Engineered acetoacetate-inducible whole-cell biosensors based on the AtoSC two-component system

Whole-cell biosensors hold potential in a variety of industrial, medical and environmental applications. These biosensors can be constructed through the repurposing of bacterial sensing mechanisms, including the common two-component system. Here we report on the construction of a range of novel biosensors that are sensitive to acetoacetate, a molecule that plays a number of roles in human health and biology. These biosensors are based on the AtoSC two-component system. An ordinary differential equation model to describe the action of the AtoSC two-component system was developed and sensitivity analysis of this model used to help inform biosensor design. The final collection of biosensors constructed displayed a range of switching behaviours, at physiologically relevant acetoacetate concentrations and can operate in several Escherichia coli host strains. It is envisaged that these biosensor strains will offer an alternative to currently available commercial strip tests and, in future, may be adopted for more complex in vivo or industrial monitoring applications

How early can myocardial iron overload occur in Beta thalassemia major?

BACKGROUND: Myocardial siderosis is the most common cause of death in patients with beta thalassemia major(TM). This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Chinese population with beta TM. METHODS AND RESULTS: We analyzed T2* cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in 201 beta TM patients. The median age was 9 years old. Patients received an average of 13 units of blood per year. The median SF level was 4536 ng/ml and 165 patients (82.1%) had SF>2500 ng/ml. Myocardial iron overload was detected in 68 patients (33.8%) and severe myocardial iron overload was detected in 26 patients (12.6%). Twenty-two patients ≤10 years old had myocardial iron overload, three of whom were only 6 years old. No myocardial iron overload was detected under the age of 6 years. Median LVEF was 64% (measured by CMR in 175 patients). Five of 6 patients with a LVEF<56% and 8 of 10 patients with cardiac disease had myocardial iron overload. CONCLUSIONS: The TM patients under follow-up at this regional centre in China patients are younger than other reported cohorts, more poorly-chelated, and have a high burden of iron overload. Myocardial siderosis occurred in patients younger than previously reported, and was strongly associated with impaired LVEF and cardiac disease. For such poorly-chelated TM patients, our data shows that the first assessment of cardiac T2* should be performed as early as 6 years old

The Stature of Boys Is Inversely Correlated to the Levels of Their Sertoli Cell Hormones: Do the Testes Restrain the Maturation of Boys?

The testes of preadolescent boys appear to be dormant, as they produce only trace levels of testosterone [1]. However, they release supra-adult levels of Müllerian Inhibiting Substance (MIS, anti-Müllerian hormone) and lesser levels of inhibin B (InhB), for unknown reasons [2], [3]. Boys have a variable rate of maturation, which on average is slower than girls. The height of children relative to their parents is an index of their maturity [4], [5]. We report here that a boy's level of MIS and InhB is stable over time and negatively correlates with his height and his height relative to his parent's height. This suggests that boy's with high levels of MIS and InhB are short because they are immature, rather than because they are destined to be short men. The levels of MIS and InhB in the boys did not correlate with known hormonal modulators of growth, and were additive with age and the growth hormone/IGF1 axis as predictors of a boy's height. If MIS and InhB were causal regulators of maturity, then the inter-boy differences in the levels of these hormone produces variation in maturation equivalent to 18-months of development. MIS and InhB may thus account for most of the variation in the rate of male development. If boys lacked these hormones, then an average 5-year-old boy would be over 5 cm taller than age-matched girls, making boys almost as dimorphic as men, for height. This indicates that boys have a high growth potential that is initially suppressed by their testes. The concept of the childhood testes suppressing an adult male feature appears paradoxical. However, the growth of children requires intergenerational transfer of nutrients. Consequently, the MIS/InhB slowing of male growth may have been historically advantageous, as it would minimizes any sex bias in the maternal cost of early child rearing

A systematic review of the evidence for single stage and two stage revision of infected knee replacement

BACKGROUND: Periprosthetic infection about the knee is a devastating complication that may affect between 1% and 5% of knee replacement. With over 79 000 knee replacements being implanted each year in the UK, periprosthetic infection (PJI) is set to become an important burden of disease and cost to the healthcare economy. One of the important controversies in treatment of PJI is whether a single stage revision operation is superior to a two-stage procedure. This study sought to systematically evaluate the published evidence to determine which technique had lowest reinfection rates. METHODS: A systematic review of the literature was undertaken using the MEDLINE and EMBASE databases with the aim to identify existing studies that present the outcomes of each surgical technique. Reinfection rate was the primary outcome measure. Studies of specific subsets of patients such as resistant organisms were excluded. RESULTS: 63 studies were identified that met the inclusion criteria. The majority of which (58) were reports of two-stage revision. Reinfection rated varied between 0% and 41% in two-stage studies, and 0% and 11% in single stage studies. No clinical trials were identified and the majority of studies were observational studies. CONCLUSIONS: Evidence for both one-stage and two-stage revision is largely of low quality. The evidence basis for two-stage revision is significantly larger, and further work into direct comparison between the two techniques should be undertaken as a priority

Índice de Massa Corporal, Idade, Maturação Sexual e a Incidência de Hiperlordose Lombar em crianças e adolescentes

Introduction: Hyperlordosis can cause several degenerative spinal pathologies in children and adolescents. Objective: Determine whether body mass index, age and sexual maturation predict the occurrence of hyperlordosis in children and adolescents. Method: The study analyzed 380 students aged between 10 and 18 years. Body mass index was evaluated using the reference values suggested by the Fitnessgram test battery, and sexual maturation through Tanner’s scale of self-assessed pubic hair growth. Postural assessment was conducted using the DIPA photogrammetry method, version 3.1. (Digital Image Based Postural Assessment) The SPSS 24.0 program was used to analyze the data, and the following statistical tests were applied: chi squared, Mann-Whitney, Fisher’s exact and binary logistic regression. Results: There was statistical significance between hyperlordosis, girls’ age and puberty in boys (p 0.05). Conclusion: The girls’ age and boys’ stage of puberty were associated with the occurrence of hyperlordosis.Introdução: A Hiperlordose lombar pode ocasionar diversas patologias degenerativas na coluna vertebral de crianças e adolescentes. Objetivo: Identificar se o Índice de Massa Corporal, a Idade e a Maturação Sexual são previsores da ocorrência da hiperlordose lombar em crianças e adolescentes. Método: O estudo analisou 380 estudantes entre 10 e 18 anos. O Índice de Massa Corporal foi avaliado por meio dos valores de referência sugeridos pela bateria de testes Fitnessgram e a maturação sexual por meio da auto-avaliação da pilosidade pubiana de Tanner. A avaliação postural foi realizada pelo método de fotogrametria DIPA versão 3.1. (Avaliação Postural Baseada em Imagem Digital). Para análise dos dados foi utilizado o programa SPSS 24.0, tendo sido aplicados os testes estatísticos: Qui-Quadrado, Mann Whitney, Exato de Fisher e Regressão Logística Binária. Resultados: Observou-se que houve significância estatística entre a Hiperlordose lombar e a idade das meninas e a puberdade dos meninos (p0,05). Conclusão: A idade das meninas e a puberdade dos meninos foi associada à ocorrência da hiperlordose lombar.This study was funded by CIEC (Center for Investigations in Childhood Studies), Strategic Project UID/CED/00317/2013, via National FCT (Science and Technology Foundation) funds and co-funded by the European Regional Development Fund (FEDER), via COMPETE 2020 – Competitivity and Internalization Operational Program (POCI) under reference number POCI-01-0145-FEDER-007562

On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure

<p>Abstract</p> <p>Background</p> <p>Trials of iron chelator regimens have increased the treatment options for cardiac siderosis in beta-thalassemia major (TM) patients. Treatment effects with improved left ventricular (LV) ejection fraction (EF) have been observed in patients without overt heart failure, but it is unclear whether these changes are clinically meaningful.</p> <p>Methods</p> <p>This retrospective study of a UK database of TM patients modelled the change in EF between serial scans measured by cardiovascular magnetic resonance (CMR) to the relative risk (RR) of future development of heart failure over 1 year. Patients were divided into 2 strata by baseline LVEF of 56-62% (below normal for TM) and 63-70% (lower half of the normal range for TM).</p> <p>Results</p> <p>A total of 315 patients with 754 CMR scans were analyzed. A 1% absolute increase in EF from baseline was associated with a statistically significant reduction in the risk of future development of heart failure for both the lower EF stratum (EF 56-62%, RR 0.818, p < 0.001) and the higher EF stratum (EF 63-70%, RR 0.893 p = 0.001).</p> <p>Conclusion</p> <p>These data show that during treatment with iron chelators for cardiac siderosis, small increases in LVEF in TM patients are associated with a significantly reduced risk of the development of heart failure. Thus the iron chelator induced improvements in LVEF of 2.6% to 3.1% that have been observed in randomized controlled trials, are associated with risk reductions of 25.5% to 46.4% for the development of heart failure over 12 months, which is clinically meaningful. In cardiac iron overload, heart mitochondrial dysfunction and its relief by iron chelation may underlie the changes in LV function.</p

Empirical Models of Transitions between Coral Reef States: Effects of Region, Protection, and Environmental Change

There has been substantial recent change in coral reef communities. To date, most analyses have focussed on static patterns or changes in single variables such as coral cover. However, little is known about how community-level changes occur at large spatial scales. Here, we develop Markov models of annual changes in coral and macroalgal cover in the Caribbean and Great Barrier Reef (GBR) regions

Effects of Androgen Receptor and Androgen on Gene Expression in Prostate Stromal Fibroblasts and Paracrine Signaling to Prostate Cancer Cells

The androgen receptor (AR) is expressed in a subset of prostate stromal cells and functional stromal cell AR is required for normal prostate developmental and influences the growth of prostate tumors. Although we are broadly aware of the specifics of the genomic actions of AR in prostate cancer cells, relatively little is known regarding the gene targets of functional AR in prostate stromal cells. Here, we describe a novel human prostate stromal cell model that enabled us to study the effects of AR on gene expression in these cells. The model involves a genetically manipulated variant of immortalized human WPMY-1 prostate stromal cells that overexpresses wildtype AR (WPMY-AR) at a level comparable to LNCaP cells and is responsive to dihydrotestosterone (DHT) stimulation. Use of WPMY-AR cells for gene expression profiling showed that the presence of AR, even in the absence of DHT, significantly altered the gene expression pattern of the cells compared to control (WPMY-Vec) cells. Treatment of WPMY-AR cells, but not WPMY-Vec control cells, with DHT resulted in further changes that affected the expression of 141 genes by 2-fold or greater compared to vehicle treated WPMY-AR cells. Remarkably, DHT significantly downregulated more genes than were upregulated but many of these changes reversed the initial effects of AR overexpression alone on individual genes. The genes most highly effected by DHT treatment were categorized based upon their role in cancer pathways or in cell signaling pathways (transforming growth factor-β, Wnt, Hedgehog and MAP Kinase) thought to be involved in stromal-epithelial crosstalk during prostate or prostate cancer development. DHT treatment of WPMY-AR cells was also sufficient to alter their paracrine potential for prostate cancer cells as conditioned medium from DHT-treated WPMY-AR significantly increased growth of LNCaP cells compared to DHT-treated WPMY-Vec cell conditioned medium

Suicidality among adolescents engaging in nonsuicidal self-injury (NSSI) and firesetting: The role of psychosocial characteristics and reasons for living

Background: Co-occurrence of problem behaviors, particularly across internalizing and externalizing spectra, increases the risk of suicidality (i.e., suicidal ideation and attempt) among youth. Methods: We examined differences in psychosocial risk factors across levels of suicidality in a sample of 77 school-based adolescents engaging in both nonsuicidal self-injury (NSSI) and repeated firesetting. Participants completed questionnaires assessing engagement in problem behaviors, mental health difficulties, negative life events, poor coping, impulsivity, and suicidality. Results: Adolescents endorsing suicidal ideation reported greater psychological distress, physical and sexual abuse, and less problem solving/goal pursuit than those with no history of suicidality; adolescents who had attempted suicide reported more severe NSSI, higher rates of victimization and exposure to suicide, relative to those with suicidal ideation but no history of attempt. Additional analyses suggested the importance of coping beliefs in protecting against suicidality. Conclusions: Clinical implications and suggestions for future research relating to suicide prevention are discussed

Lower limb strength training in children with cerebral palsy – a randomized controlled trial protocol for functional strength training based on progressive resistance exercise principles

<p>Abstract</p> <p>Background</p> <p>Until recently, strength training in children with cerebral palsy (CP) was considered to be inappropriate, because it could lead to increased spasticity or abnormal movement patterns. However, the results of recent studies suggest that progressive strength training can lead to increased strength and improved function, but low methodological quality and incomplete reporting on the training protocols hampers adequate interpretation of the results. This paper describes the design and training protocol of a randomized controlled trial to assess the effects of a school-based progressive functional strength training program for children with CP.</p> <p>Methods/Results</p> <p>Fifty-one children with Gross Motor Function Classification Systems levels I to III, aged of 6 to 13 years, were recruited. Using stratified randomization, each child was assigned to an intervention group (strength training) or a control group (usual care). The strength training was given in groups of 4–5 children, 3 times a week, for a period of 12 weeks. Each training session focussed on four exercises out of a 5-exercise circuit. The training load was gradually increased based on the child's maximum level of strength, as determined by the 8 Repetition Maximum (8 RM). To evaluate the effectiveness of the training, all children were evaluated before, during, directly after, and 6 weeks after the intervention period. Primary outcomes in this study were gross motor function (measured with the Gross Motor Function Measure and functional muscle strength tests) and walking ability (measured with the 10-meter, the 1-minute and the timed stair test). Secondary outcomes were lower limb muscle strength (measured with a 6 RM test, isometric strength tests, and a sprint capacity test), mobility (measured with a mobility questionnaire), and sport activities (measured with the Children's Assessment of Participation and Enjoyment). Spasticity and range of motion were assessed to evaluate any adverse events.</p> <p>Conclusion</p> <p>Randomized clinical trials are considered to present the highest level of evidence. Nevertheless, it is of utmost importance to report on the design, the applied evaluation methods, and all elements of the intervention, to ensure adequate interpretation of the results and to facilitate implementation of the intervention in clinical practice if the results are positive.</p> <p>Trial Registration</p> <p>Trial Register NTR1403</p