Analysis and design optimization of an integrated micropump-micromixer operated for bio-MEMS applications

This paper was presented at the 4th Micro and Nano Flows Conference (MNF2014), which was held at University College, London, UK. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute, ASME Press, LCN London Centre for Nanotechnology, UCL University College London, UCL Engineering, the International NanoScience Community, www.nanopaprika.eu.A generic microfluidic system composed by two single chamber valveless micropumps connected to a simple T-type channel intersection is examined numerically. The characteristics of a feasible valveless micropump have been used in the design, where efficient mixing is produced due to the pulsating flow generated by the micropumps. The advantages of using time pulsing inlet flows for enhancing mixing in channels have been harnessed through the activation of intrinsic characteristics of the pumps required to achieve the periodic flows. A parametric study is carried out on this microfluidic system using Computational Fluids Dynamics (CFD)on a design space defined by a Design-of-Experiments (DOE) technique. The frequency f and the phase difference f of the periodic fluid velocities (operation parameters) and the angle q formed by the inlet channels at the intersection (geometric parameter) are used as design parameters, whereas mixing quality, pressure drop and maximum shear strain rate in the channel are the performance parameters. The study identifies design features for which the pressure drop and shear strain are reduced whereas the mixing quality is increased. The proposed microfluidic system achieves high mixing quality with performance parameters that enable manipulation of biological fluids in microchannels

Electromagnetic Actuated stirring in Microbioreactors enabling easier multiplexing & flexible device design

This paper was presented at the 4th Micro and Nano Flows Conference (MNF2014), which was held at University College, London, UK. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute, ASME Press, LCN London Centre for Nanotechnology, UCL University College London, UCL Engineering, the International NanoScience Community, www.nanopaprika.eu.The development of a novel electromagnetically (EM) actuated stirring method, for use in microbioreactors, is reported. Mixing in microbioreactors is critical to ensure even distribution of nutrients to microorganisms and cells. Magnetically driven stirrer bars or peristaltic mixing are the most commonly utilised mixing methods employed in completely liquid-filled microbioreactors. However the circular reactor shape required for mixing with a stirrer bar and frequently used for peristaltically mixed microbioreactors presents difficulties for bubble-free priming in a microfluidic bioreactor. Moreover the circular shape and the hardware required for both types of mixing reduces the potential packing density of multiplexed reactors. We present a new method of mixing, displaying design flexibility by demonstrating mixing in circular and diamond-shaped reactors and a duplex diamond reactor and fermentation of the gram-positive bacteria S. carnosus in a diamond-shaped microbioreactor system. The results of the optimisation of this mixing method for performing fermentations alongside both batch and continuous culture fermentations are presented

The Ankyrin Repeat Domain of the TRPA Protein Painless Is Important for Thermal Nociception but Not Mechanical Nociception

The Drosophila TRPA channel Painless is required for the function of polymodal nociceptors which detect noxious heat and noxious mechanical stimuli. These functions of Painless are reminiscent of mammalian TRPA channels that have also been implicated in thermal and mechanical nociception. A popular hypothesis to explain the mechanosensory functions of certain TRP channels proposes that a string of ankyrin repeats at the amino termini of these channels acts as an intracellular spring that senses force. Here, we describe the identification of two previously unknown Painless protein isoforms which have fewer ankyrin repeats than the canonical Painless protein. We show that one of these Painless isoforms, that essentially lacks ankyrin repeats, is sufficient to rescue mechanical nociception phenotypes of painless mutant animals but does not rescue thermal nociception phenotypes. In contrast, canonical Painless, which contains Ankyrin repeats, is sufficient to largely rescue thermal nociception but is not capable of rescuing mechanical nociception. Thus, we propose that in the case of Painless, ankryin repeats are important for thermal nociception but not for mechanical nociception

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: results from a large Japanese postmarketing surveillance study

Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor–α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P < 0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment

Basal cutaneous pain threshold in headache patients

The aim of this study was to analyze cutaneous pain threshold (CPT) during the interictal phase in headache patients, and the relationships between headache frequency and analgesic use. A consecutive series of 98 headache patients and 26 sex- and age-balanced controls were evaluated. Acute allodynia (AA) was assessed by Jakubowski questionnaire, and interictal allodynia (IA) by a skin test with calibrated monofilaments. AA is widely known as a symptom more present in migraine than in TTH spectrum: in our study this was confirmed only in cases of episodic attacks. When headache index rises towards chronicization, the prevalence of AA increases in both headache spectrums (χ2 13.55; p < 0.01). AA was associated with IA only in cases of chronic headache. When headache becomes chronic, mostly in presence of medication overuse, interictal CPT decreases and IA prevalence increases (χ2 20.44; p < 0.01), with closer association than AA. In MOH patients there were no significant differences depending on the diagnosis of starting headache (migraine or tension type headache) and, in both groups, we found the overuse of analgesics plays an important role: intake of more than one daily drug dramatically reduces the CPT (p < 0.05). Thus, when acute allodynia increases frequency, worsens or appears for the first time in patients with a long-standing history of chronic headache, it could reasonably suggest that the reduction of CPT had started, without using a specific practical skin test but simply by questioning clinical headache history. In conclusion, these results indicate that the role of medication overuse is more important than chronicization in lowering CPT, and suggest that prolonged periods of medication overuse can interfere with pain perception by a reduction of the pain threshold that facilitates the onset of every new attack leading to chronicization

Tumour inoculation site-dependent induction of cachexia in mice bearing colon 26 carcinoma

Murine colon 26 carcinoma growing at either subcutaneous (s.c.) or intramuscular (i.m.) inoculation sites causes cachexia in mice. Such animals show extensive loss of body weight, wasting of the muscle and adipose tissues, hypoglycaemia, and hypercalcaemia, even when the tumour weight comprises only about 1.9% of carcass weight. In contrast, the same tumour when inoculated into the liver does not cause any sign of tumour-related cachexia even when the tumour becomes much larger (6.6% of carcass weight). Interleukin 6 (IL-6), a mediator associated with cachexia in this tumour model, is detected at high levels both in the tumour tissues and in the circulating blood of mice bearing colon 26 tumour at the s.c. inoculation site. In contrast, only minute levels of IL-6 are detected in the tumour grown in the liver. The colon 26 tumour grown in the liver does not lose its ability to cause cachexia, because the tumour when re-inoculated s.c. is able to cause extensive weight loss and produce IL-6 as did the original colon 26 cell line. Histological studies revealed differences in the composition of tumour tissues: the tumours grown in the subcutis consist of many polygonal tumour cells, extended-intercellular space, and high vascular density, whereas those grown in the liver consist of spindle-shaped tumour cells. Thus, the environment where tumour cells grow would be a critical factor in determining the cachectic phenotype of cancer cells, including their ability to produce IL-6. 1999 Cancer Research Campaig

Multifactorial day hospital intervention to reduce falls in high risk older people in primary care: a multi-centre randomised controlled trial [ISRCTN46584556]

Falls in older people are a major public health concern in terms of morbidity, mortality and cost. Previous studies suggest that multifactorial interventions can reduce falls, and many geriatric day hospitals are now offering falls intervention programmes. However, no studies have investigated whether these programmes, based in the day hospital are effective, nor whether they can be successfully applied to high-risk older people screened in primary care. The hypothesis is that a multidisciplinary falls assessment and intervention at Day hospitals can reduce the incidence of falls in older people identified within primary care as being at high risk of falling. This will be tested by a pragmatic parallel-group randomised controlled trial in which the participants, identified as at high risk of falling, will be randomised into either the intervention Day hospital arm or to a control (current practice) arm. Those participants preferring not to enter the full randomised study will be offered the opportunity to complete brief diaries only at monthly intervals. This data will be used to validate the screening questionnaire. Three day hospitals (2 Nottingham, 1 Derby) will provide the interventions, and the University of Nottingham's Departments of Primary Care, the Division of Rehabilitation and Ageing Unit, and the Trent Institute for Health Service Research will provide the methodological and statistical expertise. Four hundred subjects will be randomised into the two arms. The primary outcome measure will be the rate of falls over one year. Secondary outcome measures will include the proportion of people experiencing at least one fall, the proportion of people experiencing recurrent falls (>1), injuries, fear of falling, quality of life, institutionalisation rates, and use of health services. Cost-effectiveness analyses will be performed to inform health commissioners about resource allocation issues. The importance of this trial is that the results may be applicable to any UK day hospital setting. SITES: General practices across Nottinghamshire and Derbyshire. Day hospitals: Derbyshire Royal Infirmary (Southern Derbyshire Acute Hospitals NHS Trust) Sherwood Day Service (Nottingham City Hospital Trust) Leengate Day Hospital (Queen's Medical Centre Nottingham University Hospital NHS Trust