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.

Transient heart rate reduction improves acute decompensated heart failure-induced left ventricular and coronary dysfunction.

AIMS: Acute decompensated heart failure (ADHF), a live-threatening complication of heart failure (HF), associates a further decrease of the already by HF-impaired cardiac function with an increase in heart rate. We evaluated, using a new model of ADHF, whether heart rate reduction (HRR) opposes the acute decompensation-related aggravation of cardiovascular dysfunction. METHODS AND RESULTS: Cardiac output (echocardiography), cardiac tissue perfusion (magnetic resonance imaging), pulmonary wet weight, and in vitro coronary artery relaxation (Mulvany) were assessed 1 and 14 days after acute decompensation induced by salt-loading (1.8 g/kg, PO) in rats with well-established HF due to coronary ligation. HRR was induced by administration of the If current inhibitor S38844, 12 mg/kg PO twice daily for 2.5 days initiated 12 h or 6 days after salt-loading (early or delayed treatment, respectively). After 24 h, salt-loading resulted in acute decompensation, characterized by a reduction in cardiac output (HF: 130 ± 5 mL/min, ADHF: 105 ±  8 mL/min; P < 0.01), associated with a decreased myocardial perfusion (HF: 6.41 ± 0.53 mL/min/g, ADHF: 4.20 ± 0.11 mL/min/g; P < 0.01), a slight increase in pulmonary weight (HF: 1.68 ± 0.09 g, ADHF: 1.81 ± 0.15 g), and impaired coronary relaxation (HF: 55 ± 1% of pre-contraction at acetylcholine 4.5 10-5  M, ADHF: 27 ± 7 %; P < 0.01). Fourteen days after salt-loading, cardiac output only partially recovered (117 ± 5 mL/min; P < 0.05), while myocardial tissue perfusion (4.51 ± 0.44 mL/min; P < 0.01) and coronary relaxation (28 ± 4%; P < 0.01) remained impaired, but pulmonary weight further increased (2.06 ± 0.15 g, P < 0.05). Compared with untreated ADHF, HRR induced by S38844 improved cardiac output (125 ± 1 mL/min; P < 0.05), myocardial tissue perfusion (6.46 ± 0.42 mL/min/g; P < 0.01), and coronary relaxation (79 ± 2%; P < 0.01) as soon as 12 h after S38844 administration. These effects persisted beyond S38844 administration, illustrated by the improvements in cardiac output (130 ± 6 mL/min; P < 0.05), myocardial tissue perfusion (6.38 ± 0.48 mL/min/g; P < 0.01), and coronary relaxation (71 ± 4%; P < 0.01) at Day 14. S38844 did not modify pulmonary weight at Day 1 (1.78 ± 0.04 g) but tended to decrease pulmonary weight at Day 14 (1.80 ± 0.18 g). While delayed HRR induced by S38844 never improved cardiac function, early HRR rendered less prone to a second acute decompensation. CONCLUSIONS: In a model mimicking human ADHF, early, but not delayed, transient HRR induced by the If current inhibitor S38844 opposes acute decompensation by preventing the decompensated-related aggravation of cardiovascular dysfunction as well as the development of pulmonary congestion, and these protective effects persist beyond the transient treatment. Whether early transient HRR induced by If current inhibitors or other bradycardic agents, i.e. beta-blockers, exerts beneficial effects in human ADHF warrants further investigation.

Antifibrotic effect of novel neutrophil gelatinase-associated lipocalin inhibitors in cardiac and renal disease models.

Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8-12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.

Cardiopulmonary bypass increases endothelial dysfunction after pulmonary ischaemia-reperfusion in an animal model.

OBJECTIVES: Endothelial dysfunction during ischaemia-reperfusion (IR) is a major cause of primary graft dysfunction during lung transplantation. The routine use of cardiopulmonary bypass (CPB) during lung transplantation remains controversial. However, the contribution of CPB to pulmonary endothelial dysfunction remains unclear. The objective was to investigate the impact of CPB on endothelial dysfunction in a lung IR rat model. METHODS: Rats were allocated to 4 groups: (i) Sham, (ii) IR, (iii) CPB and (iv) IR-CPB. The primary outcome was the study of pulmonary vascular reactivity by wire myograph. We also assessed glycocalyx degradation by enzyme-linked immunosorbent assay and electron microscopy and both systemic and pulmonary inflammation by enzyme-linked immunosorbent assay and immunohistochemistry. Rats were exposed to 45 min of CPB and IR. We used a CPB model allowing femoro-femoral support with left pulmonary hilum ischaemia for IR. RESULTS: Pulmonary endothelium-dependent relaxation to acetylcholine was markedly reduced in the IR-CPB group (10.7 ± 9.1%) compared to the IR group (50.5 ± 5.2%, P < 0.001), the CPB group (54.1 ± 4.7%, P < 0.001) and the sham group (80.8 ± 6.7%, P < 0.001), suggesting that the association of pulmonary IR and CPB increases endothelial dysfunction. In IR-CPB, IR and CPB groups, vasorelaxation was completely abolished when inhibiting nitric oxide synthase, suggesting that this relaxation process was mainly mediated by nitric oxide. We observed higher syndecan-1 plasma levels in the IR-CPB group in comparison with the other groups, reflecting an increased degradation of glycocalyx. We also observed higher systemic inflammation in the IR-CPB group as shown by the increased plasma levels of IL-1ß, IL-10. CONCLUSIONS: CPB significantly increased the IR-mediated effects on pulmonary endothelial dysfunction. Therefore, the use of CPB during lung transplantation could be deleterious, by increasing endothelial dysfunction.

Nitrogen Dioxide Inhalation Exposures Induce Cardiac Mitochondrial Reactive Oxygen Species Production, Impair Mitochondrial Function and Promote Coronary Endothelial Dysfunction.

Traffic air pollution is a major health problem and is recognized as an important risk factor for cardiovascular (CV) diseases. In a previous experimental study, we showed that diesel exhaust (DE) exposures induced cardiac mitochondrial and CV dysfunctions associated with the gaseous phase. Here, we hypothesized that NO2 exposures to levels close to those found in DE induce a mitochondrial reactive oxygen species (ROS) production, which contribute to an endothelial dysfunction, an early indicator for numerous CV diseases. For this, we studied the effects of NO2 on ROS production and its impacts on the mitochondrial, coronary endothelial and cardiac functions, after acute (one single exposure) and repeated (three h/day, five days/week for three weeks) exposures in Wistar rats. Acute NO2 exposure induced an early but reversible mitochondrial ROS production. This event was isolated since neither mitochondrial function nor endothelial function were impaired, whereas cardiac function assessment showed a reversible left ventricular dysfunction. Conversely, after three weeks of exposure this alteration was accompanied by a cardiac mitochondrial dysfunction highlighted by an alteration of adenosine triphosphate (ATP) synthesis and oxidative phosphorylation and an increase in mitochondrial ROS production. Moreover, repeated NO2 exposures promoted endothelial dysfunction of the coronary arteries, as shown by reduced acetylcholine-induced vasodilatation, which was due, at least partially, to a superoxide-dependent decrease of nitric oxide (NO) bioavailability. This study shows that NO2 exposures impair cardiac mitochondrial function, which, in conjunction with coronary endothelial dysfunction, contributes to cardiac dysfunction. Together, these results clearly identify NO2 as a probable risk factor in ischemic heart diseases.

Abdominal aortic aneurysm patients remain at risk for delirium on the surgical ward after intensive care unit dismissal.

BACKGROUND: The incidence of delirium following open abdominal aortic aneurysm (AAA) surgery is significant, with incidence rates ranging from 12% to 33%. However, it remains unclear on what level of care a delirium develops in AAA patients. The aim of this study was to investigate the incidence of delirium in the ICU and on the surgical ward after AAA surgery. METHODS: A single-center retrospective cohort study was conducted that included all patients treated electively for an open AAA repair and patients who underwent emergency treatment for a ruptured AAA between 2013 and 2018. The diagnosis of delirium was verified by a psychiatrist or geriatrician using the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria. The incidence of delirium was calculated. Cox proportional hazards regression analyses were used to analyze 6- and 12-month survival. RESULTS: A total of 135 patients were included, 46 patients (34%) had a delirium during admission. Of these, 30 patients (65%) developed a delirium in the ICU and 16 patients (35%) on the surgical ward. There was no significant difference in six months and twelve months mortality between the ICU and ward delirium groups (HR=1.64, 95% CI: 0.33-8.13, and HR=1.12, 95% CI: 0.28-4.47, respectively). CONCLUSIONS: Delirium frequently occurs in patients who undergo AAA surgery. This study demonstrated that patients on the surgical ward remain at risk of developing a delirium after ICU dismissal. Patients with ICU delirium differ in clinical characteristics and outcomes from patients with a delirium on the surgical ward.

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.

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.

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.

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.

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.

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.

Soluble Epoxide Hydrolase Inhibition Prevents Experimental Type 4 Cardiorenal Syndrome.

Objectives: Cardiovascular diseases (CVD) remain the leading cause of morbimortality in patients with chronic kidney disease (CKD). The aim of this study was to assess the cardiovascular impact of the pharmacological inhibition of soluble epoxide hydrolase (sEH), which metabolizes the endothelium-derived vasodilatory and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acid (DHETs), in the 5/6 nephrectomy (Nx) mouse model. Methods and Results: Compared to sham-operated mice, there was decrease in EET-to-DHET ratio 3 months after surgery in vehicle-treated Nx mice but not in mice treated with the sEH inhibitor t-AUCB. Nx induced an increase in plasma creatinine and in urine albumin-to-creatinine ratio as well as the development of kidney histological lesions, all of which were not modified by t-AUCB. In addition, t-AUCB did not oppose Nx-induced blood pressure increase. However, t-AUCB prevented the development of cardiac hypertrophy and fibrosis induced by Nx, as well as normalized the echocardiographic indices of diastolic and systolic function. Moreover, the reduction in endothelium-dependent flow-mediated dilatation of isolated mesenteric arteries induced by Nx was blunted by t-AUCB without change in endothelium-independent dilatation to sodium nitroprusside. Conclusion: Inhibition of sEH reduces the cardiac remodelling, and the diastolic and systolic dysfunctions associated with CKD. These beneficial effects may be mediated by the prevention of endothelial dysfunction, independent from kidney preservation and antihypertensor effect. Thus, inhibition of sEH holds a therapeutic potential in preventing type 4 cardiorenal syndrome.

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.

Does robotic rectal cancer surgery improve the results of experienced laparoscopic surgeons? An observational single institution study comparing 168 robotic assisted with 184 laparoscopic rectal resections.

BACKGROUND: The role of robotic assistance in colorectal cancer surgery has not been established yet. We compared the results of robotic assisted with those of laparoscopic rectal resections done by two surgeons experienced in laparoscopic as well as in robotic rectal cancer surgery. METHODS: Two surgeons who were already experienced laparoscopic colorectal surgeons in 2005 started robotic surgery with the daVinci SI system in 2012. All their rectal cancer resections between 2005 and 2015 were retrieved from a prospectively recorded colorectal database of routinely collected patient data. Multi-organ resections were excluded. Patient data, diagnostic data, data on preceding operations and neoadjuvant treatment, perioperative and operative data, logistic data, and short-term outcomes were gathered. Multivariable analyses (multiple linear and logistic regression) were used to assess differences in several outcomes between the two resection methods while adjusting for all potential confounders we could identify. Results are presented as adjusted mean differences for continuous outcome variables or as adjusted odds ratios (OR) for dichotomous outcome variables. RESULTS: Three hundred and fifty-two patients with rectal cancers were identified: 168 robotic and 184 conventional laparoscopic cases, 178 operated by surgeon A and 174 operated by surgeon B. Adjusted mean operation time was 215 min in the robotic group which was 40 min (95% CI 24-56; p < 0.0005) longer than the 175 min in the laparoscopic group. Robotic treatment had significantly lesser numbers of conversions (OR 0.09 (0.03-0.32); p < 0.0005) and other complications (SSI and anastomic leakage excluded) (OR 0.32 (0.15-0.69); p = 0.004), adjusted for potential confounders. CONCLUSIONS: Our study suggests that robotic surgery in the hands of experienced laparoscopic rectal cancer surgeons improves the conversion rate and complication rate drastically compared to conventional laparoscopic surgery, but operation time is longer.

Peri-Operative Nasal Eradication Therapy Prevents Staphylococcus aureus Surgical Site Infections in Aortoiliac Surgery.

BACKGROUND: Surgical site infections (SSIs) cause considerable morbidity and deaths among patients undergoing vascular surgery. Pre-operative screening and subsequent treatment of nasal Staphylococcus aureus carriers with mupirocin and chlorhexidine reduces the risk of SSIs in cardiothoracic and orthopedic surgery. The aim of this study was to investigate the effect of this screen-and-treat strategy on the development of SSI in patients undergoing aortoiliac surgery. METHODS: A prospective study was performed that enrolled an intervention cohort comprising all patients undergoing aortoiliac surgery from February 2013 to December 2016. Before surgery, patients were screened for S. aureus nasal carriage and, if positive, were treated with mupirocin nasal ointment and chlorhexidine body washes. The presence of SSI was recorded on the basis of the criteria of the U.S. Centers for Disease Control and Prevention. A historic control group was used, consisting of aortoiliac surgery patients in 2010 who tested positive for S. aureus but received no treatment. RESULTS: A total of 374 patients in the study cohort were screened of whom 75 (20.1%) tested positive for S. aureus. Of these patients, 68 were given eradication therapy. In the 2010 cohort, 22 patients (15.7%) were positive. The incidence of S. aureus infection was 0 of 75 in the treatment group versus 3 of 22 (13.6%) in the control group (p = 0.021). Both the 30-day mortality rate (1.3% vs. 13.6%; p = 0.035) and the rate of re-interventions (12.0% vs. 31.8%) were significantly lower in the treated group. CONCLUSION: We conclude that S. aureus nasal screening and eradication with mupirocin and chlorhexidine reduces S. aureus SSI and its complications after aortoiliac surgery.

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.

Life Expectancy and Outcome of Different Treatment Strategies for Critical Limb Ischemia in the Elderly Patients.

BACKGROUND: The treatment of critical limb ischemia (CLI) in the elderly patients is challenging because of the comorbidity and fragility of these patients. We analyzed survival in relation to different treatment options and estimated life expectancy of our study group by age and gender. METHODS: All patients aged ≥70 years, presenting with chronic CLI, between 2006 and 2013 were included. The treatment was conservative, endovascular, surgical, or by primary major amputation. The interest was in the effect of conservative versus nonconservative treatment on survival. Furthermore, we compared mortality and life expectancy between the study population to the overall Dutch population by age and gender. RESULTS: In total, 686 legs in 651 patients were treated. Initial treatment of patients was conservative (n = 181), endovascular (n = 259), surgical (n = 169), or amputation (n = 42). The overall 1-year mortality was 29%. Patients were stratified by age: 70-79 (n = 350) years and ≥80 (n = 301) years. Higher mortality rate ratios (RR) were found in octogenarians compared with patients aged 70-79 years, in the endovascular (P < 0.001) and surgical (P < 0.001) group. The mortality RRs of conservative relatively to nonconservative treatment was 0.84 (95% confidence interval: 0.65-1.09; P = 0.19), not significantly differing between both age groups (P = 0.74). The mortality RR of 3.72 of our study population to the Dutch general population was high, with an excess mortality of 272%. Life expectancy at the age of 70 years was substantially decreased by 9 and 8 years for, respectively, the male and female population. CONCLUSIONS: Mortality rates in elderly patients with CLI are high, corresponding with a decreased life expectancy, regardless of the type of intervention. Revascularization is associated with high periprocedural mortality, especially in octogenarians. Conservative treatment is noninferior to nonconservative treatment in terms of mortality and should be considered as the treatment in octogenarians with substantial comorbidity.

Mortality after major amputation in elderly patients with critical limb ischemia.

BACKGROUND: Owing to the aging population, the number of elderly patients with critical limb ischemia (CLI) has increased. The consequence of amputation is immense. However, at the moment, information about the mortality after amputation in the elderly vascular patients is unknown. For this reason, this study evaluated mortality rates and patient-related factors associated with mortality after a major amputation in elderly patients with CLI. METHODS: From 2006 to 2013, we included patients aged >70 years who were treated for chronic CLI by primary or secondary major amputation within or after 3 months of initial therapy (revascularization or conservative management). Outcome measurements were mortality after major amputation and factors associated with mortality (age, comorbidity and timing of amputation). RESULTS: In total, 168/651 patients (178 legs; 26%) underwent a major amputation. Patients were stratified by age: 70-80 years (n=86) and >80 years (n=82). Overall mortality after major amputation was 44%, 66% and 85% after 1, 3 and 5 years, respectively. The 6-month and 1-year mortality in patients aged 80 years or older was, respectively, 59% or 63% after a secondary amputation <3 months versus 34% and 44% after a secondary amputation >3 months. Per year of age, the mortality rate increased by 4% (P=0.005). No significant difference in mortality after major amputation was found in the presence of comorbidity or according to Rutherford classification. CONCLUSION: Despite developments in the treatment of CLI by revascularization, amputation rates remain high and are associated with tremendous mortality rates. Secondary amputation after a failed attempt of revascularization causes a higher mortality. Further research concerning timing of amputation and patient-related outcome is needed to evaluate if selected patients might benefit from primary amputation.

Aldosterone Target NGAL (Neutrophil Gelatinase-Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NFκB Pathway.

Myocardial infarction (MI) is accompanied by cardiac fibrosis, which contributes to cardiac dysfunction. Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with left ventricular (LV) dysfunction after MI. We herein investigated the role of the MR target NGAL (neutrophil gelatinase-associated lipocalin) in post-MI cardiac damages. Both higher baseline NGAL and a greater increase in serum NGAL levels during follow-up were significantly associated with lower 6-month LV ejection fraction recovery in a cohort of 119 post-MI patients, as assessed by cardiac magnetic resonance imaging. NGAL protein levels increased in the LV at 7 days post-MI in wild-type mice with MI. This effect was prevented by treatment with the nonsteroidal MR antagonist finerenone (1 mg/kg per day). NGAL knockout mice with MI had lower LV interstitial fibrosis and inflammation, better LV contractility and compliance, and greater stroke volume and cardiac output than wild-type mice with MI at 3 months post-MI. Aldosterone (10-8 mol/L) increased NGAL expression in cultured human cardiac fibroblasts. Cells treated with aldosterone or NGAL (500 ng/mL) showed increased production of collagen type I. The effects of aldosterone were abolished by finerenone (10-6 mol/L) or NGAL knockdown. This NGAL-mediated activity relied on NFκB (nuclear factor-κB) activation, confirmed by the use of the NFκB-specific inhibitor BAY11-7082, which prevented the effect of both aldosterone and NGAL on collagen type I production. In conclusion, NGAL, a downstream MR activation target, is a key mediator of post-MI cardiac damage. NGAL may be a potential therapeutic target in cardiovascular pathological situations in which MR is involved.