Grading the severity of the rotator cuff tendinosis on MRI: Assessment of inter-observer agreement and evaluation of a novel objective assessment tool.

Introduction: MRI is generally considered the modality of choice for the assessment of rotator cuff pathology including tendinosis. Assessment of severity is currently subjective primarily based on tendon morphology and signal intensity. Limited data are available evaluating the inter-observer agreement regarding the assessment of tendinosis severity.

Induction of labour indications and timing: A systematic analysis of clinical guidelines.

Background: There is widespread and some unexplained variation in induction of labour rates between hospitals. Some practice variation may stem from variability in clinical guidelines. This review aimed to identify to what extent induction of labour guidelines provide consistent recommendations in relation to reasons for, and timing of, induction of labour and ascertain whether inconsistencies can be explained by variability guideline quality.

Indications for, and timing of, planned caesarean section: A systematic analysis of clinical guidelines.

Background: There has been a worldwide rise in planned caesarean sections over recent decades, with significant variations in practice between hospitals and countries. Guidelines are known to influence clinical decision-making and, potentially, unwarranted clinical variation. The aim of this study was to review guidelines for recommendations in relation to the timing and indications for planned caesarean section as well as recommendations around the process of decision-making.

Follicle Rupture and Zymography in .

Ovulation, the process of releasing a mature oocyte from the ovary, is crucial for animal reproduction. In order for the process of ovulation to occur, a follicle must be fully matured and signaled to rupture from the ovary. During follicle rupture in both mammals and , somatic follicle cells are enzymatically degraded to allow the oocyte to be liberated from the follicle.

The zinc-finger transcription factor Hindsight regulates ovulation competency of follicles.

Follicle rupture, the final step in ovulation, utilizes conserved molecular mechanisms including matrix metalloproteinases (Mmps), steroid signaling, and adrenergic signaling. It is still unknown how follicles become competent for follicle rupture/ovulation. Here, we identify a zinc-finger transcription factor Hindsight (Hnt) as the first transcription factor regulating follicle's competency for ovulation in .

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli.

Alveolar macrophages are lung-resident sentinel cells that develop perinatally and protect against pulmonary infection. Molecular mechanisms controlling alveolar macrophage generation have not been fully defined. Here, we show that the actin-bundling protein L-plastin (LPL) is required for the perinatal development of alveolar macrophages.

L-Plastin promotes podosome longevity and supports macrophage motility.

Elucidating the molecular regulation of macrophage migration is essential for understanding the pathophysiology of multiple human diseases, including host responses to infection and autoimmune disorders. Macrophage migration is supported by dynamic rearrangements of the actin cytoskeleton, with formation of actin-based structures such as podosomes and lamellipodia. Here we provide novel insights into the function of the actin-bundling protein l-plastin (LPL) in primary macrophages.

Evidence of healing of partial-thickness rotator cuff tears following arthroscopic augmentation with a collagen implant: a 2-year MRI follow-up.

Background: partial-thickness rotator cuff tears frequently enlarge due to increased local strain and often progress to full-thickness tears. Studies suggest the addition of new tendinous tissue to injured cuff tendons would significantly decrease peak strain, possibly protecting against tear progression. The aim of this study was to assess the ability of a highly-porous collagen implant to induce new tissue formation and limit tear progression when placed on the bursal surface of partial-thickness cuff tears.

Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation.

Central to malaria pathogenesis is the invasion of human red blood cells by Plasmodium falciparum parasites. Following each cycle of intracellular development and replication, parasites activate a cellular program to egress from their current host cell and invade a new one. The orchestration of this process critically relies upon numerous organised phospho-signaling cascades, which are mediated by a number of central kinases.

Preliminary investigation of a biological augmentation of rotator cuff repairs using a collagen implant: a 2-year MRI follow-up.

Background: the inability to restore the normal tendon footprint and limit strains on the repair site are thought to contribute to re-tearing following rotator cuff repair. The purpose of this study was to use a collagen implant to augment rotator cuff repairs through the restoration of the native tendon footprint and the induction of new tissue to decrease overall tendon strain.

Methods: repairs of full-thickness rotator cuff lesions in 9 adult patients were augmented with a novel collagen implant placed over the bursal surface of the repair.

A Follicle Rupture Assay Reveals an Essential Role for Follicular Adrenergic Signaling in Drosophila Ovulation.

Ovulation is essential for the propagation of the species and involves a proteolytic degradation of the follicle wall for the release of the fertilizable oocyte. However, the precise mechanisms for regulating these proteolytic events are largely unknown. Work from our lab and others have shown that there are several parallels between Drosophila and mammalian ovulation at both the cellular and molecular levels.

Matrix metalloproteinase 2 is required for ovulation and corpus luteum formation in Drosophila.

Ovulation is critical for successful reproduction and correlates with ovarian cancer risk, yet genetic studies of ovulation have been limited. It has long been thought that the mechanism controlling ovulation is highly divergent due to speciation and fast evolution. Using genetic tools available in Drosophila, we now report that ovulation in Drosophila strongly resembles mammalian ovulation at both the cellular and molecular levels.

Synthesis and biological evaluation of 2-anilino-4-substituted-7H-pyrrolopyrimidines as PDK1 inhibitors.

PDK1, a biological target that has attracted a large amount of attention recently, is responsible for the positive regulation of the PI3K/Akt pathway that is often activated in a large number of human cancers. A series of second-generation 2-anilino-4-substituted-7H-pyrrolopyrimidines were synthesised by installation of various functions at the 4-position of the 7H-pyrrolopyrimidine scaffold. All compounds were screened against the isolated PDK1 enzyme and dose response analysis was obtained on the best compounds of the series.

Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors.

PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald-Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines.

L-plastin is essential for alveolar macrophage production and control of pulmonary pneumococcal infection.

We report that mice deficient for the hematopoietic-specific, actin-bundling protein L-plastin (LPL) succumb rapidly to intratracheal pneumococcal infection. The increased susceptibility of LPL(-/-) mice to pulmonary pneumococcal challenge correlated with reduced numbers of alveolar macrophages, consistent with a critical role for this cell type in the immediate response to pneumococcal infection. LPL(-/-) mice demonstrated a very early clearance defect, with an almost 10-fold-higher bacterial burden in the bronchoalveolar lavage fluid 3 h following infection.

Action of octopamine and tyramine on muscles of Drosophila melanogaster larvae.

Octopamine (OA) and tyramine (TA) play important roles in homeostatic mechanisms, behavior, and modulation of neuromuscular junctions in arthropods. However, direct actions of these amines on muscle force production that are distinct from effects at the neuromuscular synapse have not been well studied. We utilize the technical benefits of the Drosophila larval preparation to distinguish the effects of OA and TA on the neuromuscular synapse from their effects on contractility of muscle cells.

Intrinsic T- and B-cell defects impair T-cell-dependent antibody responses in mice lacking the actin-bundling protein L-plastin.

Germinal center development, critical for long-term humoral immunity, requires the trafficking of T and B lymphocytes to defined tissues and locations after antigenic challenge. The molecular mechanisms that support lymphocyte trafficking through the linkage of extracellular chemotactic and adhesive cues to the actin cytoskeleton are not yet fully defined. We have previously identified the actin-bundling protein L-plastin (LPL) as a requisite intermediary in both naive B and T lymphocyte migration and in T-cell activation.

Potent inhibitors of phosphatidylinositol 3 (PI3) kinase that have antiproliferative activity only when delivered as prodrug forms.

Prodrugs for PI3K: A series of substituted analogues of the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 were prepared and found to potently inhibit the isolated enzyme but not MCF7 cell proliferation. Two tetrazolyl-substituted analogues were further derivatized as prodrugs resulting in restoration of cell-based activity. These data provide a conceptual model for development of tumor-targeting prodrug forms of cell-impermeable PI3K inhibitors.

The actin-bundling protein L-plastin is essential for marginal zone B cell development.

B cell development is exquisitely sensitive to location within specialized niches in the bone marrow and spleen. Location within these niches is carefully orchestrated through chemotactic and adhesive cues. In this article, we demonstrate the requirement for the actin-bundling protein L-plastin (LPL) in B cell motility toward the chemokines CXCL12 and CXCL13 and the lipid chemoattractant sphingosine-1-phosphate, which guide normal B cell development.

Imaging of tumors in the ankle and foot.

Common bone and soft tissue tumors in the foot and ankle are described in this article, and x-ray and magnetic resonance imaging characteristics are given. Ultrasound can be used for limited indications only, noting that ultrasound features are nonspecific. Of the bone and soft tissue tumors, approximately 7% occur in the foot and ankle.

Skiing and snowboarding injuries: a review with a focus on mechanism of injury.

Skiing and snowboarding are ever increasing in popularity, with participation across a wide patient demographic. This article focuses on common skiing and snowboarding injuries, with an emphasis on unique mechanisms of injury and discusses the contribution of equipment design to evolving patterns of injury. Knowledge of mechanisms of injury and injury patterns allows a targeted approach to the interpretation of imaging modalities in this patient population.

Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum.

In recent years, resistance to the antimalarial drug, chloroquine, has become widespread. It is, therefore, imperative to find compounds that could replace chloroquine or work synergistically with this drug to overcome chloroquine resistance. We have examined the interaction between chloroquine, a 4-aminoquinoline, and a number of 8-aminoquinolines, including primaquine, a drug that is widely used to treat Plasmodium vivax infections.

Synthesis and cytotoxic activity of N-[(alkylamino)alkyl]carboxamide derivatives of 7-oxo-7H-benz[de]anthracene, 7-oxo-7H-naphtho[1,2,3-de]quinoline, and 7-oxo-7H-benzo[e]perimidine.

7-Oxo-7H-naphtho[1,2,3-de]quinoline-11-carboxamides and analogues were prepared and evaluated for in vitro and in vivo antitumor activity. Chromophore variations included 'deaza' (7-oxo-7H-benz[de]anthracene) and 'diaza' (7-oxo-7H-benzo[e]perimidine) analogues, and side chain variations included chiral alpha-methyl compounds. The naphthoquinolines were the most cytotoxic, with IC(50) values of 5-20 nM, and showed the strongest DNA binding, with high selectivity for G-C rich DNA.

Synthesis and cytotoxic activity of carboxamide derivatives of benzo[b][1,6]naphthyridin-(5H)ones.

A previous reaction leading to 2-substituted 6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acids has been extended to encompass a broad range of 2-substituents. Derived carboxamides, particularly 4-N-[2-(dimethylamino)ethyl], were tested for growth inhibitory properties. Potent cytotoxicity against murine P388 leukemia and Lewis lung carcinoma (LLTC) was retained for compounds bearing a remarkably diverse range of 2-substituents with a number having IC50 values <10 nM.

Synergistic interaction of a chloroquine metabolite with chloroquine against drug-resistant malaria parasites.

We have previously shown that structural modification of chlorpromazine to introduce a basic side chain converts this chloroquine (CQ) resistance-reversing agent into a compound that has activity against Plasmodium falciparum in vitro. In an effort to further dissect the structural features that determine quinoline antimalarial activity and drug resistance-reversing activity, we have studied a series of aminoquinolines that are structurally related to CQ. We have analysed their haematin-binding activities, their antimalarial activities and their abilities to synergise the effect of CQ against drug-resistant P.