BCP-ALL cases at initial diagnosis and in 19 diagnosis-relapse pairs. Mutations were present in 44.2% of patients, with 24.1% carrying a clonal mutation. Mutation frequencies were highest in high hyperdiploid, infant t(4;11)-rearranged, BCR-ABL1-like and B-other cases (50-70%), whereas mutations were less frequent in ETV6-RUNX1-rearranged, and rare in TCF3-PBX1- and BCR-ABL1-rearranged cases (27-4%). RAS pathway-mutated cells were more resistant to prednisolone and vincristine ex vivo. Clonal, but not subclonal, mutations were linked to unfavorable outcome in standard- and high-risk-treated patients. At relapse, most RAS pathway mutations were clonal (9 of 10). RAS mutant cells were sensitive to the MEK inhibitor trametinib ex vivo, and trametinib sensitized resistant cells to prednisolone. We conclude that RAS pathway mutations are frequent, and that clonal, but not subclonal, mutations are associated with unfavorable risk parameters in newly diagnosed pediatric BCP-ALL. These mutations may designate patients eligible for MEK inhibitor treatment.

MN1 overexpression is driven by loss of DNMT3B methylation activity in inv(16) pediatric AML.

In acute myeloid leukemia (AML), specific genomic aberrations induce aberrant methylation, thus directly influencing the transcriptional programing of leukemic cells. Therefore, therapies targeting epigenetic processes are advocated as a promising therapeutic tool for AML treatment. However, to develop new therapies, a comprehensive understanding of the mechanism(s) driving the epigenetic changes as a result of acquired genetic abnormalities is necessary. This understanding is still lacking. In this study, we performed genome-wide CpG-island methylation profiling on pediatric AML samples. Six differentially methylated genomic regions within two genes, discriminating inv(16)(p13;q22) from non-inv(16) pediatric AML samples, were identified. All six regions had a hypomethylated phenotype in inv(16) AML samples, and this was most prominent at the regions encompassing the meningioma (disrupted in balanced translocation) 1 (MN1) oncogene. MN1 expression primarily correlated with the methylation level of the 3' end of the MN1 exon-1 locus. Decitabine treatment of different cell lines showed that induced loss of methylation at the MN1 locus can result in an increase of MN1 expression, indicating that MN1 expression is coregulated by DNA methylation. To investigate this methylation-associated mechanism, we determined the expression of DNA methyltransferases in inv(16) AML. We found that DNMT3B expression was significantly lower in inv(16) samples. Furthermore, DNMT3B expression correlated negatively with MN1 expression in pediatric AML samples. Importantly, depletion of DNMT3B impaired remethylation efficiency of the MN1 exon-1 locus in AML cells after decitabine exposure. These findings identify DNMT3B as an important coregulator of MN1 methylation. Taken together, this study shows that the methylation level of the MN1 exon-1 locus regulates MN1 expression levels in inv(16) pediatric AML. This methylation level is dependent on DNMT3B, thus suggesting a role for DNMT3B in leukemogenesis in inv(16) AML, through MN1 methylation regulation.