A new mouse model for the neurodevelopmental ciliopathy Joubert syndrome

Recent recognition of the key role of primary cilia in orchestrating human development and of the dire consequences of their dysfunction on human health has placed this small organelle in the spotlight. While the causal link between mutations in ciliary genes and central nervous system malformations and dysfunction is well established, the mechanisms by which primary cilia dysfunction acts on development and function of the CNS remain partly unknown. The recent article by Bashford and Subramanian in The Journal of Pathology describes a new mouse model for the neurodevelopmental ciliopathy Joubert syndrome, supporting a role for ciliary-mediated Hedgehog signaling on proliferation, survival, and differentiation of cerebellar granule cell progenitors. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Clinical features and outcome of maintenance hemodialysis patients with COVID-19 from a tertiary nephrology care center in Romania

Background There is limited information about the clinical characteristics, treatment and outcome of maintenance hemodialysis patients with COVID-19. Moreover, regional differences are also conceivable since the extend and severity of outbreaks varied among countries.Methods In this retrospective, observational, single-center study, we analyzed the clinical course and outcomes of 37 maintenance hemodialysis patients (median age 64 years, 51% men) hospitalized with COVID-19 from 24 March to 22 May 2020 as confirmed by real-time PCR.Results The most common symptoms at admission were fatigue (51%), fever (43%), dyspnea (38%) and cough (35%). There were 59% mild/moderate patients and 41% severe/critical patients. Patients in the severe/critical group had a significantly higher atherosclerotic burden since diabetic kidney disease and vascular nephropathies were the most common primary kidney diseases and eighty percent of them had coronary heart disease. Also, Charlson comorbidity score was higher in this group. At admission chest X-ray, 46% had ground-glass abnormalities. Overall, 60% patients received hydroxychloroquine, 22% lopinavir–ritonavir, 11% tocilizumab, 24% systemic glucocorticoids, and 54% received prophylactic anticoagulation. Seven (19%) patients died during hospitalization and 30 were discharged. The main causes of death were cardiovascular (5 patients) and respiratory distress syndrome (2 patients). In Cox regression analysis, lower oxygen saturation, anemia and hypoalbuminemia at admission were associated with increased mortality.Conclusions In conclusion, we observed a high mortality rate among maintenance hemodialysis patients hospitalized for COVID-19. Anemia, lower serum albumin and lower basal oxygen saturation at admission were factors associated with poor prognosis.     

Right Ventricular Function Predicts Clinical Response to Specific Vasodilator Therapy in Patients with Pulmonary Hypertension

Introduction: We followed patients with pulmonary arterial hypertension (PAH) receiving specific vasodilator therapy and tested for predictors of clinical outcome. Methods: Thirty‐two patients (mean age 39 ± 15 years, 22 women, diagnosed with pulmonary hypertension; PH): 29 with PAH and 3 patients with inoperable chronic thromboembolic PH received therapy with either bosentan, sildenafil, or both and were evaluated with clinical parameters, biomarkers (B‐type natriuretic peptide values), and echocardiography before receiving specific medication and every 3 months thereafter. A right heart catheterization was performed at baseline. A composite endpoint of death, worsening of functional class, or the need of a second vasodilator agent was used to define the clinical nonresponders. Results: Patients were followed for 14 months (7.5–21). The endpoint was reached by 15 patients: four patients died (two idiopathic PAH and two PAH in context of Eisenmenger syndrome), seven patients showed 1 functional class worsening, and four patients needed to be switched to combination therapy. Patients who remained clinically stable or improved had at baseline a better cardiac output with a less remodeled right ventricle (RV) and better functioning RV (all P < 0.05). A RV fractional area change (RVFAC) lower than 25.7% and a RV global strain value higher than ?13.4% predict with 87% sensitivity and 83% specificity (AUC 87.3%, P = 0.001) and 73% sensitivity and 91% specificity (AUC 84.2%, P = 0.003), respectively, patients who will deteriorate clinically under specific vasodilator therapy. A multivariate model showed RVFAC to be the only independent predictor of the endpoint with a HR of 0.87 (0.8–0.96), P = 0.007. Conclusions: Over an average period of 1 year, almost half of patients showed signs of clinical deterioration despite specific vasodilator therapy. Parameters of right ventricular morphology and function had prognostic value in these patients.     

Superior mesenteric artery first approach versus standard pancreaticoduodenectomy:a systematic review and meta-analysis

BACKGROUND: The superior mesenteric artery (SMA) first approach was proposed recently as a new modification of the standard pancreaticoduodenectomy. Increasing evidence showed that a periadventiceal dissection of the SMA with early transection of the inflow during pancreaticoduodenec-tomy associates better early perioperative results, and setup the scene for long-term oncological benefits. The objectives of the current study are to compare the operative results and long-term oncological outcomes of SMA first approach pan-creaticoduodenectomy (SMA-PD) with standard pancreatico-duodenectomy (S-PD).DATA SOURCES: Electronic search of the PubMed/MEDLINE, EMBASE, Web of Science and Cochrane Library was performed until July 2015. We considered randomized controlled trials (RCTs) and non-randomized comparative studies (NRCSs) comparing SMA-PD with S-PD to be eligible if they included patients with periampullary cancers.RESULTS: A total of one RCT and thirteen NRCSs met the in-clusion criteria, involving 640 patients with SMA-PD and 514 patients with S-PD. The SMA-PD was associated with less in-traoperative bleeding, less blood transfusions and higher rate of associated venous resections. The pancreatic fistula and delayed gastric emptying had a significantly lower rate in the SMA-PD group. There were no differences between the two approaches regarding overall complications, major complica-tion rates and in-hospital mortality. There was no difference regarding R0 resection rate, and one-, two- or three-year over-all survival. The SMA-PD was associated with a lower local, hepatic and extrahepatic metastatic rate.CONCLUSIONS: The SMA-PD is associated with better perioperative outcomes, such as blood loss, transfusion re-quirements, pancreatic fistula, and delayed gastric emptying. Although the one-, two- or three-year overall survival rate is not superior, the SMA-PD has a lower local and metastatic re-currence rate.     

Parkes-Weber Syndrome and double orifice atrial septal defect as a combined rare cause of severe pulmonary hypertension

The International Journal of Cardiovascular Imaging -     

New Definition Criteria of Myocardial Dysfunction in Patients with Liver Cirrhosis: A Speckle Tracking and Tissue Doppler Imaging Study

There are no clear recommendations regarding cirrhotic cardiomyopathy (CC) evaluation in patients with pre-transplant liver cirrhosis. The roles of new methods, tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) in the diagnosis and prognosis of cirrhotic cardiomyopathy remain controversial. We investigated the utility of TDI/STE parameters in cirrhotic cardiomyopathy diagnosis and also in predicting mortality in patients with liver cirrhosis. Left/right ventricular function was studied using conventional TDI (velocities) and STE (strain/strain rate). We assessed left ventricular diastolic dysfunction, graded into four new classes (I/Ia/II/III). Serum NTproBNP (N-terminal prohormone of brain natriuretic peptide), troponin I, β-crosslaps, QTc interval, arterial compliance and endothelial function were measured. Liver-specific scores (Child–Pugh, MELD, MELDNa) were computed. There was a 1-y follow-up visit to determine mortality. We observed resting biventricular diastolic myocardial dysfunction, not presently included in the definition of cirrhotic cardiomyopathy. We provided an improved characterization of cardiac dysfunction in patients with liver cirrhosis. This might change the current definition. However, the utility of STE/TDI parameters in predicting long-term mortality in patients with liver cirrhosis remains controversial.     

The Mandibular Ridge Oral Mucosa Model of Stromal Influences on the Endothelial Tip Cells: An Immunohistochemical and TEM Study

This study aimed to evaluate by immunohistochemistry and transmission electron microscopy (TEM) the morphological features of the oral mucosa endothelial tip cells (ETCs) and to determine the immune and ultrastructural patterns of the stromal nonimmune cells which could influence healing processes. Immune labeling was performed on bioptic samples obtained from six edentulous patients undergoing surgery for dental implants placement; three normal samples were collected from patients prior to the extraction of the third mandibular molar. The antibodies were tested for CD34, CD117(c‐kit), platelet derived growth factor receptor‐alpha (PDGFR‐α), Mast Cell Tryptase, CD44, vimentin, CD45, CD105, alpha‐smooth muscle actin, FGF2, Ki67. In light microscopy, while stromal cells (StrCs) of the reparatory and normal oral mucosa, with a fibroblastic appearance, were found positive for a CD34/CD44/CD45/CD105/PDGFR‐α/vimentin immune phenotype, the CD117/c‐kit labeling led to a positive stromal reaction only in the reparatory mucosa. In TEM, non‐immune StrCs presenting particular ultrastructural features were identified as circulating fibrocytes (CFCs). Within the lamina propria CFCs were in close contact with ETCs. Long processes of the ETCs were moniliform, and hook‐like collaterals were arising from the dilated segments, suggestive for a different stage migration. Maintenance and healing of oral mucosa are so supported by extensive processes of angiogenesis, guided by ETCs that, in turn, are influenced by the CFCs that populate the stromal compartment both in normal and reparatory states. Therefore, CFCs could be targeted by specific therapies, with pro‐ or anti‐angiogenic purposes. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.     

Ferritin above 100 mcg/L could rule out colon cancer, but not gastric or rectal cancer in patients with involuntary weight loss

ABSTRACT: BACKGROUND: A tenth of patients with involuntary weight loss (IWL) have gastrointestinal cancer. Ferritin is the first parameter to be modified during the process leading to iron deficiency anaemia, therefore it should be the most sensitive. The aim of this study was to assess the ability of ferritin to rule out gastrointestinal cancer in patients with involuntary weight loss. METHODS: All consecutive patients with IWL admitted in a secondary care university hospital were prospectively studied. Ferritin, haemoglobin with erythrocyte indices and serum iron were recorded for all patients. The reference standard was bidirectional endoscopy and/or 6 months follow-up. RESULTS: 290 patients were included, a quarter had cancer, of which 22 (7.6%) had gastrointestinal cancer (8 gastric cancer, 1 ileum cancer, 13 colorectal cancer). Ferritin had the best area under the curve (AUC), both for gastrointestinal cancer (0.746, CI: 0.691-0.794), and colorectal cancer (0.765, CI: 0.713-0.813), compared to the other parameters of iron deficiency. In the diagnosis of colorectal cancer, ferritin with a cut-off value of 100 mcg/L had a sensitivity of 93% (CI: 69-100%), and negative likelihood ratio of 0.13, with a negative predictive value of 99% (96-100%), while for gastrointestinal cancer, the sensitivity was lower (89%, CI: 67-95%), with a negative likelihood ratio of 0.24. There were three false negative patients, two with gastric cancer, and one with rectal cancer. CONCLUSION: In patients with involuntary weight loss, a ferritin above 100mcg/L could rule out colon cancer, but not gastric or rectal cancer.