SCAMP:standardised, concentrated, additional macronutrients, parenteral nutrition in very preterm infants: a phase IV randomised, controlled exploratory study of macronutrient intake, growth and other aspects of neonatal care

<p>Abstract</p> <p>Background</p> <p>Infants born <29 weeks gestation are at high risk of neurocognitive disability. Early postnatal growth failure, particularly head growth, is an important and potentially reversible risk factor for impaired neurodevelopmental outcome. Inadequate nutrition is a major factor in this postnatal growth failure, optimal protein and calorie (macronutrient) intakes are rarely achieved, especially in the first week. Infants <29 weeks are dependent on parenteral nutrition for the bulk of their nutrient needs for the first 2-3 weeks of life to allow gut adaptation to milk digestion. The prescription, formulation and administration of neonatal parenteral nutrition is critical to achieving optimal protein and calorie intake but has received little scientific evaluation. Current neonatal parenteral nutrition regimens often rely on individualised prescription to manage the labile, unpredictable biochemical and metabolic control characteristic of the early neonatal period. Individualised prescription frequently fails to translate into optimal macronutrient delivery. We have previously shown that a standardised, concentrated neonatal parenteral nutrition regimen can optimise macronutrient intake.</p> <p>Methods</p> <p>We propose a single centre, randomised controlled exploratory trial of two standardised, concentrated neonatal parenteral nutrition regimens comparing a standard macronutrient content (maximum protein 2.8 g/kg/day; lipid 2.8 g/kg/day, dextrose 10%) with a higher macronutrient content (maximum protein 3.8 g/kg/day; lipid 3.8 g/kg/day, dextrose 12%) over the first 28 days of life. 150 infants 24-28 completed weeks gestation and birthweight <1200 g will be recruited. The primary outcome will be head growth velocity in the first 28 days of life. Secondary outcomes will include a) auxological data between birth and 36 weeks corrected gestational age b) actual macronutrient intake in first 28 days c) biomarkers of biochemical and metabolic tolerance d) infection biomarkers and other intravascular line complications e) incidence of major complications of prematurity including mortality f) neurodevelopmental outcome at 2 years corrected gestational age</p> <p>Trial registration</p> <p>Current controlled trials: <a href="http://www.controlled-trials.com/ISRCTN76597892">ISRCTN76597892</a>; EudraCT Number: 2008-008899-14</p

Suppression of HBV by Tenofovir in HBV/HIV coinfected patients : a systematic review and meta-analysis

Background: Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. Methods: A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. Results: Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. Interpretation: TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways

Interference of functional dual-tasks on gait in untrained people with Parkinson's disease and healthy controls: a cross-sectional study

[EN] Background In Parkinson's disease (PD) population, performing secondary tasks while walking further deteriorates gait and restrict mobility in functional contexts of daily life. This study (1) analyzed the interference of functional cognitive and motor secondary task on untrained people with PD and (2) compared their walking with healthy subjects. Methods Forty people with PD (aged 66.72 [7.5] years, Hoehn and Yahr stage I-II-III, on-medication) composed the PD group (PDG) and 43 participants (aged 66.60 [8.75] years) formed the group of healthy counterparts (HG). Gait was evaluated through spatiotemporal, kinematic and kinetic outcomes in five conditions: single task (ST) and visual, verbal, auditory and motor dual-task (DT). Results The velocity, stride length, and braking force performance of both groups was statistically higher in the ST condition than in verbal, auditory and motor DT (p.05). Conclusions: In untrained participants with PD, verbal and motor secondary tasks affect gait significantly, while auditory and visual tasks interfere to a lesser extent. Untrained people with PD have a poorer gait performance than their healthy counterparts, but in different grades according to the analyzed variables. Trial registration The data in this paper are part of a single-blind, randomized, controlled trial and correspond to the evaluations performed before a physical rehabilitation program, retrospectively registered with the number at clinicaltrial.govNCT04038866.San Martín Valenzuela, C.; Dueñas Moscardó, L.; Lopez Pascual, J.; Serra-Añó, P.; Tomás, JM. (2020). Interference of functional dual-tasks on gait in untrained people with Parkinson's disease and healthy controls: a cross-sectional study. BMC Musculoskeletal Disorders. 21(1):1-11. https://doi.org/10.1186/s12891-020-03431-xS111211Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79:368–76.Soh S-E, McGinley JL, Watts JJ, Iansek R, Murphy AT, Menz HB, et al. Determinants of health-related quality of life in people with Parkinson’s disease: a path analysis. Qual Life Res. 2013;22:1543–53.Tan D, Danoudis M, McGinley J, Morris ME. Relationships between motor aspects of gait impairments and activity limitations in people with Parkinson’s disease: a systematic review. Parkinsonism Relat Disord. 2012;18:117–24.Kelly VE, Eusterbrock AJ, Shumway-Cook A. A review of dual-task walking deficits in people with Parkinson’s disease: motor and cognitive contributions, mechanisms, and clinical implications. Parkinson’s Disease. 2012;918719.Sofuwa O, Nieuwboer A, Desloovere K, Willems A-M, Chavret F, Jonkers I. Quantitative gait analysis in Parkinson’s disease: comparison with a healthy control group. Arch Phys Med Rehabil. 2005;86:1007–13.Beauchet O, Berrut G. Gait and dual-task: definition, interest, and perspectives in the elderly. Psychologie et NeuroPsychiatrie du Vieillissement. 2006;4:215–25.Raffegeau TE, Krehbiel LM, Kang N, Thijs FJ, Altmann LJP, Cauraugh JH, et al. A meta-analysis: Parkinson’s disease and dual-task walking. Parkinsonism Relat Disord. 2019 May;62:28–35.Eric R. Kandel, James H. Schwartz, Thomas M. Jessell, Steven a. Siegelbaum, A. J. Hudspeth. Principles of neural science. Fifth edition. McGraw-Hill Medical: United States of America; 2013.Eisinger RS, Cernera S, Gittis A, Gunduz A, Okun MS. A review of basal ganglia circuits and physiology: application to deep brain stimulation. Parkinsonism Relat Disord. 2019 Feb;59:9–20.Isella V, Mapelli C, Morielli N, De Gaspari D, Siri C, Pezzoli G, et al. Validity and metric of MiniMental Parkinson and MiniMental state examination in Parkinson’s disease. Neurol Sci. 2013;34:1751–8.Morris ME, McGinley J, Huxham F, Collier J, Iansek R. Constraints on the kinetic, kinematic and spatiotemporal parameters of gait in Parkinson’s disease. Hum Mov Sci. 1999;18:461–83.Brauer SG, Morris ME. Can people with Parkinson’s disease improve dual tasking when walking? Gait & Posture. 2010;31:229–33.Baron EI, Miller Koop M, Streicher MC, Rosenfeldt AB, Alberts JL. Altered kinematics of arm swing in Parkinson’s disease patients indicates declines in gait under dual-task conditions. Parkinsonism Relat Disord. 2018;48:61–7.Rochester L, Galna B, Lord S, Burn D. The nature of dual-task interference during gait in incident Parkinson’s disease. Neuroscience. 2014;265:83–94.Logan D, Kiemel T, Dominici N, Cappellini G, Ivanenko Y, Lacquaniti F, et al. The many roles of vision during walking. Exp Brain Res. 2010;206:337–50.de Luna RA, Mihailovic A, Nguyen AM, Friedman DS, Gitlin LN, Ramulu PY. The Association of Glaucomatous Visual Field Loss and Balance. Transl Vis Sci Technol. 2017 May 22;6(3):8.Suarez H, Geisinger D, Ferreira ED, Nogueira S, Arocena S, Roman CS, et al. Balance in Parkinson’s disease patients changing the visual input. Brazilian Journal of Otorhinolaryngology. 2011;77:651–5.Wu T, Hallett M. Neural correlates of dual task performance in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2008;79:760–6.Canning CG. The effect of directing attention during walking under dual-task conditions in Parkinson’s disease. Parkinsonism Relat Disord. 2005;11:95–9.Wu T, Liu J, Zhang H, Hallett M, Zheng Z, Chan P. Attention to automatic movements in Parkinson’s disease: modified automatic mode in the striatum. Cereb Cortex. 2015;25:3330–42.de Roiz R. M, Cacho EWA, Pazinatto MM, Reis JG, Cliquet a. Barasnevicius-Quagliato EMA Gait analysis comparing Parkinson’s disease with healthy elderly subjects Arq Neuropsiquiatr. 2010;68:81–6.Grabli D, Karachi C, Welter M-L, Lau B, Hirsch EC, Vidailhet M, et al. Normal and pathological gait: what we learn from Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2012 Oct;83(10):979–85.Anna C, Serena F, Maurizio F. Del Sorbo Francesca, Romito Luigi M., Elia Antonio E., et al. quantitative gait analysis in parkin disease: possible role of dystonia. Mov Disord. 2016;31:1720–8.Morris M, Iansek R, McGinley J, Matyas T, Huxham F. Three-dimensional gait biomechanics in Parkinson’s disease: evidence for a centrally mediated amplitude regulation disorder. Mov Disord. 2005;20:40–50.Peterson CL, Kautz SA, Neptune RR. Braking and propulsive impulses increase with speed during accelerated and decelerated walking. Gait Posture. 2011;33:562–7.Chiu M-C, Wang M-J. The effect of gait speed and gender on perceived exertion, muscle activity, joint motion of lower extremity, ground reaction force and heart rate during normal walking. Gait & Posture. 2007;25:385–92.Muniz AMS, Liu H, Lyons KE, Pahwa R, Liu W, Nobre FF, et al. Comparison among probabilistic neural network, support vector machine and logistic regression for evaluating the effect of subthalamic stimulation in Parkinson disease on ground reaction force during gait. J Biomech. 2010;43:720–6.Chastan N, Do MC, Bonneville F, Torny F, Bloch F, Westby GWM, et al. Gait and balance disorders in Parkinson’s disease: impaired active braking of the fall of Centre of gravity. Mov Disord. 2009;24:188–95.Perneger T. What's wrong with Bonferroni adjustments. BMJ. 1998 Apr 18;316(7139):1236–8

Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12

Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia–ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2α-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856)

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

High-Resolution Imaging of the Retinal Nerve Fiber Layer in Normal Eyes Using Adaptive Optics Scanning Laser Ophthalmoscopy

To conduct high-resolution imaging of the retinal nerve fiber layer (RNFL) in normal eyes using adaptive optics scanning laser ophthalmoscopy (AO-SLO).AO-SLO images were obtained in 20 normal eyes at multiple locations in the posterior polar area and a circular path with a 3-4-mm diameter around the optic disc. For each eye, images focused on the RNFL were recorded and a montage of AO-SLO images was created.AO-SLO images for all eyes showed many hyperreflective bundles in the RNFL. Hyperreflective bundles above or below the fovea were seen in an arch from the temporal periphery on either side of a horizontal dividing line to the optic disc. The dark lines among the hyperreflective bundles were narrower around the optic disc compared with those in the temporal raphe. The hyperreflective bundles corresponded with the direction of the striations on SLO red-free images. The resolution and contrast of the bundles were much higher in AO-SLO images than in red-free fundus photography or SLO red-free images. The mean hyperreflective bundle width around the optic disc had a double-humped shape; the bundles at the temporal and nasal sides of the optic disc were narrower than those above and below the optic disc (P<0.001). RNFL thickness obtained by optical coherence tomography correlated with the hyperreflective bundle widths on AO-SLO (P<0.001)AO-SLO revealed hyperreflective bundles and dark lines in the RNFL, believed to be retinal nerve fiber bundles and Müller cell septa. The widths of the nerve fiber bundles appear to be proportional to the RNFL thickness at equivalent distances from the optic disc

High-throughput 454 resequencing for allele discovery and recombination mapping in Plasmodium falciparum

<p>Abstract</p> <p>Background</p> <p>Knowledge of the origins, distribution, and inheritance of variation in the malaria parasite (<it>Plasmodium falciparum</it>) genome is crucial for understanding its evolution; however the 81% (A+T) genome poses challenges to high-throughput sequencing technologies. We explore the viability of the Roche 454 Genome Sequencer FLX (GS FLX) high throughput sequencing technology for both whole genome sequencing and fine-resolution characterization of genetic exchange in malaria parasites.</p> <p>Results</p> <p>We present a scheme to survey recombination in the haploid stage genomes of two sibling parasite clones, using whole genome pyrosequencing that includes a sliding window approach to predict recombination breakpoints. Whole genome shotgun (WGS) sequencing generated approximately 2 million reads, with an average read length of approximately 300 bp. <it>De novo </it>assembly using a combination of WGS and 3 kb paired end libraries resulted in contigs ≤ 34 kb. More than 8,000 of the 24,599 SNP markers identified between parents were genotyped in the progeny, resulting in a marker density of approximately 1 marker/3.3 kb and allowing for the detection of previously unrecognized crossovers (COs) and many non crossover (NCO) gene conversions throughout the genome.</p> <p>Conclusions</p> <p>By sequencing the 23 Mb genomes of two haploid progeny clones derived from a genetic cross at more than 30× coverage, we captured high resolution information on COs, NCOs and genetic variation within the progeny genomes. This study is the first to resequence progeny clones to examine fine structure of COs and NCOs in malaria parasites.</p