Anthracyclines induce cardiotoxicity through a shared gene expression response signature.

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

Excitability properties of mouse and human skeletal muscle fibres compared by muscle velocity recovery cycles.

Mouse models of skeletal muscle channelopathies are not phenocopies of human disease. In some cases (e.g. Myotonia Congenita) the phenotype is much more severe, whilst in others (e.g. Hypokalaemic periodic paralysis) rodent physiology is protective. This suggests a species' difference in muscle excitability properties. In humans these can be measured indirectly by the post-impulse changes in conduction velocity, using Muscle Velocity Recovery Cycles (MVRCs). We performed MVRCs in mice and compared their muscle excitability properties with humans. Mouse Tibialis Anterior MVRCs (n = 70) have only one phase of supernormality (increased conduction velocity), which is smaller in magnitude (p = 9 × 10-21), and shorter in duration (p = 3 × 10-24) than human (n = 26). This abbreviated supernormality is followed by a period of late subnormality (reduced velocity) in mice, which overlaps in time with the late supernormality seen in human MVRCs. The period of late subnormality suggests increased t-tubule Na+/K+-pump activity. The subnormal phase in mice was converted to supernormality by blocking ClC-1 chloride channels, suggesting relatively higher chloride conductance in skeletal muscle. Our findings help explain discrepancies in phenotype between mice and humans with skeletal muscle channelopathies and potentially other neuromuscular disorders. MVRCs are a valuable new tool to compare in vivo muscle membrane properties between species and will allow further dissection of the molecular mechanisms regulating muscle excitability.

Optical analysis of glutamate spread in the neuropil.

Fast synaptic communication uses diffusible transmitters whose spread is limited by uptake mechanisms. However, on the submicron-scale, the distance between two synapses, the extent of glutamate spread has so far remained difficult to measure. Here, we show that quantal glutamate release from individual hippocampal synapses activates extracellular iGluSnFr molecules at a distance of >1.5 µm. 2P-glutamate uncaging near spines further showed that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-Rs and N-methyl-D-aspartate (NMDA)-Rs respond to distant uncaging spots at approximately 800 and 2000 nm, respectively, when releasing the amount of glutamate contained in approximately five synaptic vesicles. The uncaging-induced remote activation of AMPA-Rs was facilitated by blocking glutamate transporters but only modestly decreased by elevating the recording temperature. When mimicking release from neighboring synapses by three simultaneous uncaging spots in the microenvironment of a spine, AMPA-R-mediated responses increased supra-additively. Interfering with extracellular glutamate diffusion through a glutamate scavenger system weakly reduced field synaptic responses but not the quantal amplitude. Together, our data suggest that the neuropil is more permissive to short-range spread of transmitter than suggested by theory, that multivesicular release could regularly coactivate nearest neighbor synapses and that on this scale glutamate buffering by transporters primarily limits the spread of transmitter and allows for cooperative glutamate signaling in extracellular microdomains.

Clinical and genetic spectrum of a Chinese cohort with SCN4A gene mutations.

Skeletal muscle sodium channelopathies due to SCN4A gene mutations have a broad clinical spectrum. However, each phenotype has been reported in few cases of Chinese origin. We present detailed phenotype and genotype data from a cohort of 40 cases with SCN4A gene mutations seen in neuromuscular diagnostic service in Huashan hospital, Fudan University. Cases were referred from 6 independent provinces from 2010 to 2018. A questionnaire covering demographics, precipitating factors, episodes of paralysis and myotonia was designed to collect the clinical information. Electrodiagnostic studies and muscle MRI were retrospectively analyzed. The clinical spectrum of patients included: 6 Hyperkalemic periodic paralysis (15%), 18 Hypokalemic periodic paralysis (45%), 7 sodium channel myotonia (17.5%), 4 paramyotonia congenita (10%) and 5 heterozygous asymptomatic mutation carriers (12.5%). Review of clinical information highlights a significant delay to diagnosis (median 15 years), reports of pain and myalgia in the majority of patients, male predominance, circadian rhythm and common precipitating factors. Electrodiagnostic studies revealed subclinical myotonic discharges and a positive long exercise test in asymptomatic carriers. Muscle MRI identified edema and fatty infiltration in gastrocnemius and soleus. A total of 13 reported and 2 novel SCN4A mutations were identified with most variants distributed in the transmembrane helix S4 to S6, with a hotspot mutation p.Arg675Gln accounting for 32.5% (13/40) of the cohort. Our study revealed a higher proportion of periodic paralysis in SCN4A-mutated patients compared with cohorts from England and the Netherlands. It also highlights the importance of electrodiagnostic studies in diagnosis and segregation studies.

The next step: a strategic focus on physical activity and sedentary behaviour in Irish mental health care.

People with severe mental illnesses have dramatically reduced life expectancy compared with the general population, which is largely attributed to physical comorbidity. Physical activity and sedentary behaviour interventions offer a safe and viable therapeutic resource for multi-disciplinary mental health care teams. The accumulating evidence supporting the role of these interventions has changed the focus of mental health strategy in some countries, with new developing roles for certain mental health professionals in this field. However, in Ireland the absence of specialised exercise practitioners places a leadership role for mental health nurses in this regard. National mental health strategy in Ireland should prioritise physical activity and sedentary behaviour interventions, make recommendations for the integration of specialised exercise practitioners in all mental health multidisciplinary teams, and recommend the provision of training and awareness for mental health nurses and other multidisciplinary professionals who are already well placed to address this issue.

Importance of immunohistochemical evaluation of developmentally regulated myosin heavy chains in human muscle biopsies.

Our retrospective immunohistochemical study of normal quadriceps muscle biopsies shows that embryonic myosin heavy chains are down-regulated by, or soon after, birth. Fetal myosin heavy chains are down-regulated by 4-6 months. Thus the presence of an appreciable number of fibres with embryonic myosin heavy chains at birth or of fetal myosin heavy chains after 6 months of age suggests a delay in maturation or an underlying abnormality. Regenerating fibres in dystrophic muscle often co-express both embryonic and fetal myosin heavy chains but more fibres with fetal than embryonic myosin heavy chains can occur. Embryonic myosin heavy chains are a useful marker of regeneration but effects of denervation, stress, disuse, and fibre maintenance also have to be taken into account. In neurogenic disorders fibres with embryonic myosin heavy chains are rare but fetal myosin heavy chain expression is common, particularly in 5q spinal muscle atrophy. Nuclear clumps in denervated muscle show fetal and sometimes embryonic myosin heavy chains. Developmentally regulated myosins are useful for highlighting the perifascicular atrophy in juvenile dermatomyositis. Our studies highlight the importance of baseline data for embryonic and fetal myosin heavy chains in human muscle biopsies and the importance of assessing them in a spectrum of neuromuscular disorders.

Oral saline consumption and pressor responses to acute physical stress.

Sodium induced volume loading may alter pressor responses to physical stress, an early symptom of cardiovascular disease. PURPOSE: Study 1: Determine the time point where total blood volume and serum sodium were elevated following saline consumption. Study 2: Examine the BP response to isometric handgrip (HG) and the cold pressor test (CPT) following saline consumption. METHODS: Study 1: Eight participants drank 423 mL of normal saline (sodium 154 mmol/L) and had blood draws every 30 min for 3 h. Study 2: Sixteen participants underwent two randomized data collection visits; a control and experimental visit 90 min following saline consumption. Participants underwent 2 min of isometric HG, post exercise ischemia (PEI), and CPT. RESULTS: Study 1: Total blood volume (3.8 ± 3.0 Δ%) and serum sodium (3.5 ± 3.6 Δ%) were elevated (P < 0.05) by the 90 min time point. Study 2: There were no differences in mean arterial pressure (MAP) during HG (EXP: 17.4 ± 8.2 ΔmmHg; CON: 19.1 ± 6.0 ΔmmHg), PEI (EXP: 16.9 ± 11.7 ΔmmHg; CON: 16.9 ± 7.8 ΔmmHg), or the CPT (EXP: 20.3 ± 10.8 ΔmmHg; CON: 20.9 ± 11.7 ΔmmHg) between conditions (P > 0.05). MAP recovery from the CPT was slower following saline consumption (1 min recovery: EXP; 15.7 ± 7.9 ΔmmHg, CON; 12.3 ± 8.9 ΔmmHg, P < 0.05). CONCLUSION: Data showed no difference in cardiovascular responses during HG or the CPT between conditions. BP recovery was delayed by saline consumption following the CPT.

Methane emission from high latitude lakes: methane-centric lake classification and satellite-driven annual cycle of emissions.

Methane (CH4) is emitted from lakes by several processes: bubbles released from bottom sediments that reach the atmosphere (ebullition); spring release of CH4 trapped in bubbles in and under the ice during fall freeze (bubble release), and diffusion of CH4 from sediments to the surface. Each of these emission routes is highly variable over space and time, and episodic in the extreme, making reliable measurements difficult to carry out. However, lakes are receiving increasing interest for their important contribution to global CH4 emissions. Their area, distribution and emissions respond to interannual and longer-term climate fluctuations and close to half the world's lake area is in high northern latitudes that are experiencing rapidly-warming temperatures and lengthening thaw periods. We report on a new spatially-explicit data set of lakes > 50°N, classified with methane-relevant criteria. The seasonality of daily CH4 fluxes is driven with satellite observations of thaw timing and duration. We found that observed thaw seasons are 10-30% shorter than those assumed in previous studies. The area of lakes is 1,095 × 103 km2 and total CH4 emission is 13.8-17.7 Tg CH4 year-1: 11.2-14.4 Tg via diffusion and ebullition and 2.6-3.3 Tg from spring release of CH4 stored in bubbles in winter lake ice. This novel suite of data and methodologies provides a unique framework to model CH4 emission from lakes under current, past and future climates.

Meta-analyses of randomized controlled trials reporting the effect of home foot temperature monitoring, patient education or offloading footwear on the incidence of diabetes-related foot ulcers.

AIM: The aim of this study was to perform an up-to-date systematic review and meta-analysis of randomized controlled trials (RCTs) examining the efficacy of home foot temperature monitoring, patient education and offloading footwear in reducing the incidence of diabetes-related foot ulcers. METHODS: A literature search was performed using MEDLINE, PubMed, CINAHL, Scopus and Cochrane databases to identify relevant original studies. Meta-analyses were performed using intention-to-treat principals for worst (main analysis) and best (sub-analysis) case scenarios. Leave-one-out sensitivity analyses were used to assess the consistency of findings. RESULTS: Of 7575 unique records, 17 RCTs involving 2729 participants were included. Four tested home foot temperature monitoring (n = 468), six examined patient education (n = 823) and seven assessed offloading footwear (n = 1438). Participants' who performed home foot temperature monitoring [odds ratio (OR) 0.51, 95% confidence interval (CI) 0.31 to 0.84; n = 468] and those provided offloading footwear (OR 0.48, 95% CI 0.29 to 0.80; n = 1438) were less likely to develop a diabetes-related foot ulcer. Patient education programmes did not significantly reduce diabetes-related foot ulcer incidence (OR 0.59, 95% CI 0.29 to 1.20; n = 823). Sensitivity analyses suggested that offloading footwear findings were consistent, but home foot temperature findings were dependent on the individual inclusion of one trial. All RCTs had either high or unclear risk of bias. CONCLUSION: This meta-analysis suggests that offloading footwear is effective in reducing the incidence of diabetes-related foot ulcers. Home foot temperature monitoring also appears beneficial but larger trials are needed (PROSPERO registration no.: CRD42019135226).

Assessing physical activity in people with mental illness: 23-country reliability and validity of the simple physical activity questionnaire (SIMPAQ).

BACKGROUND: Physical inactivity is a key contributor to the global burden of disease and disproportionately impacts the wellbeing of people experiencing mental illness. Increases in physical activity are associated with improvements in symptoms of mental illness and reduction in cardiometabolic risk. Reliable and valid clinical tools that assess physical activity would improve evaluation of intervention studies that aim to increase physical activity and reduce sedentary behaviour in people living with mental illness. METHODS: The five-item Simple Physical Activity Questionnaire (SIMPAQ) was developed by a multidisciplinary, international working group as a clinical tool to assess physical activity and sedentary behaviour in people living with mental illness. Patients with a DSM or ICD mental illness diagnoses were recruited and completed the SIMPAQ on two occasions, one week apart. Participants wore an Actigraph accelerometer and completed brief cognitive and clinical assessments. RESULTS: Evidence of SIMPAQ validity was assessed against accelerometer-derived measures of physical activity. Data were obtained from 1010 participants. The SIMPAQ had good test-retest reliability. Correlations for moderate-vigorous physical activity was comparable to studies conducted in general population samples. Evidence of validity for the sedentary behaviour item was poor. An alternative method to calculate sedentary behaviour had stronger evidence of validity. This alternative method is recommended for use in future studies employing the SIMPAQ. CONCLUSIONS: The SIMPAQ is a brief measure of physical activity and sedentary behaviour that can be reliably and validly administered by health professionals.

Between- and within-herd variation in blood and milk biomarkers in Holstein cows in early lactation.

Both blood- and milk-based biomarkers have been analysed for decades in research settings, although often only in one herd, and without focus on the variation in the biomarkers that are specifically related to herd or diet. Biomarkers can be used to detect physiological imbalance and disease risk and may have a role in precision livestock farming (PLF). For use in PLF, it is important to quantify normal variation in specific biomarkers and the source of this variation. The objective of this study was to estimate the between- and within-herd variation in a number of blood metabolites (ß-hydroxybutyrate (BHB), non-esterified fatty acids, glucose and serum IGF-1), milk metabolites (free glucose, glucose-6-phosphate, urea, isocitrate, BHB and uric acid), milk enzymes (lactate dehydrogenase and N-acetyl-ß-D-glucosaminidase (NAGase)) and composite indicators for metabolic imbalances (Physiological Imbalance-index and energy balance), to help facilitate their adoption within PLF. Blood and milk were sampled from 234 Holstein dairy cows from 6 experimental herds, each in a different European country, and offered a total of 10 different diets. Blood was sampled on 2 occasions at approximately 14 days-in-milk (DIM) and 35 DIM. Milk samples were collected twice weekly (in total 2750 samples) from DIM 1 to 50. Multilevel random regression models were used to estimate the variance components and to calculate the intraclass correlations (ICCs). The ICCs for the milk metabolites, when adjusted for parity and DIM at sampling, demonstrated that between 12% (glucose-6-phosphate) and 46% (urea) of the variation in the metabolites' levels could be associated with the herd-diet combination. Intraclass Correlations related to the herd-diet combination were generally higher for blood metabolites, from 17% (cholesterol) to approximately 46% (BHB and urea). The high ICCs for urea suggest that this biomarker can be used for monitoring on herd level. The low variance within cow for NAGase indicates that few samples would be needed to describe the status and potentially a general reference value could be used. The low ICC for most of the biomarkers and larger within cow variation emphasises that multiple samples would be needed - most likely on the individual cows - for making the biomarkers useful for monitoring. The majority of biomarkers were influenced by parity and DIM which indicate that these should be accounted for if the biomarker should be used for monitoring.

Incorporating sprouted chickpea flour in pasta increases brachial artery flow-mediated dilation.

PURPOSE: Consumption of alternative flours, such as sprouted chickpea flour, has shown increased popularity in recent years. Foods rich in antioxidants have been shown to influence brachial artery flow-mediated dilation (FMD), a non-invasive test of a crucial layer of the artery called the endothelium. Partially replacing the semolina flour in pasta with sprouted chickpea flour (SCF) may acutely affect endothelial function post-digestion. We sought to determine if FMD was higher, lower, or the same post-digestion of pasta made with 60% semolina flour and 40% SCF (SCF40) vs. post-digestion of pasta made with 100% semolina flour (SEM100, i.e., control). METHODS: Trolox equivalent antioxidant capacity (TEAC) analysis was performed on the same flour samples. Healthy participants underwent a screening visit and two randomized controlled meal data collection visits (SCF40 and SEM100). At each data collection visit, participants consumed 255 g of pasta with butter. FMD was assessed 2-3 h after pasta consumption. RESULTS: TEAC results showed that SCF40 (2.031 ± 0.096 mmol trolox/100 g sample) had significantly greater antioxidant capacity than SEM100 (1.736 ± 0.046 mmol trolox/100 g sample; p = 0.02). Twenty-two healthy participants (5 men and 17 women; 26 ± 2 years, 66.6 ± 2.3 kg, BMI = 24 ± 1 kg/m2, SBP = 114 ± 3 mmHg, DBP = 75 ± 2 mmHg, HR = 74 ± 3 BPM) were studied. FMD in the SCF40 condition (10.3% ± 1.2%) was greater than the SEM100 condition (7.9% ± 0.8%, p = 0.02). CONCLUSION: These data suggest that partial substitution with sprouted chickpea flour in place of semolina flour in pasta acutely improves post-digestion FMD, which may be beneficial for cardiovascular health (ClinicalTrials.gov Identifier: NCT03801486).

A comparison of canine whole and intact parathyroid hormone concentrations as measured by different assays.

OBJECTIVES: To compare an intact immunoradiometric parathyroid hormone assay with (1) a non-isotopic technique; and, (2) a whole parathyroid hormone immunoradiometric assay. MATERIALS AND METHODS: Intact parathyroid hormone concentrations were measured using immunoradiometric (Scantibodies) and chemiluminescent (Immulite 2000) assays. Whole parathyroid hormone concentration was measured using an immunoradiometric assay (Scantibodies). RESULTS: A total of 48 and 47 samples, respectively, were used to compare immunoradiometric and chemiluminescent intact parathyroid concentrations and intact and whole parathyroid hormone concentrations by immunoradiometric assays. Using chemiluminescence, 39 (81.3%) samples had intact parathyroid hormone concentrations at or below the reported limit of detection of the assay (0.3 pmol/L). Intact [6.3 (2.0 to 95.5) pmol/L] and whole [3.3 (0.8 to 125.2) pmol/L] immunoradiometric parathyroid hormone concentrations exhibited excellent correlation. CLINICAL SIGNIFICANCE: Not all parathyroid hormone assays perform similarly. The chemiluminescent assay in this study cannot be recommended for use in dogs. The immunoradiometric intact parathyroid hormone assay proved to be a more reliable method. Given the correlation between intact and whole parathyroid hormone concentrations, it remains unclear which one is superior for routine clinical decision-making.

Prediction of metabolic clusters in early-lactation dairy cows using models based on milk biomarkers.

The aim of this study was to describe metabolism of early-lactation dairy cows by clustering cows based on glucose, insulin-like growth factor I (IGF-I), free fatty acid, and ß-hydroxybutyrate (BHB) using the k-means method. Predictive models for metabolic clusters were created and validated using 3 sets of milk biomarkers (milk metabolites and enzymes, glycans on the immunogamma globulin fraction of milk, and Fourier-transform mid-infrared spectra of milk). Metabolic clusters are used to identify dairy cows with a balanced or imbalanced metabolic profile. Around 14 and 35 d in milk, serum or plasma concentrations of BHB, free fatty acids, glucose, and IGF-I were determined. Cows with a favorable metabolic profile were grouped together in what was referred to as the "balanced" group (n = 43) and were compared with cows in what was referred to as the "other balanced" group (n = 64). Cows with an unfavorable metabolic profile were grouped in what was referred to as the "imbalanced" group (n = 19) and compared with cows in what was referred to as the "other imbalanced" group (n = 88). Glucose and IGF-I were higher in balanced compared with other balanced cows. Free fatty acids and BHB were lower in balanced compared with other balanced cows. Glucose and IGF-I were lower in imbalanced compared with other imbalanced cows. Free fatty acids and BHB were higher in imbalanced cows. Metabolic clusters were related to production parameters. There was a trend for a higher daily increase in fat- and protein-corrected milk yield in balanced cows, whereas that of imbalanced cows was higher. Dry matter intake and the daily increase in dry matter intake were higher in balanced cows and lower in imbalanced cows. Energy balance was continuously higher in balanced cows and lower in imbalanced cows. Weekly or twice-weekly milk samples were taken and milk metabolites and enzymes (milk glucose, glucose-6-phosphate, BHB, lactate dehydrogenase, N-acetyl-ß-d-glucosaminidase, isocitrate), immunogamma globulin glycans (19 peaks), and Fourier-transform mid-infrared spectra (1,060 wavelengths reduced to 15 principal components) were determined. Milk biomarkers with or without additional cow information (days in milk, parity, milk yield features) were used to create predictive models for the metabolic clusters. Accuracy for prediction of balanced (80%) and imbalanced (88%) cows was highest using milk metabolites and enzymes combined with days in milk and parity. The results and models of the present study are part of the GplusE project and identify novel milk-based phenotypes that may be used as predictors for metabolic and performance traits in early-lactation dairy cows.

Meta-analysis of the association between peripheral artery disease and growth of abdominal aortic aneurysms.

BACKGROUND: The role of atherosclerosis in the pathogenesis of abdominal aortic aneurysm (AAA) is controversial. Atherosclerosis-associated peripheral artery disease (PAD) has been reported to be a risk factor for AAA in population screening studies; its relationship with AAA growth is controversial. METHODS: A systematic search of MEDLINE, Scopus, CINAHL and the Cochrane Central Register of Controlled Trials was conducted in April 2016 and repeated in January 2017. Databases were screened for studies reporting AAA growth rates in patients with, and without PAD. The included studies underwent quality assessment and, where possible, were included in the meta-analysis. A subgroup analysis was performed, including only studies that adjusted for confounding factors. RESULTS: Seventeen studies, including a total of 4873 patients, met the review entry criteria. Data from 15 studies were included in the meta-analysis. There was marked heterogeneity in study design, methodology and statistical analyses used. In the main analysis, PAD was associated with reduced AAA growth (mean difference - 0·13, 95 per cent c.i. -0·27 to -0·00; P = 0·04). However, statistical significance was not maintained in sensitivity analysis. In a subanalysis that included only data adjusted for other risk factors, no significant association between PAD and AAA growth was found (mean difference -0·11, -0·23 to 0·00; P = 0·05). CONCLUSION: This systematic review suggests that currently reported studies demonstrate no robust and consistent association between PAD and reduced AAA growth.

Laryngeal amyloidosis: diagnosis, pathophysiology and management.

BACKGROUND: Laryngeal amyloidosis represents approximately 1 per cent of all benign laryngeal lesions, and can cause variable symptoms depending on anatomical location and size. Treatment ranges from observation through to endoscopic microsurgery, laser excision and laryngectomy. OBJECTIVES: To highlight the diversity of presentations, increase awareness of paediatric amyloidosis and update the reader on current management. CASE SERIES: Five cases are illustrated. Four adult patients were female, and the one child, the second youngest in the literature, was male. Amyloid deposits were identified in all laryngeal areas, including the supraglottis, glottis and subglottis. Treatment consisted of balloon dilatation, endoscopic excision, laser cruciate incision, and resection with carbon dioxide laser, a microdebrider and coblation wands. CONCLUSION: Laryngeal amyloidosis remains a rare and clinically challenging condition. Diagnosis should be considered for unusual appearing submucosal laryngeal lesions. Treatment of this disease needs to be evaluated on a case-by-case basis and managed within an appropriate multidisciplinary team.

Relationship between prenatal growth, postnatal growth and childhood obesity: a review.

Evidence is accumulating that obesity risks become established early in life. The goal of this systematic review is to assess whether there is evidence that rapid postnatal growth holds different implications for childhood obesity risks for children who experienced different patterns of prenatal growth. We conducted systematic database searches in PubMed and Embase in October 2014 for studies assessing the implications of prenatal and postnatal growth for childhood obesity. The 18 studies meeting inclusion criteria indicated that risks of obesity increased with birthweight; risks of obesity also increased with rapid postnatal growth for children across the birthweight distribution. Fifteen studies indicated that rapid postnatal growth is linearly associated with obesity for children and adolescents of all sizes at birth, with no interaction effect. Three studies reported interaction effects with postnatal growth, conferring additional increased risk of obesity among children and adolescents who were small at birth. Both prenatal and postnatal growth are important risk factors for obesity, and their combined effects should be analyzed further to understand how obesity risks develop early in life.