Review: Improving access to mental health interventions for children from birth to five years: A Scoping Review.

BACKGROUND: In spite of infants and children aged 0-5 years experiencing mental health difficulties being estimated to be in the range of 6%-18% globally, the mental health care needs for this age group are often overlooked in the design of specialist mental health services. Although there is increasing recognition of the importance of infant mental health services and treatments for younger children, access remains a barrier. Mental health services specifically designed for children 0-5 years are vital; however, little is known about how these services ensure access for infants at risk of mental health difficulties and their families. This scoping review seeks to address this knowledge gap. METHODS: A scoping review methodology framework was used to search for relevant articles published between January 2000 and July 2021, identified using five databases: MEDLINE, CINAHL, PsycINFO, SocIndex and Web of Science. The selection of studies was based on empirical research about access to infant mental health services and models of care. A total of 28 relevant articles met the eligibility criteria for inclusion in this review. RESULTS: Findings can be summarised under five broad themes: (1) accessibility for at-risk populations (2) the importance of early detection of infants in need of mental health services and interventions; (3) the promotion of culturally responsive services and interventions; (4) ensuring the sustainability of IMH services and programs and (5) the integration of innovative interventions to improve existing practice models. CONCLUSIONS: The findings from this scoping review highlight barriers to access and provision of infant mental health services. Future infant mental health service design, informed by research, is needed to improve access for infants and young children with mental health difficulties and their families.

Changing Practice: Clinical Application of Resistance Training Evidence for Children With Cerebral Palsy.

PURPOSE: Describe the development and application of a progressive resistance exercise (PRE) program for children with cerebral palsy (CP), which became a standard care model at an urban specialty hospital network. SUMMARY OF KEY POINTS: Muscle structure and performance have been shown to impact function and participation in children with CP. Use of PRE to achieve function and participation goals is supported by a growing body of evidence. A novel guideline, focused on individualized, goal-focused PRE dosing, professional development, program monitoring, and outcome measures use, facilitated application of a new clinical practice. CONCLUSIONS: Practice change was accomplished by translating evidence using a clinical guideline resulting in positive child function and participation outcomes. RECOMMENDATIONS FOR CLINICAL PRACTICE: This Special Communication provides an example of addressing goal-related muscle performance impairments in children with CP. Clinicians should consider updating long-standing physical therapy intervention strategies by incorporating goal-specific PRE into practice.

Assessing the Unmet Preconception Care Needs of Men in the United States by Race/Ethnicity and Nativity.

OBJECTIVE: To estimate the percentage of men in the U.S. in need of preconception care and to assess gaps in utilization of services by race/ethnicity and nativity, irrespective of intention for children, via cross-sectional analysis of 2017-2019 National Survey for Family Growth (NSFG). METHODS: The need for preconception care was defined as non-sterile men who had sexual experience and were with female partner(s) who were not sterile. Thirteen preconception care services were assessed across six domains: family planning, blood pressure, HIV, STD, weight management, and smoking cessation. Multivariable weighted analyses were performed to obtain odds ratios to assess differences in preconception care utilization among participants. RESULTS: Approximately 64% of men were estimated to need preconception care. Substantial disparities in need and service use were found across sociodemographic characteristics. Foreign-born men had significantly higher odds of not receiving three of the thirteen preconception care services, including condom use screening (aOR = 1.67; CI = 1.23-2.26), HIV advice (aOR = 1.76; CI = 1.35-2.29), and STD testing (aOR = 1.66; CI = 1.13-2.44), than U.S.-born. Hispanic men had higher odds of not receiving blood pressure (aOR = 1.39; CI = 1.09-1.79) and smoking screenings (aOR = 1.33; CI = 1.02-1.73) than White men. Black men had the highest use in six of the thirteen preconception care services. CONCLUSION: Gaps in preconception care utilization suggest a need to further explore potential drivers of disparities, specifically for Hispanic and foreign-born men. Additional research into the timing and quality of care received by men are needed to assess the scope, severity, and prevalence of unmet needs within medically underserved communities.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Urinary catheter use in patients with hip fracture: Are current guidelines appropriate? A retrospective review.

BACKGROUND: Guidelines for urinary catheterization in patients with hip fracture recommend limiting catheter use and using intermittent catheterization preferentially to avoid complications such as urinary tract infection (UTI) and postoperative urinary retention (POUR). We aimed to compare current practices to clinical guidelines, describe the incidence of POUR and UTI, and determine factors that increase the risk of these complications. METHODS: We retrospectively reviewed the charts of patients with hip fracture who presented to a single large tertiary care centre in southeastern Ontario between November 2015 and October 2017. Data collected included comorbidities, catheter use and length of stay. We compared catheter use to guidelines, and investigated the incidence of and risk factors for POUR and UTI. RESULTS: We reviewed the charts of 583 patients, of whom 450 (77.2%) were treated with a catheter, primarily indwelling (416 [92.4%]). Postoperative urinary retention developed in 98 patients (16.8%); however, it did not affect length of stay (p = 0.2). Patients with indwelling catheters for more than 24 hours after surgery had a higher incidence of POUR than those who had their catheter removed before 24 hours (65/330 [19.7%] v. 10/98 [10.2%]) (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.06-4.38). A UTI developed postoperatively in 62 patients (10.6%). Catheter use was associated with a 6.6-fold increased risk of UTI (OR 6.6, 95% CI 2.03-21.4). Patients with indwelling catheters did not have a significantly higher incidence of UTI than those with intermittent catheterization (57/416 [13.7%] v. 2/34 [5.9%]) (p = 0.2). Patients who developed a UTI had significantly longer catheter use than patients who did not (p < 0.002). CONCLUSION: Indwelling catheters were used frequently, which suggests low compliance with clinical guidelines. Longer duration of catheter use led to higher rates of UTI and POUR. Further investigation of the reasons for the common use of indwelling rather than intermittent catheterization is needed.

Patient-reported outcomes and quality of life in dominant dystrophic epidermolysis bullosa: A global cross-sectional survey.

INTRODUCTION: Dystrophic epidermolysis bullosa is a debilitating skin condition, without curative treatment. Previous research has focused on the recessive variant, which is known to cause severe disease. Limited work focusing on the clinical manifestations and outcomes of dominant dystrophic epidermolysis bullosa is found (DDEB). METHODS: Analysis of an online survey of 42 DDEB patients. RESULTS: Self-reported severity of disease did not correlate with size of the wound or number of dressing changes, but did correlate with severity of pain reported in the last 12 months (3.4 mild vs 6.8 severe disease, P = 0.0002). Patients with severe DDEB also reported more severe internal disease symptoms, such as difficulty swallowing (62.5%, P = 0.01) and greater analgesic use during dressing changes (4.4% mild vs 81.3% severe, P = <0.001). DISCUSSION: Patient perception of disease severity in DDEB appears to be most impacted by pain, presence of chronic open wounds, difficulty swallowing, difficulty walking, and anal strictures. As research on DDEB increases, future studies focused on these symptoms might be the most impactful for DDEB patients. However, distinguishing DDEB from other subtypes remains a challenge.

Cannabinoid use and effects in patients with epidermolysis bullosa: an international cross-sectional survey study.

BACKGROUND: Epidermolysis bullosa (EB) patient anecdotes and case reports indicate that cannabinoid-based medicines (CBMs) may alleviate pain and pruritus and improve wound healing. CBM use has not been characterized in the EB patient population. OBJECTIVES: To evaluate CBM use among EB patients, including CBM types, effects on symptoms (e.g., pain and pruritus), disease process (e.g., blistering, wounds, and inflammation), well-being (e.g., sleep, appetite) and concomitant medications. METHODS: English-speaking EB patients or caregivers completed an online international, anonymous, cross-sectional survey regarding CBM use. Respondents reported the types of CBMs, subsequent effects including perceived EB symptom alteration, changes in medication use, and side effects. RESULTS: Seventy-one EB patients from five continents reported using or having used CBMs to treat their EB. Missing question responses ranged between 0 (0%) and 33 (46%). Most used more than one CBM preparation (mean: 2.4 ± 1.5) and route of administration (mean: 2.1 ± 1.1). Topical and ingested were the most common routes. Pain and pruritus were reported retrospectively to decrease by 3 points (scale: 0-10; p < 0.001 for both) after CBM use. Most reported that CBM use improved their overall EB symptoms (95%), pain (94%), pruritus (91%) and wound healing (81%). Most participants (79%) reported decreased use of pain medications. The most common side-effect was dry mouth (44%). CONCLUSIONS: CBMs improve the perception of pain, pruritus, wound healing, and well-being in EB patients and reduced concomitant medication use. Nevertheless, a direct relation between the use of CBMs and reduction of the above-mentioned symptoms cannot be proven by these data. Therefore, future controlled studies using pharmaceutically standardised CBM preparations in EB are warranted to delineate the risks and benefits of CBMs.

Preventing hip fractures with multidisciplinary teams: a Canadian perspective.

Fragility fractures (FFs) are low-energy trauma fractures that occur at or below standing height. Among FFs, hip fractures are associated with the greatest morbidity, mortality and cost to Canadian health care systems. This review highlights the current state of medical care for hip fractures in Canada, with specific focus on the role of the multidisciplinary team. Gaps in care exist, as FFs represent a unique challenge requiring both acute and chronic management. Furthermore, there is a lack of ownership of FFs by a medical specialty. These gaps can be addressed through the use of multidisciplinary teams, which have been shown to be efficacious and cost-effective. This model of care also addresses numerous patient-identified barriers to treatment, including inadequate patient counselling. However, there is still room for improvement in both the identification of patients at risk for hip fracture and patient adherence to therapy.

Les fractures de fragilisation (FF) sont des fractures qui surviennent lors d'un traumatisme léger se produisant depuis la position debout ou d'une hauteur moindre. Les fractures de la hanche sont les FF associées aux plus grands taux de morbidité et de mortalité et aux plus grands coûts pour les systèmes de santé au Canada. La présente revue s'intéresse à l'état actuel des soins médicaux pour une fracture de la hanche au pays et porte une attention spéciale au rôle de l'équipe multidisciplinaire. Des lacunes dans les soins existent et sont mises en évidence par les FF, qui posent un défi bien particulier en nécessitant une prise en charge à la fois aiguë et chronique. De plus, cette prise en charge ne relève d'aucune spécialité médicale. La correction de ces lacunes peut passer par le recours aux équipes multidisciplinaires, dont l'efficacité et la rentabilité ont été démontrées. Ce modèle de soins élimine également de nombreux obstacles au traitement signalés par les patients, y compris le counseling inadéquat. Des améliorations sont néanmoins encore nécessaires dans l'identification des patients à risque de fracture de la hanche et dans l'observance du traitement.

Electronic Cigarettes: Exposure to Secondhand Vapors at a Long-Term Healthcare Company.

Introduction: Healthcare workers in long term care settings have limited control over their occupational secondhand exposure to electronic cigarettes and other tobacco products. Methods: The study aimed to identify the perceived frequency of exposure to exhaled electronic cigarette vapor on healthcare workers within two sites of a long-term healthcare company. An online survey was completed by 149 (out of approximately 500) employees that asked about electronic cigarette personal usage, concerns for exposure, exposure times, and demographic data. Results: Twelve percent of all survey respondents expressed concerns related to second-hand exposure. Of those exposed, employee estimated exposure time was 2.1 minutes per shift for electronic cigarettes compared to 12.1 minutes per shift for cigarettes/cigars/pipes. Conclusions: Overall self-reported secondhand exposure to electronic cigarettes and cigarettes/cigars/pipes was low. To determine a definitive exposure level, quantitative sampling can be done related to chemical exposure via passive inhalation of the smoke and vapor cloud for cigarettes and electronic cigarettes, respectively. Education can be provided to healthcare workers and residents in long-term care facilities regarding risk of exposure to secondhand smoke to alleviate employees concerns with exposure.

Wide-field amacrine cell inputs to ON parasol ganglion cells in macaque retina.

Parasol cells are one of the major types of primate retinal ganglion cells. The goal of this study was to describe the synaptic inputs that shape the light responses of the ON type of parasol cells, which are excited by increments in light intensity. A connectome from central macaque retina was generated by serial blockface scanning electron microscopy. Six neighboring ON parasol cells were reconstructed, and their synaptic inputs were analyzed. On average, they received 21% of their input from bipolar cells, excitatory local circuit neurons receiving input from cones. The majority of their input was from amacrine cells, local circuit neurons of the inner retina that are typically inhibitory. Their contributions to the neural circuit providing input to parasol cells are not well-understood, and the focus of this study was on the presynaptic wide-field amacrine cells, which provided 17% of the input to ON parasol cells. These are GABAergic amacrine cells with long, relatively straight dendrites, and sometimes also axons, that run in a single, narrow stratum of the inner plexiform layer. The presynaptic wide-field amacrine cells were reconstructed, and two types were identified based on their characteristic morphology. One presynaptic amacrine cell was identified as semilunar type 2, a polyaxonal cell that is electrically coupled to ON parasol cells. A second amacrine was identified as wiry type 2, a type known to be sensitive to motion. These inputs likely make ON parasol cells more sensitive to stimuli that are rapidly changing outside their classical receptive fields.

CCL27/CCL28-CCR10 Chemokine Signaling Mediates Migration of Lymphatic Endothelial Cells.

Metastasis via the lymphatic vasculature is an important step in cancer progression. The formation of new lymphatic vessels (lymphangiogenesis), or remodeling of existing lymphatics, is thought to facilitate the entry and transport of tumor cells into lymphatic vessels and on to distant organs. The migration of lymphatic endothelial cells (LEC) toward guidance cues is critical for lymphangiogenesis. While chemokines are known to provide directional navigation for migrating immune cells, their role in mediating LEC migration during tumor-associated lymphangiogenesis is not well defined. Here, we undertook gene profiling studies to identify chemokine-chemokine receptor pairs that are involved in tumor lymphangiogenesis associated with lymph node metastasis. CCL27 and CCL28 were expressed in tumor cells with metastatic potential, while their cognate receptor, CCR10, was expressed by LECs and upregulated by the lymphangiogenic growth factor VEGFD and the proinflammatory cytokine TNFα. Migration assays demonstrated that LECs are attracted to both CCL27 and CCL28 in a CCR10-dependent manner, while abnormal lymphatic vessel patterning in CCR10-deficient mice confirmed the significant role of CCR10 in lymphatic patterning. In vivo analyses showed that LECs are recruited to a CCL27 or CCL28 source, while VEGFD was required in combination with these chemokines to enable formation of coherent lymphatic vessels. Moreover, tumor xenograft experiments demonstrated that even though CCL27 expression by tumors enhanced LEC recruitment, the ability to metastasize was dependent on the expression of VEGFD. These studies demonstrate that CCL27 and CCL28 signaling through CCR10 may cooperate with inflammatory mediators and VEGFD during tumor lymphangiogenesis. SIGNIFICANCE: The study shows that the remodeling of lymphatic vessels in cancer is influenced by CCL27 and CCL28 chemokines, which may provide a future target to modulate metastatic spread.

Biologically active constituents of the secretome of human W8B2+ cardiac stem cells.

The benefits of adult stem cells for repair of the heart have been attributed to the repertoire of salutary paracrine activities they appear to exert. We previously isolated human W8B2+ cardiac stem cells (CSCs) and found they powerfully influence cardiomyocytes and endothelial cells to collectively promote cardiac repair and regeneration. Here, the complexity of the W8B2+ CSC secretomes was characterised and examined in more detail. Using ion exchange chromatography to separate soluble proteins based on their net surface charge, the secreted factors responsible for the pro-survival activity of W8B2+ CSCs were found within the low and medium cation fractions. In addition to the soluble proteins, extracellular vesicles generated from W8B2+ CSCs not only exhibited pro-survival and pro-angiogenic activities, but also promoted proliferation of neonatal cardiomyocytes. These extracellular vesicles contain a cargo of proteins, mRNA and primary microRNA precursors that are enriched in exosomes and are capable of modulating collectively many of the cellular pathways involved in protein metabolism, cell growth, as well as cellular responses to stress and organisation of the extracellular matrix. Thus the W8B2+ CSC secretome contains a multitude of bioactive paracrine factors we have now characterised, that might well be harnessed for therapeutic application for cardiac repair and regeneration.

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling.

Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified individual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that LGALS1, which encodes the glycan-binding protein Galectin-1, promoted lymphatic vascular growth in vitro and in vivo and contributed to maintenance of the lymphatic endothelial phenotype. Our results provide insight into the signaling networks that control lymphangiogenesis and lymphatic remodeling and potentially identify therapeutic targets and biomarkers in disease specific to lymphatic or blood vessels.

Targeted ultrasound of the liver: Impact on scanning time of a new approach in chronic liver disease.

INTRODUCTION: Targeted ultrasound of the liver (TUSL) has been proposed as a new approach in chronic liver disease to meet the increasing demands on ultrasound services in this patient population. This study analyses the impact of TUSL on examination time. METHODS: Retrospective cohort analysis of time taken to perform liver ultrasound on consecutive chronic liver disease patients pre- (n = 230) and post- (n = 147) introduction of TUSL. Within each cohort, patients were subdivided into three categories based on the clinical indication: Group 1. hepatocellular carcinoma (HCC) surveillance; Group 2. detection of cirrhosis, fibrosis or fatty liver; Group 3. detection of portal hypertension. The primary outcome was difference in examination time in the pre- and post-intervention groups. RESULTS: Introduction of TUSL led to 49% reduction in examination time (median (Q1-Q3) 23.7 (16.7-36.2) min in pre-TUSL period vs 12.1 (6.4-19.5) min in post, P < 0.001) and it was consistent across all three clinical indication groups (gr1: median 23.1 minutes vs 8.1 minutes (P < 0.001), gr2: 23.0 minutes vs 14.3 minutes (P < 0.001), gr3: 32.2 minutes vs 15.3 minutes (P = 0.006)). After the adjustment for clinical indication and sonographer's experience, impact of TUSL on time reduction remained significant with a 66.6% time reduction (95% CI 53.6 to 79.5). CONCLUSION: Targeted ultrasound of the liver improves efficiency of chronic liver disease ultrasound with halving of examination times and consequently has the potential to greatly improve resource utilization.

Differential Receptor Binding and Regulatory Mechanisms for the Lymphangiogenic Growth Factors Vascular Endothelial Growth Factor (VEGF)-C and -D.

VEGF-C and VEGF-D are secreted glycoproteins that induce angiogenesis and lymphangiogenesis in cancer, thereby promoting tumor growth and spread. They exhibit structural homology and activate VEGFR-2 and VEGFR-3, receptors on endothelial cells that signal for growth of blood vessels and lymphatics. VEGF-C and VEGF-D were thought to exhibit similar bioactivities, yet recent studies indicated distinct signaling mechanisms (e.g. tumor-derived VEGF-C promoted expression of the prostaglandin biosynthetic enzyme COX-2 in lymphatics, a response thought to facilitate metastasis via the lymphatic vasculature, whereas VEGF-D did not). Here we explore the basis of the distinct bioactivities of VEGF-D using a neutralizing antibody, peptide mapping, and mutagenesis to demonstrate that the N-terminal α-helix of mature VEGF-D (Phe93-Arg108) is critical for binding VEGFR-2 and VEGFR-3. Importantly, the N-terminal part of this α-helix, from Phe93 to Thr98, is required for binding VEGFR-3 but not VEGFR-2. Surprisingly, the corresponding part of the α-helix in mature VEGF-C did not influence binding to either VEGFR-2 or VEGFR-3, indicating distinct determinants of receptor binding by these growth factors. A variant of mature VEGF-D harboring a mutation in the N-terminal α-helix, D103A, exhibited enhanced potency for activating VEGFR-3, was able to promote increased COX-2 mRNA levels in lymphatic endothelial cells, and had enhanced capacity to induce lymphatic sprouting in vivo This mutant may be useful for developing protein-based therapeutics to drive lymphangiogenesis in clinical settings, such as lymphedema. Our studies shed light on the VEGF-D structure/function relationship and provide a basis for understanding functional differences compared with VEGF-C.

Acoustic radiation force impulse accuracy and the impact of hepatic steatosis on liver fibrosis staging.

INTRODUCTION: The accuracy of Acoustic Radiation Force Impulse (ARFI) imaging has been validated in the setting of hepatitis C, however, the accuracy in the setting of fatty liver disease (FLD) has been less well-established. The aim of this study was to assess the accuracy of ARFI in the setting of hepatic steatosis. METHODS: Patients with biopsy proven or sonographically diagnosed liver steatosis were assessed for ARFI trends including: inter-operator concordance, interquartile range, ARFI failure rate, relationship between ARFI velocity and steatosis severity, and concordance between biopsy and ARFI fibrosis scores. RESULTS: Three hundred and forty-nine patients were assessed (53 'biopsy' cohort and 296 'ultrasound' cohort), with 28 patients having biopsy on the same day as ARFI. Low stages of fibrosis (F0/1) were over-estimated by ARFI in 62% of cases with biopsy correlation (n = 16, P < 0.001), with ARFI offering increased accuracy in regard to higher-stage fibrosis (14/15 cases, 93%). In both the biopsy and ultrasound cohorts the failure rate and median inter-quartile range increased with increasing steatosis, and the inter-operator concordance remained good across all liver steatosis severities. CONCLUSION: In the setting of steatosis, ARFI is very sensitive in detecting, and accurate in diagnosing, higher stages of fibrosis regardless of steatosis severity. It tends to overestimate the fibrosis category in lower stages of fibrosis. The present study does not show conclusively if the presence of steatosis or its severity independently alters ARFI measurements.

Inhibition of glioblastoma cell proliferation, migration and invasion by the proteasome antagonist carfilzomib.

Glioblastoma multiforme is the most aggressive and lethal tumor of the central nervous system with limited treatment strategies on offer, and as such the identification of effective novel therapeutic agents is paramount. To examine the efficacy of proteasome inhibitors, we tested bortezomib, carfilzomib, nafamostat mesylate, gabexate mesylate and acetylsalicylic acid on glioblastoma cell viability, migration and invasion. Both bortezomib and carfilzomib produced significant reduction of cell viability, while nafamostat mesylate, gabexate mesylate and acetylsalicylic acid did not. Subsequent testing showed that carfilzomib significantly reduced cell viability at nM concentrations. Carfilzomib also reduced cell migration, secretion and activation of MMP2 and also cell invasion of all four glioblastoma cells tested. In summary, carfilzomib represents a novel, yet FDA-approved agent for the treatment of glioblastoma multiforme.

VEGF-D promotes pulmonary oedema in hyperoxic acute lung injury.

Leakage of fluid from blood vessels, leading to oedema, is a key feature of many diseases including hyperoxic acute lung injury (HALI), which can occur when patients are ventilated with high concentrations of oxygen (hyperoxia). The molecular mechanisms driving vascular leak and oedema in HALI are poorly understood. VEGF-D is a protein that promotes blood vessel leak and oedema when overexpressed in tissues, but the role of endogenous VEGF-D in pathological oedema was unknown. To address these issues, we exposed Vegfd-deficient mice to hyperoxia. The resulting pulmonary oedema in Vegfd-deficient mice was substantially reduced compared to wild-type, as was the protein content of bronchoalveolar lavage fluid, consistent with reduced vascular leak. Vegf-d and its receptor Vegfr-3 were more highly expressed in lungs of hyperoxic, versus normoxic, wild-type mice, indicating that components of the Vegf-d signalling pathway are up-regulated in hyperoxia. Importantly, VEGF-D and its receptors were co-localized on blood vessels in clinical samples of human lungs exposed to hyperoxia; hence, VEGF-D may act directly on blood vessels to promote fluid leak. Our studies show that Vegf-d promotes oedema in response to hyperoxia in mice and support the hypothesis that VEGF-D signalling promotes vascular leak in human HALI. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Cardiac Repair With a Novel Population of Mesenchymal Stem Cells Resident in the Human Heart.

Cardiac resident stem cells (CRSCs) hold much promise to treat heart disease but this remains a controversial field. Here, we describe a novel population of CRSCs, which are positive for W8B2 antigen and were obtained from adult human atrial appendages. W8B2(+) CRSCs exhibit a spindle-shaped morphology, are clonogenic and capable of self-renewal. W8B2(+) CRSCs show high expression of mesenchymal but not hematopoietic nor endothelial markers. W8B2(+) CRSCs expressed GATA4, HAND2, and TBX5, but not C-KIT, SCA-1, NKX2.5, PDGFRα, ISL1, or WT1. W8B2(+) CRSCs can differentiate into cardiovascular lineages and secrete a range of cytokines implicated in angiogenesis, chemotaxis, inflammation, extracellular matrix remodeling, cell growth, and survival. In vitro, conditioned medium collected from W8B2(+) CRSCs displayed prosurvival, proangiogenic, and promigratory effects on endothelial cells, superior to that of other adult stem cells tested, and additionally promoted survival and proliferation of neonatal rat cardiomyocytes. Intramyocardial transplantation of human W8B2(+) CRSCs into immunocompromised rats 1 week after myocardial infarction markedly improved cardiac function (∼40% improvement in ejection fraction) and reduced fibrotic scar tissue 4 weeks after infarction. Hearts treated with W8B2(+) CRSCs showed less adverse remodeling of the left ventricle, a greater number of proliferating cardiomyocytes (Ki67(+) cTnT(+) cells) in the remote region, higher myocardial vascular density, and greater infiltration of CD163(+) cells (a marker for M2 macrophages) into the border zone and scar regions. In summary, W8B2(+) CRSCs are distinct from currently known CRSCs found in human hearts, and as such may be an ideal cell source to repair myocardial damage after infarction.