Intermittent control models of human standing: similarities and differences

Two architectures of intermittent control are compared and contrasted in the context of the single inverted pendulum model often used for describing standing in humans. The architectures are similar insofar as they use periods of open-loop control punctuated by switching events when crossing a switching surface to keep the system state trajectories close to trajectories leading to equilibrium. The architectures differ in two significant ways. Firstly, in one case, the open-loop control trajectory is generated by a system-matched hold, and in the other case, the open-loop control signal is zero. Secondly, prediction is used in one case but not the other. The former difference is examined in this paper. The zero control alternative leads to periodic oscillations associated with limit cycles; whereas the system-matched control alternative gives trajectories (including homoclinic orbits) which contain the equilibrium point and do not have oscillatory behaviour. Despite this difference in behaviour, it is further shown that behaviour can appear similar when either the system is perturbed by additive noise or the system-matched trajectory generation is perturbed. The purpose of the research is to come to a common approach for understanding the theoretical properties of the two alternatives with the twin aims of choosing which provides the best explanation of current experimental data (which may not, by itself, distinguish beween the two alternatives) and suggesting future experiments to distinguish between the two alternatives

Screening rules for growth to detect celiac disease: A case-control simulation study

Background: It is generally assumed that most patients with celiac disease (CD) have a slowed growth in terms of length (or height) and weight. However, the effectiveness of slowed growth as a tool for identifying children with CD is unknown. Our aim is to study the diagnostic efficiency of several growth criteria used to detect CD children. Methods: A case-control simulation study was carried out. Longitudinal length and weight measurements from birth to 2.5 years of age were used from three groups of CD patients (n = 134) (one group diagnosed by screening, two groups with clinical manifestations), and a reference group obtained from the Social Medical Survey of Children Attending Child Health Clinics (SMOCC) cohort (n = 2,151) in The Netherlands. The main outcome measures were sensitivity, specificity and positive predictive value (PPV) for each criterion. Results: Body mass index (BMI) performed best for the groups with clinical manifestations. Thirty percent of the CD children with clinical manifestations and two percent of the reference children had a BMI Standard Deviation Score (SDS) less than -1.5 and a decrease in BMI SDS of at least -2.5 (PPV = 0.85%). The growth criteria did not discriminate between the screened CD group and the reference group. Conclusion: For the CD children with clinical manifestations, the most sensitive growth parameter is a decrease in BMI SDS. BMI is a better predictor than weight, and much better than length or height. Toddlers with CD detected by screening grow normally at this stage of the disease

Patterns of clinical presentation of adult coeliac disease in a rural setting

BACKGROUND: In recent years there has been increasing recognition that the pattern of presentation of coeliac disease may be changing. The classic sprue syndrome with diarrhoea and weight loss may be less common than the more subtle presentations of coeliac disease such as an isolated iron deficiency anaemia. As a result, the diagnosis of this treatable condition is often delayed or missed. Recent serologic screening tests allow non-invasive screening to identify most patients with the disease and can be applied in patients with even subtle symptoms indicative of coeliac disease. Both benign and malignant complications of coeliac disease can be avoided by early diagnosis and a strict compliance with a gluten free diet. AIM: The aim of this study is to evaluate the trends in clinical presentation of patients diagnosed with adult coeliac disease. In addition, we studied the biochemical and serological features and the prevalence of associated conditions in patients with adult coeliac disease. METHODS: This is an observational, retrospective, cross-sectional review of the medical notes of 32 adult patients attending the specialist coeliac clinic in a district general hospital. RESULTS: Anaemia was the most common mode of presentation accounting for 66% of patients. Less than half of the patients had any of the classical symptoms of coeliac disease and 25% had none of the classical symptoms at presentation. Anti-gliadin antibodies, anti-endomysial antibody and anti-tissue transglutaminase showed 75%, 68% and 90% sensitivity respectively. In combination, serology results were 100% sensitive as screening tests for adult coeliac disease. Fifty nine percent patients had either osteoporosis or osteopenia. There were no malignant complications observed during the follow up of our patients. CONCLUSION: Most adults with coeliac disease have a sub clinical form of the disease and iron deficiency anaemia may be its sole presenting symptom. Only a minority of adult coeliac disease patients present with classical mal-absorption symptoms of diarrhoea and weight loss. Patients with atypical form of disease often present initially to hospital specialists other than a gastro-enterologist. An awareness of the broad spectrum of presentations of adult coeliac disease, among doctors both in primary care and by the various hospital specialists in secondary care, is necessary to avoid delays in diagnosis. It is important to include serological screening tests for coeliac disease systematically in the evaluation of adult patients with unexplained iron deficiency anaemia or unexplained gastro-intestinal symptoms and in those who are considered to be at increased risk for coeliac disease

Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice

conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration. primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures.In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration

Targeting HSP90 for cancer therapy

Heat-shock proteins (HSPs) are molecular chaperones that regulate protein folding to ensure correct conformation and translocation and to avoid protein aggregation. Heat-shock proteins are increased in many solid tumours and haematological malignancies. Many oncogenic proteins responsible for the transformation of cells to cancerous forms are client proteins of HSP90. Targeting HSP90 with chemical inhibitors would degrade these oncogenic proteins, and thus serve as useful anticancer agents. This review provides an overview of the HSP chaperone machinery and the structure and function of HSP90. We also highlight the key oncogenic proteins that are regulated by HSP90 and describe how inhibition of HSP90 could alter the activity of multiple signalling proteins, receptors and transcriptional factors implicated in carcinogenesis

Effectiveness of dual-task functional power training for preventing falls in older people: Study protocol for a cluster randomised controlled trial

Background: Falls are a major public health concern with at least one third of people aged 65 years and over falling at least once per year, and half of these will fall repeatedly, which can lead to injury, pain, loss of function and independence, reduced quality of life and even death. Although the causes of falls are varied and complex, the age-related loss in muscle power has emerged as a useful predictor of disability and falls in older people. In this population, the requirements to produce explosive and rapid movements often occurs whilst simultaneously performing other attention-demanding cognitive or motor tasks, such as walking while talking or carrying an object. The primary aim of this study is to determine whether dual-task functional power training (DT-FPT) can reduce the rate of falls in community-dwelling older people. Methods/Design: The study design is an 18-month cluster randomised controlled trial in which 280 adults aged =65 years residing in retirement villages, who are at increased risk of falling, will be randomly allocated to: 1) an exercise programme involving DT-FPT, or 2) a usual care control group. The intervention is divided into 3 distinct phases: 6 months of supervised DT-FPT, a 6-month 'step down' maintenance programme, and a 6-month follow-up. The primary outcome will be the number of falls after 6, 12 and 18 months. Secondary outcomes will include: lower extremity muscle power and strength, grip strength, functional assessments of gait, reaction time and dynamic balance under single- and dual-task conditions, activities of daily living, quality of life, cognitive function and falls-related self-efficacy. We will also evaluate the cost-effectiveness of the programme for preventing falls. Discussion: The study offers a novel approach that may guide the development and implementation of future community-based falls prevention programmes that specifically focus on optimising muscle power and dual-task performance to reduce falls risk under 'real life' conditions in older adults. In addition, the 'step down' programme will provide new information about the efficacy of a less intensive maintenance programme for reducing the risk of falls over an extended period. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12613001161718. Date registered 23 October 2013

Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

BACKGROUND: Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. METHODS: We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. RESULTS: We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to expression of the known HGF receptor Met, as neither LNCaP nor clonally-derived C4-2 sub-line contain any detectable Met protein. Even in the absence of Met, small GTPases are activated, linking HGF stimulation to membrane protrusion and integrin activation. Membrane-localized nucelolin levels increase during cancer progression, as modeled by both the PC3 and LNCaP prostate cancer progression cell lines. CONCLUSION: We propose that cell surface localized nucleolin protein may function in these cells as a novel HGF receptor. Membrane localized nucleolin binds heparin-bound growth factors (including HGF) and appears upregulated during prostate cancer progression. Antibodies against nucleolin are able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. HGF-nucleolin interactions could be partially responsible for the complexity of HGF responses and met expression reported in the literature