Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

Benefits of the Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in Metabolic Syndrome-Related Heart Failure with Preserved Ejection Fraction.

The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits.

Lim Domain Binding 3 (Ldb3) Identified as a Potential Marker of Cardiac Extracellular Vesicles.

Extracellular vesicles (EVs) are considered as transporters of biomarkers for the diagnosis of cardiac diseases, playing an important role in cell-to-cell communication during physiological and pathological processes. However, specific markers for the isolation and analysis of cardiac EVs are missing, imposing limitation on understanding their function in heart tissue. For this, we performed multiple proteomic approaches to compare EVs isolated from neonate rat cardiomyocytes and cardiac fibroblasts by ultracentrifugation, as well as EVs isolated from minced cardiac tissue and plasma by EVtrap. We identified Ldb3, a cytoskeletal protein which is essential in maintaining Z-disc structural integrity, as enriched in cardiac EVs. This result was validated using different EV isolation techniques showing Ldb3 in both large and small EVs. In parallel, we showed that Ldb3 is almost exclusively detected in the neonate rat heart when compared to other tissues, and specifically in cardiomyocytes compared to cardiac fibroblasts. Furthermore, Ldb3 levels, specifically higher molecular weight isoforms, were decreased in the left ventricle of ischemic heart failure patients compared to control groups, but not in the corresponding EVs. Our results suggest that Ldb3 could be a potential cardiomyocytes derived-EV marker and could be useful to identify cardiac EVs in physiological and pathological conditions.

Protein Alterations in Cardiac Ischemia/Reperfusion Revealed by Spatial-Omics.

Myocardial infarction is the most common cause of death worldwide. An understanding of the alterations in protein pathways is needed in order to develop strategies that minimize myocardial damage. To identify the protein signature of cardiac ischemia/reperfusion (I/R) injury in rats, we combined, for the first time, protein matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and label-free proteomics on the same tissue section placed on a conductive slide. Wistar rats were subjected to I/R surgery and sacrificed after 24 h. Protein MALDI-MSI data revealed ischemia specific regions, and distinct profiles for the infarct core and border. Firstly, the infarct core, compared to histologically unaffected tissue, showed a significant downregulation of cardiac biomarkers, while an upregulation was seen for coagulation and immune response proteins. Interestingly, within the infarct tissue, alterations in the cytoskeleton reorganization and inflammation were found. This work demonstrates that a single tissue section can be used for protein-based spatial-omics, combining MALDI-MSI and label-free proteomics. Our workflow offers a new methodology to investigate the mechanisms of cardiac I/R injury at the protein level for new strategies to minimize damage after MI.

Priming of Cardiopulmonary Bypass with Human Albumin Decreases Endothelial Dysfunction after Pulmonary Ischemia-Reperfusion in an Animal Model.

The routine use of mechanical circulatory support during lung transplantation (LTx) is still controversial. The use of prophylactic human albumin (HA) or hypertonic sodium lactate (HSL) prime in mechanical circulatory support during LTx could prevent ischemia−reperfusion (IR) injuries and pulmonary endothelial dysfunction and thus prevent the development of pulmonary graft dysfunction. The objective was to investigate the impact of cardiopulmonary bypass (CPB) priming with HA and HSL compared to a CPB prime with Gelofusine (GF) on pulmonary endothelial dysfunction in a lung IR rat model. Rats were assigned to four groups: IR-CPB-GF group, IR-CPB-HA group, IR-CPB-HSL group and a sham group. The study of pulmonary vascular reactivity by wire myograph was the primary outcome. Glycocalyx degradation (syndecan-1 and heparan) was also assessed by ELISA and electron microscopy, systemic and pulmonary inflammation by ELISA (IL-1ß, IL-10, and TNF-α) and immunohistochemistry. Clinical parameters were evaluated. We employed a CPB model with three different primings, permitting femoral−femoral assistance with left pulmonary hilum ischemia for IR. Pulmonary endothelium-dependent relaxation to acetylcholine was significantly decreased in the IR-CPB-GF group (11.9 ± 6.2%) compared to the IR-CPB-HA group (52.8 ± 5.2%, p < 0.0001), the IR-CPB-HSL group (57.7 ± 6.3%, p < 0.0001) and the sham group (80.8 ± 6.5%, p < 0.0001). We did not observe any difference between the groups concerning glycocalyx degradation, and systemic or tissular inflammation. The IR-CPB-HSL group needed more vascular filling and developed significantly more pulmonary edema than the IR-CPB-GF group and the IR-CPB-HA group. Using HA as a prime in CPB during Ltx could decrease pulmonary endothelial dysfunction's IR-mediated effects. No effects of HA were found on inflammation.

Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction.

OBJECTIVE: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-CC156S therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4+ and CD8+ T cells potently suppress, in part through interferon-γ, cardiac lymphangiogenesis post-MI. CONCLUSIONS: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-CC156S. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21.

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.

Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities.

Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.

A mortality prediction model for elderly patients with critical limb ischemia.

OBJECTIVE: To aid physicians in the process of shared decision-making, many predictive models for critical limb ischemia (CLI) have been constructed. However, none of these models is in widespread use. Predicting survival outcomes for a specific individual may be used to guide treatment selection. The aim of this study was to construct a 6-month survival-predicting model representative of elderly patients with CLI undergoing surgical or endovascular treatment. METHODS: An observational cohort study including all patients with CLI aged ≥65 years who underwent surgical or endovascular treatment of CLI between January 2013 and June 2018 was conducted. The model to predict survival at 6 months was based on a multivariable Cox proportional hazards regression model and a penalized likelihood method. The performance of the model was judged by means of the area under the receiver operating characteristic curve. RESULTS: In total, 449 patients were included in the study population. The median age was 76 years (range, 65-97 years), and 52.8% of the population was male. Surgical treatment was performed in 303 patients (67.5%), and 146 underwent endovascular treatment (32.5%). The estimated 30-day survival was 92.7% (standard error [SE], 1.2%); 6-month survival, 80% (SE, 1.9%); and 12-month survival, 71% (SE, 2.1%). Variables with the strongest association with 6-month mortality were age, living in a nursing home, physical impairment, and American Society of Anesthesiologists class. The area under the receiver operating characteristic curve of the 6-month mortality model was 0.81 (95% confidence interval, 0.76-0.85; P < .001). CONCLUSIONS: A prediction model constructed for 6-month mortality of elderly patients undergoing surgical or endovascular treatment of CLI showed that age, living in a nursing home, physical impairment, and American Society of Anesthesiologists class have the highest association with an increase in mortality. These factors may be used to identify patients at risk for mortality in shared decision-making.

Incidence and Risk Factors for Delirium in Elderly Patients with Critical Limb Ischaemia.

OBJECTIVE: Delirium is associated with adverse outcomes, such as increased mortality and prolonged hospital stay. Information on the risk factors for delirium in elderly patients with critical limb ischaemia (CLI) is scarce. The aim of this study was to analyse the incidence of delirium and to identify risk factors for delirium in elderly patients undergoing surgical or endovascular treatment. METHODS: A retrospective cohort study was conducted including patients aged ≥ 65 years undergoing surgical or endovascular treatment for CLI between January 2013 and June 2018. Delirium was scored using the DOSS (Delirium Observation Screening Scale) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria. Risk factors for delirium were analysed using logistic regression. The discriminative ability of the model was calculated using the area under the receiver operating characteristics (AUROC) curve. RESULTS: In total, 392 patients were included, of which 70 (17.9%) developed delirium. Factors associated with an increased risk of delirium were: age, odds ratio (OR) 1.05 (95% confidence interval (CI) 1.0-1.1), history of femoral endarterectomy, OR 4.7 (95% CI 1.5-15), physical impairment, OR 2.2 (95% CI 1.1-4.5), history of delirium, OR 2.7 (95% CI 1.4-5.3), general anaesthesia, OR 2.6 (95% CI 1.2-5.7) and pre-operative anaemia, OR 5.9 (95% CI 2.3-15). The AUROC was .82 (95% CI 0.76-0.87, p < .001). Delirium was associated with more respiratory, renal and surgical complications, as well as a prolonged hospital stay and a more frequent discharge to a nursing home. CONCLUSION: Delirium occurs frequently in patients with critical limb ischaemia undergoing any type of invasive treatment. This study identified multiple risk factors for delirium that may be helpful to delineate patients susceptible to its development.

Hypertonic sodium lactate improves microcirculation, cardiac function, and inflammation in a rat model of sepsis.

BACKGROUND: Hypertonic sodium lactate (HSL) may be of interest during inflammation. We aimed to evaluate its effects during experimental sepsis in rats (cecal ligation and puncture (CLP)). METHODS: Three groups were analyzed (n = 10/group): sham, CLP-NaCl 0.9%, and CLP-HSL (2.5 mL/kg/h of fluids for 18 h after CLP). Mesenteric microcirculation, echocardiography, cytokines, and biochemical parameters were evaluated. Two additional experiments were performed for capillary leakage (Evans blue, n = 5/group) and cardiac hemodynamics (n = 7/group). RESULTS: HSL improved mesenteric microcirculation (CLP-HSL 736 [407-879] vs. CLP-NaCl 241 [209-391] UI/pixel, p = 0.0006), cardiac output (0.34 [0.28-0.43] vs. 0.14 [0.10-0.18] mL/min/g, p < 0.0001), and left ventricular fractional shortening (55 [46-73] vs. 39 [33-52] %, p = 0.009). HSL also raised dP/dtmax slope (6.3 [3.3-12.1] vs. 2.7 [2.0-3.9] 103 mmHg/s, p = 0.04), lowered left ventricular end-diastolic pressure-volume relation (1.9 [1.1-2.3] vs. 3.0 [2.2-3.7] RVU/mmHg, p = 0.005), and reduced Evans blue diffusion in the gut (37 [31-43] vs. 113 [63-142], p = 0.03), the lung (108 [82-174] vs. 273 [222-445], p = 0.006), and the liver (24 [14-37] vs. 70 [50-89] ng EB/mg, p = 0.04). Lactate and 3-hydroxybutyrate were higher in CLP-HSL (6.03 [3.08-10.30] vs. 3.19 [2.42-5.11] mmol/L, p = 0.04; 400 [174-626] vs. 189 [130-301] µmol/L, p = 0.03). Plasma cytokines were reduced in HSL (IL-1ß, 172 [119-446] vs. 928 [245-1470] pg/mL, p = 0.004; TNFα, 17.9 [12.5-50.3] vs. 53.9 [30.8-85.6] pg/mL, p = 0.005; IL-10, 352 [267-912] vs. 905 [723-1243] pg/mL) as well as plasma VEGF-A (198 [185-250] vs. 261 [250-269] pg/mL, p = 0.009). CONCLUSIONS: Hypertonic sodium lactate fluid protects against cardiac dysfunction, mesenteric microcirculation alteration, and capillary leakage during sepsis and simultaneously reduces inflammation and enhances ketone bodies.

Adverse Cardiac Events and Mortality in Patients with Critical Limb Ischemia.

BACKGROUND: Both surgical and endovascular treatment in elderly patients with critical limb ischemia are associated with high mortality rates. Patients with critical limb ischemia are at increased risk of adverse cardiovascular events and subsequent cardiovascular death. Little is known about the incidence and consequences of these adverse events. The aim of this study was to investigate the effect of adverse cardiac events on mortality in patients with critical limb ischemia undergoing surgical or endovascular treatment. METHODS: A retrospective cohort study including all patients with critical limb ischemia aged ≥65 undergoing surgical or endovascular treatment for critical limb ischemia between January 2013 and June 2018 was conducted. Data on adverse cardiac events were collected from medical records. The effect of an adverse cardiac event on mortality during 6 months follow-up was analyzed with a multivariable cox proportional hazards model to adjust for confounders. Effects are displayed as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: A total number of 449 patients were included. Median age was 76 years, 52.8% of patients were male. In total, 51 patients (11%) developed an adverse cardiac event, 31 patients (10%) in the surgical group and 20 patients (14%) in the endovascular group. After adjustment for confounders, adverse cardiac events were associated with an increased risk of mortality (HR 3.5 95% CI 2.1-5.9). CONCLUSIONS: This study showed that adverse cardiac events commonly occur in elderly patients with critical limb ischemia. Adverse cardiac events continue to occur even months after treatment and are associated with an increased mortality risk. These findings justify routine cardiac evaluation in both surgical and endovascular treatment. Additionally, frequent postdischarge cardiac follow-up in the outpatient clinic may be helpful in limiting the occurrence of adverse cardiac events.

Major hepatectomy decreased tumor growth in an experimental model of bilobar liver metastasis.

BACKGROUND/PURPOSE: Two-stage hepatectomy (TSH), is associated with a risk of drop-out due to tumoral progression following portal vein occlusion (PVO). We explored the impact of majorhepatectomy on tumor growth by objective radiological measures comparing to PVO and minor hepatectomy, using a model of bilobar colorectal liver metastasis (CLM). METHODS: CLM were induced in 48 BDIX rats by injection of DHDK12-cells. 7 days after cells injection, animals were distributed into 4 groups of equal number (n = 12): portal vein ligation (PVL), sham laparotomy (sham), minor (30%Phx) and major (70%Phx) hepatectomy. MR imaging was used for in vivo analysis of tumor implantation, growth and volumes. RESULTS: At POD10, tumour volumes were homogeneously distributed among the 4 groups. Lower TV were significantly observed after 70%Phx comparing to PVL at POD17 (0.63 ± 0.14cm3 vs 0.9 ± 0.16cm3, p = 0.008) and to the 3 others groups at POD24: 1.78 ± 0.38cm3 vs 3.2 ± 0.62cm3 (PVL, p = 0.019), 2.41 ± 0.74cm3 (Sham, p = 0.024) and 2.32 ± 0.59cm3 (30%PHx, p = 0.019). CONCLUSION: We confirmed in a reproducible model that contrary to PVO, a major hepatectomy decreases the growth of CLM in the remnant liver. This result leads to questioning the usual TSH and justifies exploring alternative strategies. The "major hepatectomy first-approach" should be an option to be evaluated.

Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.

Development, behaviour and autism in individuals with SMC1A variants.

INTRODUCTION: Development and behaviour in Cornelia de Lange Syndrome (CdLS), including autism characteristics, have been described infrequently stratified to genetic cause and only a few studies have considered behavioural characteristics in relation to developmental level. Here, we describe the behavioural phenotype in individuals with CdLS with SMC1A variants. METHODS: We performed an international, interdisciplinary study on 51 individuals with SMC1A variants. Results of questionnaire studies are compared to those in individuals with Down Syndrome and with Autism Spectrum Disorder. Results on cognition and self-injurious behaviour (SIB) are compared to those in individuals with CdLS caused by NIPBL variants. For Dutch participants with SMC1A variants we performed direct in-person assessments of cognition, autism, and added an interview and questionnaire on adaptive behaviour and sensory processing. RESULTS: Individuals with SMC1A variants show a higher cognitive level and less SIB than individuals with NIPBL variants. Individuals with SMC1A variants without classic CdLS phenotype but with a Rett-like phenotype show more severe intellectual disability and more SIB compared to those with a CdLS phenotype. Autism is less present if outcomes in direct in-person assessments are evaluated taking developmental level into account compared to results based on a questionnaire. CONCLUSIONS: Behaviour in individuals with CdLS should be evaluated taking genetic cause into account. Detailed interdisciplinary approaches are of clinical importance to inform tailored care and may eventually improve quality of life of patients and families.

The importance of increased awareness for delirium in elderly patients with rib fractures after blunt chest wall trauma: a retrospective cohort study on risk factors and outcomes.

BACKGROUND: Rib fractures are common in ageing people after trauma and delirium is a complication often seen in acutely hospitalized elderly patients. For both conditions, elderly have an increased risk for institutionalization, morbidity, and mortality. This study is the first to investigate risk factors of delirium in elderly patients with rib fractures after trauma. METHODS: A retrospective chart review was performed on patients ≥65 years admitted with rib fractures after blunt chest wall trauma to the Amphia hospital Breda, the Netherlands, between July 2013 and June 2018. Baseline patient, trauma- and treatment-related characteristics were identified. The main objectives were identification of risk factors of delirium and investigation of the effect of delirium on outcomes after rib fractures. Outcomes were additional complications, length of hospital stay, need for institutionalization and mortality within six months. RESULTS: Forty-seven (24.6%) of 191 patients developed a delirium. Independent risk factors for delirium were increased age, physical impairment (lower KATZ-ADL score), nutritional impairment (higher SNAQ score) and the need for a urinary catheter, with odds ratios of 1.07, 0.78, 1.53 and 8.53 respectively. Overall, more complications were observed in patients with delirium. Median ICU and hospital length of stay were 4 and 7 days respectively, of which the latter was significantly longer for delirious patients (p < 0.001). Significantly more patients with delirium were discharged to a nursing home or rehabilitation institution (p < 0.001). The 6-month mortality in delirious patients was nearly twice as high as in non-delirious patients; however, differences did not reach statistical significance. CONCLUSION: Delirium in elderly patients with rib fractures is a serious and common complication, with a longer hospital stay and a higher risk of institutionalization as a consequence. Increased awareness for delirium is imperative, most importantly in older patients, in physically or nutritionally impaired patients and in patients in need of a urinary catheter.

Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice.

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.

Further delineation of Malan syndrome.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

Protein tyrosine phosphatase 1B inactivation limits aging-associated heart failure in mice.

We have previously shown that protein tyrosine phosphatase 1B (PTP1B) inactivation in mice [PTP1B-deficient (PTP1B-/-) mice] improves left ventricular (LV) angiogenesis, perfusion, remodeling, and function and limits endothelial dysfunction after myocardial infarction. However, whether PTP1B inactivation slows aging-associated cardiovascular dysfunction remains unknown. Wild-type (WT) and PTP1B-/- mice were allowed to age until 18 mo. Compared with old WT mice, in which aging increased the LV mRNA expression of PTP1B, old PTP1B-/- mice had 1) reduced cardiac hypertrophy with decreased LV mRNA levels of hypertrophic markers and atrial and brain natriuretic peptides, 2) lower LV fibrosis (collagen: 16 ± 3% in WT mice and 5 ± 3% in PTP1B-/- mice, P < 0.001) with decreased mRNA levels of transforming growth-factor-ß1 and matrix metalloproteinase-2, and 3) higher LV capillary density and lower LV mRNA level of hypoxic inducible factor-1α, which was associated over time with a higher rate of proangiogenic M2 type macrophages and a stable LV mRNA level of VEGF receptor-2. Echocardiography revealed an age-dependent LV increase in end-diastolic volume in WT mice together with alterations of fractional shortening and diastole (transmitral Doppler E-to-A wave ratio). Invasive hemodynamics showed better LV systolic contractility and better diastolic compliance in old PTP1B-/- mice (LV end-systolic pressure-volume relation: 13.9 ± 0.9 in WT mice and 18.4 ± 1.6 in PTP1B-/- mice; LV end-diastolic pressure-volume relation: 5.1 ± 0.8 mmHg/relative volume unit in WT mice and 1.2 ± 0.3 mmHg/relative volume unit in PTP1B-/- mice, P < 0.05). In addition, old PTP1B-/- mice displayed a reduced amount of LV reactive oxygen species. Finally, in isolated resistance mesenteric arteries, PTP1B inactivation reduced aging-associated endothelial dysfunction (flow-mediated dilatation: -0.4 ± 2.1% in WT mice and 8.2 ± 2.8% in PTP1B-/- mice, P < 0.05). We conclude that PTP1B inactivation slows aging-associated LV remodeling and dysfunction and reduces endothelial dysfunction in mesenteric arteries. NEW & NOTEWORTHY The present study shows that protein tyrosine phosphatase 1B inactivation in aged mice improves left ventricular systolic and diastolic function associated with reduced adverse cardiac remodeling (hypertrophy, fibrosis, and capillary rarefaction) and limits vascular endothelial dysfunction. This suggests that protein tyrosine phosphatase 1B inhibition could be an interesting treatment approach in age-related cardiovascular dysfunction.

The COSMAM TRIAL a prospective cohort study of quality of life and cosmetic outcome in patients undergoing breast conserving surgery.

BACKGROUND: Cosmetic result in breast cancer surgery is gaining increased interest. Currently, some 30-40% of the patients treated with breast conserving surgery (BCS) are dissatisfied with their final cosmetic result. In order to prevent disturbing breast deformity oncoplastic surgical techniques have been introduced. The extent of different levels of oncoplastic surgery incorporated in breast conserving surgery and its value with regard to cosmetic outcome, patient satisfaction and quality of life remains to be defined. The aim of this prospective cohort study is to investigate quality of life and satisfaction with cosmetic result in patients with breast cancer, undergoing standard lumpectomy versus level I or II oncoplastic breast conserving surgery. METHODS: Female breast cancer patients scheduled for BCS, from 18 years of age, referred to our outpatient clinic from July 2015 are asked to participate in this study. General, oncologic and treatment information will be collected. Patient satisfaction will be scored preceding surgery, and at 1 month and 1 year follow up. Photographs of the breast will be used to score cosmetic result both by the patient, an independent expert panel and BCCT.Core software. Quality of life will be measured by using the BREAST-Q BCT, EORTC-QLQ and EQ-5D-5 L questionnaires. DISCUSSION: The purpose of this prospective study is to determine the clinical value of different levels of oncoplastic techniques in breast conserving surgery, with regard to quality of life and cosmetic result. Analysis will be carried out by objective measurements of the final cosmetic result in comparison with standard breast conserving surgery. The results of this study will be used to development of a clinical decision model to guide the use oncoplastic surgery in future BCS. TRIAL REGISTRATION: Central Commission of Human Research (CCMO), The Netherlands: NL54888.015.15. Medical Ethical Commission (METC), Maxima Medical Centre, Veldhoven, The Netherlands: 15.107. Dutch Trial Register: NTR5665 , retrospectively registered, 02-25-2016.