Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles

A growing body of data suggests that therapies based on Toll-like receptors (TLR) targeting, in particular TLR4, holds promise in curing autoimmune and inflammatory pathologies still lacking specific treatment, included several rare diseases. While TLR4 activators (agonists) have already found successful clinical application as vaccine adjuvants, the use of TLR4 blockers (antagonists) as antisepsis agents or as agents against inflammatory diseases (including arthritis, multiple sclerosis, neuroinflammations) and cancer is still at a preclinical phase of development. This minireview focuses on recent achievements on the development of TLR4 modulators based on lipid A structure simplification, in particular on compounds having disaccharide or monosaccharide structures. As the TLR4 activity of natural TLR4 ligands (lipopolysaccharide, LPS and its biologically active part, the lipid A) depends on both the structure of endotoxin aggregates in solution and on single-molecule interaction with MD-2 and CD14 receptors, the rational design of TLR4 modulators should in principle take into account both these factors. In the light of the most recent advances in the field, in this minireview we discuss the structure–activity relationship in simplified lipid A analogs, with cationic or anionic amphiphilic structures.     

Antiplatelet and antithrombotic activities of essential oil from wild Ocotea quixos (Lam.) Kosterm. (Lauraceae) calices from Amazonian Ecuador.

Ocotea quixos essential oil was shown to possess significant inhibitory activity of platelet aggregation and clot retraction in rodent plasma. This study is aimed at fully characterizing the antiplatelet activity of the whole essential oil and its main components trans-cinnamaldehyde and methyl cinnamate also in human plasma, at investigating the mechanism underlying such activity and at evaluating the potential antithrombotic activity of subacute treatment of mice with Ocotea essential oil. In vitro Ocotea essential oil and trans-cinnamaldehyde inhibited arachidonic acid-, U46619-, ADP-, phorbol12-myristate13-alcetate-, collagen-induced platelet aggregation and thrombin-induced clot retraction in human and rodent plasma; Ocotea oil and trans-cinnamaldehyde competitively antagonized contractions induced by thromboxane A2 receptor agonist U46619 in rat isolated aortic ring (K(B) = 18 and 3.2 microg ml(-1), respectively). In vivo Ocotea oil, orally administered in a subacute treatment (30-100 mg kg(-1) day(-1) for 5 days) to mice, prevented acute thrombosis induced by collagen-epinephrine intravenous injection. This antithrombotic activity was not accompanied by pro-haemorragic side effect, as detected by the inactivity in bleeding test, thus showing a favourable safety profile compared to the conventional antiplatelet agent, acetylsalicylic acid. Present findings indicate that Ocotea essential oil possesses potent and safe antithrombotic activity attributable to its antiplatelet and vasorelaxant effects. The main constituent trans-cinnamaldehyde seems to be the primary responsible for this activity through a putative mechanism involving the inhibition of thromboxane A2 receptors.     

Video-EEG Study of Psychogenic Nonepileptic Seizures: Differential Characteristics in Patients with and without Epilepsy

Summary:  Purpose: Psychogenic nonepileptic seizures (PNES) are episodes that may resemble epileptic seizures (ES) but are not associated with abnormal electrical discharges in the brain. Video-EEG recording of a typical episode is considered the best diagnostic tool available. PNES are, however, also documented in patients with epilepsy (PNES/ES). The purpose of this study was to assess this comorbid population, focusing on the differences between patients with PNES/ES and patients with PNES alone.
Methods: We reviewed 110 PNES episodes, occurring spontaneously or induced by means of suggestion techniques, recorded in our video-EEG laboratory over a period of eight years. We identified two subgroups of patients, consisting of 85 PNES cases and 25 PNES/ES cases, and assessed any differences in their characteristics by reviewing a number of variables (age, sex, clinical features, antiepileptic therapy, age of onset, time to diagnosis, pathological history, and length of follow-up).
Results: The comparison between the two subgroups revealed that PNES/ES patients displayed some statistically significant differences when compared with PNES alone patients, i.e., younger age, a higher percentage of spontaneously activated events, a shorter disease duration, a longer time to PNES diagnosis, and a lower percentage lost at follow-up.
Conclusions: This study confirms that PNES is a common, though probably underestimated, occurrence in epilepsy services. Our results shed light on some different characteristics between PNES and PNES/ES patients.     

Platelet transfusions are not associated with increased morbidity or mortality in cardiac surgery

PURPOSE: To determine the independent relationship between leukoreduced platelet transfusions and adverse events in cardiac surgery. METHODS: In this observational study, detailed baseline and perioperative data were prospectively collected on consecutive patients who underwent cardiac surgery at a single institution from 1999 to 2004. The independent associations of platelet transfusion with clinical outcomes (low output syndrome, myocardial infarction, stroke, renal failure, sepsis, and death) were determined by multivariable logistic regression analysis and propensity score case-control analysis. RESULTS: Of the 11,459 patients analyzed, 2,174 (19%) received (leukoreduced) platelets - 1,408 received 5 U, 471 received 10 U, 140 received 15 U, and 155 received 20 or more units. Although all measured adverse event rates were higher in those who received platelets, in neither the logistic regression analyses nor the propensity score analyses was there any association between platelet transfusion and any of the adverse events. CONCLUSIONS: Transfusion of leukoreduced platelets in cardiac surgery is not associated with adverse clinical outcomes when adjustments are made for important confounders.     

Epilepsy and family expressed emotion: results of a prospective study.

PURPOSE: To verify the emotional components expressed by the relatives of adult patients with a diagnosis of epilepsy, and whether they are related to adjustment to the illness and the course of the illness over time. METHODS: We studied a consecutive sample of 43 outpatients suffering from epilepsy and 43 key relatives using the Camberwell Family Interview (CFI), with the expressed emotion (EE) of the relatives being rated at baseline (T0). EE refers to a construct representing some key aspects of interpersonal relationships: the relatives were assigned to the high-EE group if they scored 3 or more on the emotional over involvement (EOI) scale, or showed hostility, or made 6 or more critical comments. The patients were clinically evaluated at baseline and for 1 year of appropriate treatment by an epileptologist who was blinded to the EE ratings. They also completed STAI XI, STAI X2 and Beck's Depression Inventory at baseline. RESULTS: Twenty-six relatives (60%) were rated as showing a high degree of EE. In the 12-month follow-up study, high EE and high EOI were found to be associated with a significantly higher seizure frequency than that recorded for the patients living in low-EE households (p<0.05). The patients from households assessed as reflecting a high degree of criticism showed poor drug compliance (p<0.01), whereas those with relatives assessed as having a high degree of warmth showed better clinical and pharmacological compliance (p<0.01). High family criticism scores also correlated with higher study entry levels of depression (p<0.05) and trait and state anxiety (p<0.05) among the patients. CONCLUSIONS: The study findings highlight the impact of particular components of the family emotional climate on the clinical course and psychological adjustment of patients with epilepsy.