Valvular dystrophy associated filamin A mutations reveal a new role of its first repeats in small-GTPase regulation.

Filamin A (FlnA) is a ubiquitous actin binding protein which anchors various transmembrane proteins to the cell cytoskeleton and provides a scaffold to many cytoplasmic signaling proteins involved in actin cytoskeleton remodeling in response to mechanical stress and cytokines stimulation. Although the vast majority of FlnA binding partners interact with the carboxy-terminal immunoglobulin like (Igl) repeats of FlnA, little is known on the role of the amino-N-terminal repeats. Here, using cardiac mitral valvular dystrophy associated FlnA-G288R and P637Q mutations located in the N-terminal Igl repeat 1 and 4 respectively as a model, we identified a new role of FlnA N-terminal repeats in small Rho-GTPases regulation.

Should the dosage of controlled-release oxycodone in advanced cancer be modified on the basis of patient characteristics?

Purpose: This study aimed to investigate whether the characteristics of patients with advanced cancer explain the variability in oxycodone clearance, with the potential for this information to determine maintenance dosing.

Methods: Patients (n = 36) with advanced cancer who were receiving delayed-release oxycodone (Oxycontin®) (mean dose, 31.4 mg; range, 5-120 mg) mostly twice daily (mean duration = 80 days; range, 5-651 days) provided venous blood samples (n = 139, median = 3 per patient) drawn from 0.

Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors.

Background: Poly(ADP-ribose) polymerase (PARP) signals DNA damage and facilitates DNA repair. PARP inhibitors are being evaluated in cancers with defective DNA repair mechanisms or in combination with cytotoxic therapy or radiation. We evaluated the PARP inhibitor, olaparib, in combination with chemotherapy using in vitro and in vivo pediatric solid tumor models.

Marine ecosystem responses to Cenozoic global change.

The future impacts of anthropogenic global change on marine ecosystems are highly uncertain, but insights can be gained from past intervals of high atmospheric carbon dioxide partial pressure. The long-term geological record reveals an early Cenozoic warm climate that supported smaller polar ecosystems, few coral-algal reefs, expanded shallow-water platforms, longer food chains with less energy for top predators, and a less oxygenated ocean than today. The closest analogs for our likely future are climate transients, 10,000 to 200,000 years in duration, that occurred during the long early Cenozoic interval of elevated warmth.

Evaluation of the retinoids with cisplatin and vincristine in xenograft models of neuroblastoma.

Retinoids have been studied for the treatment of children with neuroblastoma for >25 years. Posttransplant administration of isotretinoin is standard of care for children with high-risk neuroblastoma, whereas fenretinide remains investigational. Previous preclinical studies have evaluated the interaction of retinoids and cytotoxic agents with conflicting results.

Monitoring salivary melatonin concentrations in children with sleep disorders using liquid chromatography-tandem mass spectrometry.

Background: Melatonin is synthesized in the pineal gland and is an important circadian phase marker, especially in the determination of sleep patterns. Both temporary and permanent abnormal sleep patterns occur in children; therefore, it is desirable to have methods for monitoring melatonin in biological fluids in the diagnosis and treatment of such disorders.

Objective: The objective of the study is to develop a liquid chromatography-tandem mass spectrometry method for the determination of melatonin in saliva and to apply it to monitoring salivary concentrations in children with sleep disorders.

Distinct signaling pathways activated by "extracellular" and "intracellular" serotonin in heart valve development and disease.

Cardiac valve diseases are often due to developmental anomalies that progressively lead to the abnormal distribution and organization of extracellular matrix proteins overtime. Whereas mechanisms underlying adult valvulopathies are unknown, previous work has shown a critical involvement of the monoamine serotonin in disease pathogenesis. In particular, the interaction of serotonin with its receptors can activate transforming growth factor-β1 (TGF-β1) signaling, which in turn promotes extracellular matrix gene expression.

miR-21 represses Pdcd4 during cardiac valvulogenesis.

The discovery of small non-coding microRNAs has revealed novel mechanisms of post-translational regulation of gene expression, the implications of which are still incompletely understood. We focused on microRNA 21 (miR-21), which is expressed in cardiac valve endothelium during development, in order to better understand its mechanistic role in cardiac valve development. Using a combination of in vivo gene knockdown in zebrafish and in vitro assays in human cells, we show that miR-21 is necessary for proper development of the atrioventricular valve (AV).

Four Square Step Test in ambulant persons with multiple sclerosis: validity, reliability, and responsiveness.

The aim of this study was to establish the concurrent validity and relative and absolute reliability, define the minimal detectable change, and evaluate the floor and ceiling effects of the Four Square Step Test (FSST) in ambulant persons with multiple sclerosis (pwMS). Twenty-five pwMS performed the FSST on two occasions, 8.1±4.

Ancient DNA supports southern survival of Richardson's collared lemming (Dicrostonyx richardsoni) during the last glacial maximum.

Collared lemmings (genus Dicrostonyx) are circumpolar Arctic arvicoline rodents associated with tundra. However, during the last glacial maximum (LGM), Dicrostonyx lived along the southern ice margin of the Laurentide ice sheet in communities comprising both temperate and boreal species. To better understand these communities and the fate of these southern individuals, we compare mitochondrial cytochrome b sequence data from three LGM-age Dicrostonyx fossils from south of the Laurentide ice sheet to sequences from modern Dicrostonyx sampled from across their present-day range.

A novel technique for the treatment of infected metalwork in orthopaedic patients using skin closure over irrigated negative pressure wound therapy dressings.

Introduction: There has been recent interest in the use of negative pressure wound therapy (NWPT) as an adjunct to parenteral antibiotics in the treatment of infection in orthopaedic patients with metalwork in situ. To address some of the limitations of standard NPWT in this situation, the senior author has developed a modified method of treatment for infected metalwork (excluding arthroplasty) in orthopaedic patients that includes irrigation and skin closure over the standard NPWT dressing.

Methods: This retrospective study examined the outcome of a case series of 16 trauma and orthopaedic patients with deep infection involving metalwork in whom this modified form of NPWT was used.

Simultaneous determination of thymine and its sequential catabolites dihydrothymine and β-ureidoisobutyrate in human plasma and urine using liquid chromatography-tandem mass spectrometry with pharmacokinetic application.

To study in vivo activities of dihydropyrimidine dehydrogenase, dihydropyrimidinase, and ureidoproprionase, a sensitive, accurate, selective and precise method for the determination of the endogenous pyrimidine thymine (THY) and its successive metabolites dihydrothymine (DHT) and β-ureidoisobutyric (UIB) acid in human plasma and urine has been developed and validated. Plasma or diluted urine (200 μL) was mixed with 1 mL of deuterated-THY (internal standard) in acetonitrile, then centrifuged, the supernatant evaporated, and the residue reconstituted in 150 μL 0.1% (w/w) formic acid in water.

Mef2c regulates transcription of the extracellular matrix protein cartilage link protein 1 in the developing murine heart.

Cartilage Link Protein 1 (Crtl1) is an extracellular matrix (ECM) protein that stabilizes the interaction between hyaluronan and versican and is expressed in endocardial and endocardially-derived cells in the developing heart, including cells in the atrioventricular (AV) and outflow tract (OFT) cushions. Previous investigations into the transcriptional regulation of the Crtl1 gene have shown that Sox9 regulates Crtl1 expression in both cartilage and the AV valves. The cardiac transcription factor Mef2c is involved in the regulation of gene expression in cardiac and skeletal muscle cell lineages.

Postmortem tissue distribution of MDPV following lethal intoxication by "bath salts".

3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive, synthetic analog of the central nervous system stimulant cathinone. Its recent popularity as a recreational drug in the United States has led to numerous reports to poison control centers across the country. As with other synthetic cathinones, the recreational use of MDPV has resulted in death.

FGF signaling induces mesoderm in the hemichordate Saccoglossus kowalevskii.

FGFs act in vertebrate mesoderm induction and also play key roles in early mesoderm formation in ascidians and amphioxus. However, in sea urchins initial characterizations of FGF function do not support a role in early mesoderm induction, making the ancestral roles of FGF signaling and mechanisms of mesoderm specification in deuterostomes unclear. In order to better characterize the evolution of mesoderm formation, we have examined the role of FGF signaling during mesoderm development in Saccoglossus kowalevskii, an experimentally tractable representative of hemichordates.

The effect of anterior cruciate ligament reconstruction on the progression of osteoarthritis.

Anterior cruciate ligament rupture (ACL) is a common injury, particularly among young sporting adults. Early onset osteoarthritis (OA) can be a devastating and difficult to manage consequence of such an injury. The techniques for reconstructing the ACL are advancing all the time, but the effect that this has on the progression of OA is less well understood.

Challenges and opportunities in childhood cancer drug development.

Advances made in the treatment of childhood malignancies over the past four decades have resulted in overall 5-year survival rates of approximately 80%. However, despite these advances, several childhood cancers still have unacceptably low cure rates, and, even when treatment is successful, the acute and long-term morbidity of current therapy can be substantial. The development of molecularly targeted anticancer drugs offers the prospect of more effective therapy with fewer side effects, but will require increasing partnership between governments, and the academic and private sectors.

Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis.

Developmental basis for filamin-A-associated myxomatous mitral valve disease.

Aims: We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development.

Phosphorylation of serine residues in the C-terminal cytoplasmic tail of connexin43 regulates proliferation of ovarian granulosa cells.

Connexin43 (Cx43) forms gap junctions that couple the granulosa cells of ovarian follicles. In Cx43 knockout mice, follicle growth is restricted as a result of impaired granulosa cell proliferation. We have used these mice to examine the importance of specific Cx43 phosphorylation sites in follicle growth.

A stable-isotope HPLC-MS/MS method to simplify storage of human whole blood samples for glutathione assay.

Background: Glutathione is the principal non-protein tripeptide thiol present in most mammalian cells and plays an important role in the redox status of biological systems. The accurate assessment of reduced glutathione (GSH) status as a reliable index of oxidative stress is of research and clinical significance. GSH undergoes rapid oxidation after sample collection and this presents a challenge.

Reducing the cost of lower limb wound management through industry partnership and staff education.

Following an audit of practice in North East London Foundation Trust (NELFT), obstacles in the management of lower limb conditions were identified. An appraisal of needs in terms of skills and theory updates for staff led to a fixed-term 'honorary contract' between the trust and a wound-care company to facilitate a rolling programme of education, to upskill staff in terms of assessment and treatment, and develop standardised care pathways. After 3 months, a repeated practice audit revealed a reduction in nurse contact hours of 1156 hours.

Atrioventricular valve development: new perspectives on an old theme.

Atrioventricular valve development commences with an EMT event whereby endocardial cells transform into mesenchyme. The molecular events that induce this phenotypic change are well understood and include many growth factors, signaling components, and transcription factors. Besides their clear importance in valve development, the role of these transformed mesenchyme and the function they serve in the developing prevalve leaflets is less understood.