Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment.

ContextPreeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.ObjectiveTo investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.Design and interventionFKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.Settings and participantsHuman samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid.Main outcome measuresPreeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed.ResultsThe CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis.ConclusionsThe FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes

Control of interjoint coordination during the swing phase of normal gait at different speeds

BACKGROUND: It has been suggested that the control of unconstrained movements is simplified via the imposition of a kinetic constraint that produces dynamic torques at each moving joint such that they are a linear function of a single motor command. The linear relationship between dynamic torques at each joint has been demonstrated for multijoint upper limb movements. The purpose of the current study was to test the applicability of such a control scheme to the unconstrained portion of the gait cycle – the swing phase. METHODS: Twenty-eight neurologically normal individuals walked along a track at three different speeds. Angular displacements and dynamic torques produced at each of the three lower limb joints (hip, knee and ankle) were calculated from segmental position data recorded during each trial. We employed principal component (PC) analysis to determine (1) the similarity of kinematic and kinetic time series at the ankle, knee and hip during the swing phase of gait, and (2) the effect of walking speed on the range of joint displacement and torque. RESULTS: The angular displacements of the three joints were accounted for by two PCs during the swing phase (Variance accounted for – PC1: 75.1 ± 1.4%, PC2: 23.2 ± 1.3%), whereas the dynamic joint torques were described by a single PC (Variance accounted for – PC1: 93.8 ± 0.9%). Increases in walking speed were associated with increases in the range of motion and magnitude of torque at each joint although the ratio describing the relative magnitude of torque at each joint remained constant. CONCLUSION: Our results support the idea that the control of leg swing during gait is simplified in two ways: (1) the pattern of dynamic torque at each lower limb joint is produced by appropriately scaling a single motor command and (2) the magnitude of dynamic torque at all three joints can be specified with knowledge of the magnitude of torque at a single joint. Walking speed could therefore be altered by modifying a single value related to the magnitude of torque at one joint

Cost per fall: a potentially misleading indicator of burden of disease in health and residential care settings

Rationale Little scrutiny has been applied to how ‘cost per fall’ values have been calculated and applied. This paper presents discourse discussing how the cost of fall statistic could potentially be misleading when applied to inpatient health or residential care settings and provides estimates of the cost of falls and cost of falls per person. Method Burden of disease was estimated using a decision tree approach. Data informing the decision tree were drawn from a retrospective audit of 545 falls in a residential care facility, a visual observation study of 46 residents from the same facility and a cohort study of 186 residents from nine different facilities in Australia. Acute care and transportation costs were extracted from the retrospective audit using incident reports and care note review. The distribution of falls per person and associations between falls, fractures and change in resident mobility were extracted from the cohort study. The association between resident mobility and the amount of time required to perform toileting, transfer and dressing activities was extracted from the visual observational study. Results The minimum ‘cost per fall’ was estimated to be $AUD 841 and the maximum was$AUD 1024. The ‘cost of falls per person’ estimate was $AUD 1887 (2008 base year). Conclusions This cost per fall estimate was substantially lower than three previous internationally derived estimates possibly as a consequence of how fall data were collected and modelled in these studies. Cost of falls per person may be a preferable statistic for future use

A hierarchical approach to removal of unwanted variation for large-scale metabolomics data

Liquid chromatography-mass spectrometry-based metabolomics studies are increasingly applied to large population cohorts, which run for several weeks or even years in data acquisition. This inevitably introduces unwanted intra- and inter-batch variations over time that can overshadow true biological signals and thus hinder potential biological discoveries. To date, normalisation approaches have struggled to mitigate the variability introduced by technical factors whilst preserving biological variance, especially for protracted acquisitions. Here, we propose a study design framework with an arrangement for embedding biological sample replicates to quantify variance within and between batches and a workflow that uses these replicates to remove unwanted variation in a hierarchical manner (hRUV). We use this design to produce a dataset of more than 1000 human plasma samples run over an extended period of time. We demonstrate significant improvement of hRUV over existing methods in preserving biological signals whilst removing unwanted variation for large scale metabolomics studies. Our tools not only provide a strategy for large scale data normalisation, but also provides guidance on the design strategy for large omics studies

Less waste on waist measurements: Determination of optimal waist circumference measurement site to predict visceral adipose tissue in postmenopausal women with obesity

With obesity being a leading cause of preventable death, it is vital to understand how best to identify individuals with greater risk of metabolic disease, especially those with high visceral adipose tissue (VAT). This study aimed to determine whether three commonly used waist circumference (WC) measurement sites could provide accurate estimations of VAT, as determined by magnetic resonance imaging (MRI), which is a gold standard for measuring VAT, in postmenopausal women with obesity. VAT volume was measured by MRI of the total abdomen in 97 women aged 57.7 ± 0.4 years (mean ± SEM), mean body mass index 34.5 ± 0.2 kg/m2. WC was measured at the midpoint between the lowest rib and the iliac crest (WCmid), the narrowest point of the torso (WCnarrow), and at the level of the umbilicus (WCumbilicus). WC differed significantly according to measurement site, with WCnarrow (102.1 ± 0.7 cm) mid (108.3 ± 0.7 cm) umbilicus (115.7 ± 0.8 cm) (p mid, WCnarrow and WCumbilicus were all significantly correlated with VAT, as measured by MRI (r = 0.581, 0.563 and 0.390, respectively; p mid or WCnarrowand VAT determined by MRI were stronger than for WCumbilicus. Measurement of either WCmid or WCnarrow provides valid estimates of VAT in postmenopausal women with obesity, with WCnarrow being favoured in light of its greater ease and speed of measurement in this population

Effect of Weight Loss via Severe vs Moderate Energy Restriction on Lean Mass and Body Composition Among Postmenopausal Women With Obesity: The TEMPO Diet Randomized Clinical Trial

Importance:Severely energy-restricted diets are the most effective dietary obesity treatment. However, there are concerns regarding potential adverse effects on body composition. Objective: To compare the long-term effects of weight loss via severe vs moderate energy restriction on lean mass and other aspects of body composition. Design, setting, and participants: The Type of Energy Manipulation for Promoting Optimum Metabolic Health and Body Composition in Obesity (TEMPO) Diet Trial was a 12-month, singlecenter, randomized clinical trial. A total of 101 postmenopausal women, aged 45 to 65 years with body mass index (calculated as weight in kilograms divided by height in meters squared) from 30 to 40, who were at least 5 years after menopause, had fewer than 3 hours of structured physical activity per week, and lived in the Sydney metropolitan area of New South Wales, Australia, were recruited between March 2013 and July 2016. Data analysis was conducted between October 2018 and August 2019. Intervention: Participants were randomized to either 12 months of moderate (25%-35%) energy restriction with a food-based diet (moderate intervention) or 4 months of severe (65%-75%) energy restriction with a total meal replacement diet followed by moderate energy restriction for an additional 8 months (severe intervention). Both interventions had a prescribed protein intake of 1.0 g/kg of actual body weight per day, and physical activity was encouraged but not supervised. Main outcomes and measures: The primary outcome was whole-body lean mass at 12 months after commencement of intervention. Secondary outcomes were body weight, thigh muscle area and muscle function (strength), bone mineral density, and fat mass and distribution, measured at 0, 4, 6, and 12 months. Results: A total of 101 postmenopausal women were recruited (mean [SD] age, 58.0 [4.2] years; mean [SD] weight, 90.8 [9.1] kg; mean [SD] body mass index, 34.4 [2.5]). Compared with the moderate group at 12 months, the severe group lost more weight (effect size, −6.6 kg; 95% CI, −8.2 to −5.1 kg), lost more whole-body lean mass (effect size, −1.2 kg; 95% CI, −2.0 to −0.4 kg), and lost more thigh muscle area (effect size, −4.2 cm2 ; 95% CI, −6.5 to −1.9 cm2 ). However, decreases in whole-body lean mass and thigh muscle area were proportional to total weight loss, and there was no difference in muscle (handgrip) strength between groups. Total hip bone mineral density (effect size, −0.017 g/cm2 ; 95% CI, −0.029 to −0.005 g/cm2 ), whole-body fat mass (effect size, −5.5 kg; 95% CI, −7.1 to −3.9 kg), abdominal subcutaneous adipose tissue (effect size, −1890 cm3 ; 95% CI, −2560 to −1219 cm3 ), and visceral adipose tissue (effect size, −1389 cm3 ; 95% CI, −1748 to −1030 cm3 ) loss were also greater for the severe group than for the moderate group at 12 months. Conclusions and relevance: Severe energy restriction had no greater adverse effect on relative whole-body lean mass or handgrip strength compared with moderate energy restriction and was associated with 2-fold greater weight and fat loss over 12 months. However, there was significantly greater loss of total hip bone mineral density with severe vs moderate energy restriction. Therefore, caution is necessary when implementing severe energy restriction in postmenopausal women, particularly those with osteopenia or osteoporosis.</p