Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation

Mitral valve prolapse (MVP) associated with severe mitral regurgitation is a debilitating disease with no pharmacological therapies available. MicroRNAs (miRNA) represent an emerging class of circulating biomarkers that have never been evaluated in MVP human plasma. Our aim was to identify a possible miRNA signature that is able to discriminate MVP patients from healthy subjects (CTRL) and to shed light on the putative altered molecular pathways in MVP. We evaluated a plasma miRNA profile using Human MicroRNA Card A followed by real-time PCR validations. In addition, to assess the discriminative power of selected miRNAs, we implemented a machine learning analysis. MiRNA profiling and validations revealed that miR-140-3p, 150-5p, 210-3p, 451a, and 487a-3p were significantly upregulated in MVP, while miR-223-3p, 323a-3p, 340-5p, and 361-5p were significantly downregulated in MVP compared to CTRL (p ≤ 0.01). Functional analysis identified several biological processes possible linked to MVP. In addition, machine learning analysis correctly classified MVP patients from CTRL with high accuracy (0.93) and an area under the receiving operator characteristic curve (AUC) of 0.97. To the best of our knowledge, this is the first study performed on human plasma, showing a strong association between miRNAs and MVP. Thus, a circulating molecular signature could be used as a first-line, fast, and cheap screening tool for MVP identification.     

A project scheduling approach to production planning with feeding precedence relations

In Manufacturing-to-Order or Engineering-to-Order systems producing complex and highly customised items, each item has its own characteristics that are often tailored for a specific customer. Project scheduling approaches are suitable for production planning in such environments. However, when we consider the production of complex items, the distinct production operations are often aggregated into activities representing whole production phases. In such cases, the planning and scheduling problem works on the aggregate activities, considering that, in most cases, such activities also have to be manually executed. Moreover, simple finish-to-start precedence relations no longer correctly represent the real production process, but overlapping among activities should be allowed. In this paper, a project scheduling approach is proposed for production planning in Manufacturing-to-Order systems. The Variable Intensity formulation is used to allow the effort committed to the execution of activities to vary over time. Feeding precedences are developed to model generalised precedence relations when the execution mode of activities is not known a priori. Two mathematical formulations of these precedence relations are proposed. The formulations are applied both to randomly generated instances and to an industrial system producing machining centres and are compared in terms of computational efficiency.     

Refractory angina despite patent coronary artery bypass grafts: treatment with transmyocardial laser revascularization and scintigraphic evidence of improved myocardial perfusion

Erdheim-Chester disease is a rare sporadic systemic histiocytic disease of unknown aetiology that affects multiple organ systems. The case records of all patients with Erdheim-Chester disease who had been seen at the Mayo Clinic between 1975 and 1996 were reviewed to assess the neurological manifestations of the disease. Two of 10 patients had neurological involvement. A 42 year old woman developed central diabetes insipidus and a progressive cerebellar syndrome. Brain MRI showed a lesion in the left pons with patchy gadolinium enhancement and T2 weighted signal abnormalities extending into both cerebellar peduncles and the medulla. Biopsy of the brainstem mass showed a xanthogranulomatous lesion. The second patient was a 53 year old man with retroperitoneal fibrosis secondary to xanthogranulomatous infiltration. Although he had no neurological symptoms and a normal neurological examination, MRI of the head showed multiple uniformly enhancing extra-axial masses along the dura of both convexities and the falx, and a mass in the left orbital apex. Both patients had the characteristic radiographic and bone scan findings of Erdheim-Chester disease. Review of the literature disclosed a wide variety of neurological manifestations in Erdheim-Chester disease. The most frequent CNS manifestations are diabetes insipidus, cerebellar syndromes, orbital lesions, and extra-axial masses involving the dura.     

The edge-to-edge technique: a simplified method to correct mitral insufficiency

OBJECTIVE: Repair of mitral regurgitation (MR) is more demanding in case of prolapse of the anterior leaflet, posterior leaflet with calcified annulus, or prolapse of both leaflets. We evaluated a repair which consists of anchoring the free edge of the prolapsing leaflet to the corresponding free edge of the facing leaflet: the 'edge-to-edge' (E-to-E) technique. The correction results in a double orifice valve when the prolapse is in the middle portion of the leaflet and in a smaller valve orifice when the prolapse is close to a commissure. METHODS: Out of 432 patients with MR submitted to valve repair between January 1991 and September 1997, 121 (mean age 56 +/- 15.8 years) underwent E-to-E correction. The most prevalent etiology was degenerative disease (82 patients, 68%). The mechanism of MR was anterior leaflet prolapse (61 patients), posterior leaflet prolapse (24 patients), prolapse of both leaflets (28 patients) and other complex mechanisms (8 patients). In 72 patients, a double orifice was created, the paracommissural repair was done in 49 patients. RESULTS: Hospital mortality was 1.6%. Overall survival was 92 +/- 3.1% at 6 years with 95 +/- 4.8% freedom from reoperation. Mortality was unrelated to the type of repair. Mitral stenosis was never observed after the correction. At the follow-up (mean 2.2 +/- 1.5 years), all patients but 15 are class I or II. Symptoms at the follow-up are not related to residual MR. CONCLUSIONS: Midterm results of this alternative repair technique are promising, considering the high prevalence of complex anatomical lesions. The technique is simple, easily reproducible and rapidly feasible also when mitral exposure is suboptimal.     

Potentiation of a three drug chemotherapy regimen by radiation

The combination of N-(phosphonacetyl)-L-aspartate, 6-methylmercaptopurine, and 6-aminonicotinamide has been shown to be an effective antineoplastic regimen and also to enhance the effects of other chemotherapeutic agents. The mechanism of action of this combination of drugs is not known definitively, but one possible mechanism is biochemical modulation of energy metabolism and inhibition of production of tumor ATP. Tumor-bearing mice were treated with N-(phosphonacetyl)-L-aspartate, followed 17 h later by 6-methylmercaptopurine and 6-aminonicotinamide. 31P nuclear magnetic resonance spectroscopic studies demonstrated a significant depletion of high energy phosphates at 10 h post-6-methylmercaptopurine and 6-aminonicotinamide. The addition of radiation at this time was shown to induce a significantly longer tumor growth delay and a greater number of regressions (including durable complete regressions) than either chemotherapy or radiation alone. The combination of chemotherapy and radiation was found to be supra-additive compared to the antineoplastic effects of either modality administered separately, without a measurable increase in host toxicity.     

Confocal Blood Flow Videomicroscopy of Thrombus Formation over Human Arteries and Local Targeting of P2X7

Atherothrombosis exposes vascular components to blood. Currently, new antithrombotic therapies are emerging. Herein we investigated thrombogenesis of human arteries with/without atherosclerosis, and the interaction of coagulation and vascular components, we and explored the anti-thrombogenic efficacy of blockade of the P2X purinoceptor 7 (P2X7). A confocal blood flow videomicroscopy system was performed on cryosections of internal mammary artery (IMA) or carotid plaque (CPL) determining/localizing platelets and fibrin. Blood from healthy donors elicited thrombi over arterial layers. Confocal microscopy associated thrombus with tissue presence of collagen type I, laminin, fibrin(ogen) and tissue factor (TF). The addition of antibodies blocking TF (aTF) or factor XI (aFXI) to blood significantly reduced fibrin deposition, variable platelet aggregation and aTF + aFXI almost abolished thrombus formation, showing synergy between coagulation pathways. A scarce effect of aTF over sub-endothelial regions, more abundant in tissue TF and bundles of laminin and collagen type I than deep intima, may suggest tissue thrombogenicity as molecular structure-related. Consistently with TF-related vascular function and expression of P2X7, the sections from CPL but not IMA tissue cultures pre-treated with the P2X7 antagonist A740003 demonstrated poor thrombogenesis in flow experiments. These data hint to local targeting studies on P2X7 modulation for atherothrombosis prevention/therapy.     

Gender stereotypes during adolescence: Developmental changes and the transition to junior high school.

Although much evidence suggests that gender stereotyping becomes less flexible during adolescence, results of the present study indicate that gender stereotypes may actually become more flexible at some point during certain adolescent school transitions. The authors measured the flexibility of gender stereotypes in adolescents in Grades 4 through 11, using a combined cross-sectional and longitudinal design. Results indicated that flexibility increased for stereotypes concerning the psychological attributes of men and women after the transition into junior high school, regardless of whether this transition occurred during the 7th or 8th grade. Over the remaining years of junior high and high school, stereotype flexibility decreased. These results help resolve previous inconsistencies found in the literature by suggesting when and why changes in gender stereotype flexibility versus rigidity occur during adolescence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Leishmania mexicana: proteinase activities and megasomes in axenically cultivated amastigote-like forms

Proteinase activities and megasomes were examined in axenically cultivated amastigote-like forms, freshly isolated lesion amastigotes, and promastigotes. Megasomes were absent in promastigotes and present in both amastigote stages, but they seemed to be less numerous and more homogeneous in cultured amastigote-like forms. Contrasting with the poor detection of proteinase activities in promastigote lysates, both types of amastigotes shared multiple proteinases, which were classified in two groups: (a) 60 to > 100 kDa, o-phenanthroline-sensitive activities; and (b) 23- to 40-kDa cysteine proteinases, of which those resolving as 35- to 40-kDa bands in gelatin gels were more clearly visualized in lysates of cultured amastigote-like forms. Incubation of both kinds of amastigotes with 0.25 to 1.0 microM of either Z-Phe-AlaCHN2 or Z-Tyr-AlaCHN2 selectively inactivated cysteine proteinases, but not the 35- to 40-kDa activities, which, again, were detected with higher intensity in cultured amastigote-like forms. The expression of the 35- to 40-kDa proteinases progressively increased when promastigotes were allowed to transform into amastigote-like forms or when lesion amastigotes were incubated at 34 degrees C for different time periods prior to exposure to Z-Phe-AlaCHN2; activities comparable to those of amastigote-like forms were attained within 24 to 48 hr. The activities resistant to Z-Phe-AlaCHN2 in vivo were fully inhibited by E-64 or Z-Phe-AlaCHN2 during gelatin digestion, suggesting that the 35- to 40-kDa proteinases were mainly inactive before cell lysis. The presence of cycloheximide (at 10, 50, and 100 micrograms/ml) during the pulse with Z-Phe-AlaCHN2 abolished the 35- to 40-kDa activities of lesion amastigotes and significantly reduced gelatin digestion by the similar enzymes of cultured amastigote-like forms. In the latter, the 35- to 40-kDa proteinases were no more detected when cycloheximide was given 60 min prior to Z-Phe-AlaCHN2. The results indicate higher rates of synthesis of the 35- to 40-kDa enzymes, and the existence of a more representative pool of inactive enzyme precursors, in cultured amastigote-like forms.