Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure.

AIMS: To investigate the role of the endogenous urocortin peptides in heart failure (HF) through blockade of the corticotropin-releasing factor receptor 2 (CRF-R2). METHODS AND RESULTS: Eight sheep were administered the CRF-R2 antagonist CRF(9-41) (1.5 mg bolus) before (Normal) and after development of pacing-induced HF. Compared with controls, CRF(9-41) in HF significantly increased mean arterial pressure (MAP) (71+/-2 vs. 75+/-2 mmHg, P=0.0024) and calculated total peripheral resistance (CTPR) (33.3+/-5.2 vs. 39.4+/-5.9 mmHg/L/min, P=0.0455). Similar trends were observed in the Normal state (MAP 87+/-1 vs. 89+/-2 mmHg, P=0.0689; CTPR 21.9+/-2.0 vs. 24.4+/-2.4 mmHg/L/min, P=0.0731). Left atrial pressure was elevated similarly in both states (Normal P=0.0013; HF P=0.0298), whereas cardiac output tended to be reduced (Normal P=0.0614). CRF(9-41) increased plasma urocortin-I (Normal 10.3+/-0.8 vs. 19.8+/-1.3 pmol/L, P<0.001; HF 14.4+/-0.9 vs. 25.3+/-0.8 pmol/L, P<0.001), renin (Normal 0.34+/-0.06 vs. 0.41+/-0.02 nmol/L/hr, P=0.013; HF 1.14+/-0.29 vs. 1.57+/-0.36 nmol/L/hr, P=0.0326), aldosterone (Normal 370+/-62 vs. 563+/-99 pmol/L, P=0.0813; HF 662+/-141 vs. 1024+/-209 pmol/L, P=0.095), and endothelin-1 (HF 3.18+/-0.18 vs. 4.74+/-1.04 pmol/L, P=0.0087). MAP, CTPR, renin, and endothelin-1 responses to CRF-R2 antagonism were significantly greater in HF than in the Normal state (P=0.049, 0.0427, 0.0311, and 0.0412, respectively). CONCLUSION: These data suggest that the endogenous urocortin peptides contribute to the suppression of vascular tone and renin-angiotensin-aldosterone/endothelin activation in HF and thus, play a protective compensatory role in this disorder.     

Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism.

AIMS: We investigated the value of a novel early biomarker, heart-type fatty acid-binding protein (H-FABP), in risk stratification of patients with acute pulmonary embolism (PE). METHODS AND RESULTS: We prospectively included 107 consecutive patients with confirmed PE. The endpoints were (i) PE-related death or major complications and (ii) overall 30-day mortality. Overall, 29 patients (27%) had abnormal (>6 ng/mL) H-FABP levels at presentation. Of those, 12 (41%) had a complicated course, whereas all patients with normal baseline H-FABP had a favourable 30-day outcome (OR, 71.45; P<0.0001). At multivariable analysis, H-FABP (P<0.0001), but not cardiac troponin T (P=0.13) or N-terminal pro-brain natriuretic peptide (P=0.36), predicted an adverse outcome. Evaluation of a strategy combining biomarker testing with echocardiography revealed that patients with a negative H-FABP test had an excellent prognosis regardless of echocardiographic findings. In contrast, patients with a positive H-FABP test had a complication rate of 23.1% even in the presence of a normal echocardiogram, and this rose to 57.1% if echocardiography also demonstrated right ventricular dysfunction (OR vs. a negative H-FABP test, 5.6 and 81.4, respectively). CONCLUSION: H-FABP is a promising early indicator of right ventricular injury and dysfunction in acute PE. It may help optimize risk stratification algorithms and treatment strategies.     

DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Juvenile ciliopathy syndromes that are associated with renal cysts and premature renal failure are commonly the result of mutations in the gene encoding centrosomal protein CEP290. In addition to centrosomes and the transition zone at the base of the primary cilium, CEP290 also localizes to the nucleus; however, the nuclear function of CEP290 is unknown. Here, we demonstrate that reduction of cellular CEP290 in primary human and mouse kidney cells as well as in zebrafish embryos leads to enhanced DNA damage signaling and accumulation of DNA breaks ex vivo and in vivo. Compared with those from WT mice, primary kidney cells from Cep290-deficient mice exhibited supernumerary centrioles, decreased replication fork velocity, fork asymmetry, and increased levels of cyclin-dependent kinases (CDKs). Treatment of Cep290-deficient cells with CDK inhibitors rescued DNA damage and centriole number. Moreover, the loss of primary cilia that results from CEP290 dysfunction was rescued in 3D cell culture spheroids of primary murine kidney cells after exposure to CDK inhibitors. Together, our results provide a link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes.     

Impact of Intraoperative Radiotherapy on Cosmetic Outcome and Complications after Oncoplastic Breast Surgery

Breast cancer is one of the most common tumors in the population worldwide. Conservative breast surgery (CBS) is one of the preferred surgical options, because both the oncologic and esthetic needs of the patient can be addressed. CBS surgical outcomes tend to be more effective with reduced chances of disease recurrence when radiotherapy (RT) treatment is considered as an adjunct treatment, either applied during surgery (IORT) and/or after (EBRT). The purpose of our study was to compare surgical outcomes between IORT and EBRT after CBS. In the past 5 years, we performed CBS in 489 patients in our clinic. Of these patients, 83 underwent adjunct treatment with IORT and 109 were treated with EBRT in accordance with our university approved clinical protocol. Surgical outcomes, early complication rates, and esthetic results were compared between these two groups of CBS patients, with a mean follow‐up time of 17 months. IORT allowed breast irradiation treatment to be performed without effecting overlying skin, thus cosmetic outcomes tended to be favorable. Esthetic postoperative results assessed with the Breast Cancer Conservation Treatment (BCCTcore) software showed that the differences between IORT and EBRT were not statistically significant (including those patients that underwent further oncoplastic techniques after EBRT). The disease recurrence rates between the two groups were not significantly different. IORT is a safe, fast, and feasible technique that provides effective and comparable CBS outcomes for patients with breast cancer.     

Occupational Characteristics of Adults with Pediatric-Onset Spinal Cord Injury

Background:

Employment rates among individuals with spinal cord injury (SCI) are lower than in the general population and little is known about the specific occupations in which they are employed.

Objectives:

To describe specific occupations of adults with pediatric-onset SCI using the 2010 Standard Occupational Classification (SOC) system and to determine associations between SOC occupations and demographic factors.

Methods:

Cross-sectional data specific to education and employment were collected from the last interviews of a larger longitudinal study. Occupations were categorized according to the 2010 SOC system. SOC groups were compared within gender level of injury and final education.

Results:

Of the 461 total participants 219 (47.5%) were employed and specific occupations were available for 179. Among the SOC groups Education Law Community Service Arts and Media Occupations were most prevalent (30.2%) followed by Management Business and Finance Occupations (21.1%) Computer Engineering and Science Occupations (10.6%) Administrative and Office Support Occupations (10.0%) Service Occupations (7.3%) Healthcare Practitioners and Technical Occupations (3.9%) and Production Occupations (3.4%). Differences were found in the distribution of SOC groups between gender levels of injury and final education groups.

Conclusion:

A wide variety of occupations were reported in adults with pediatric-onset SCI generally in concordance with final education and functional ability levels.     

Does Cyclophosphamide Play a Protective Role Against Neuronal Loss in Chronic <Emphasis Type="Italic">T.</Emphasis><Emphasis Type="Italic"> cruzi</Emphasis> Infection?

In this study, we verified the possible role of cyclophosphamide (CY) in protecting or not against neuronal losses in young and aged male Calomys callosus chronically infected with the MORC-1 strain of Trypanosoma cruzi through numerical quantification of neurons from the myenteric plexus of the colon and quantification of nitric-oxide concentration (NO) during the acute and chronic phase of infection. For this purpose, groups of young C. callosus were infected with the MORC-1 strain of T. cruzi. A group of infected animals received i.p. 0.2 mg/ml genuxal dissolved in distilled water treatment with CY. NO concentration in aged animals displayed reduced levels when compared to those found in young animals. No significant alterations in the number of neurons were observed in young animals, but for aged ones, a protective role of CY in reducing neuron loss was noted, in addition to enhancing the neuronal volume, area, and perimeter. These results suggest that CY administration, depending on the dose and time span, can act as a protective agent against neuronal losses.