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Chiam P.T.L.,National Heart Center | Ruiz C.E.,New Hill
JACC: Cardiovascular Interventions | Year: 2011

Surgical treatment of mitral regurgitation (MR) has evolved from mitral valve replacement (MVR) to repair (MVRe), because MVRe produces superior long-term outcomes. In addition, MVRe can be achieved through minimally invasive approaches. This desire for less invasive approaches coupled with the fact that a significant proportion of patientsespecially elderly persons or those with significant comorbidities or severe left ventricular (LV) dysfunction, are not referred for surgery, has driven the field of percutaneous MVRe. Various technologies have emerged and are at different stages of investigation. A classification of percutaneous MVRe technologies on the basis of functional anatomy is proposed that groups the devices into those targeting the leaflets (percutaneous leaflet plication, percutaneous leaflet coaptation, percutaneous leaflet ablation), the annulus (indirect: coronary sinus approach or an asymmetrical approach; direct: true percutaneous or a hybrid approach), the chordae (percutaneous chordal implantation), or the LV (percutaneous LV remodeling). The percutaneous edge-to-edge repair technology has been shown to be noninferior to open repair in a randomized clinical trial (EVEREST II [Endovascular Valve Edge-to-Edge REpair Study]). Several other technologies employing the concepts of direct and indirect annuloplasty and LV remodeling have achieved first-in-man results. Most likely a combination of these technologies will be required for satisfactory MVRe. However, MVRe is not possible for many patients, and MVR will be required. Surgical MVR is the standard of care in such patients, although percutaneous options are under development. © 2011 American College of Cardiology Foundation.

Chadman K.K.,New Hill
Pharmacology Biochemistry and Behavior | Year: 2011

Autism, a neurodevelopmental disorder, is characterized by abnormal social interactions, impaired social communication and repetitive behaviors and/or restricted interests, along with several associated symptoms including irritability and anxiety. Risperidone is approved for the irritability and self-injurious behaviors found in autism. Fluoxetine is under evaluation for the repetitive behaviors and anxiety associated with autism. These two drugs were evaluated in the BTBR T + tf/J (BTBR) mouse model of autism and C57BL/6J (B6) mice by using the three-chambered social approach test and elevated plus maze to determine effects on sociability and anxiety. Fluoxetine increased sociability, defined as time spent with a stranger mouse, in the BTBR mice without affecting anxiety-like behavior in the elevated plus maze. Fluoxetine did not significantly change either behavior in the B6 mice. Risperidone did not affect sociability or anxiety-like behaviors and had a sedative-like effect at higher doses. These findings suggest that fluoxetine may have some therapeutic efficacy for treating the social behaviors in autism. © 2010 Elsevier Inc. All rights reserved.

Coordination of actin cytoskeletal reorganization with growth and proliferation signals is a key cellular process that is not fully understood. PI-3 kinase is one of the central nodes for distributing growth and proliferation signals downstream from growth factor receptors to the nucleus. Although PI-3 kinase function has been associated with actin cytoskeleton remodeling, satisfactory explanations of the mechanisms mediating this regulation have been elusive. Here we propose that interaction of the Abi1 protein with the p85 regulatory subunit of PI-3 kinase represents the link between growth receptor signaling and actin cytoskeleton remodeling. This function of Abi1, which involves WAVE complex, was initially observed in macropinocytosis, and may explain the coincident dysregulation of PI-3 kinase and actin cytoskeleton in cancer. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Carter G.T.,New Hill
Natural Product Reports | Year: 2014

This Highlight explores the evolution of applications of mass spectrometric technologies in the context of natural products research since the 1970's. The central themes are the analysis of mixtures, dereplication (identification) and structure determination. The ascension of HPLC as the method of choice for the analysis of pharmaceuticals was a driving force for the development of interfaces for coupling of HPLC and MS. An example of sequential analysis of fragment ions or MS/MS or MSn methods to provide detailed structural information on muraymycins, a family of uridyl-peptide antibiotics, is presented. This journal is © the Partner Organisations 2014.

Rodriguez J.A.,New Hill
The bone & joint journal | Year: 2013

Large ceramic femoral heads offer several advantages that are potentially advantageous to patients undergoing both primary and revision total hip replacement. Many high-quality studies have demonstrated the benefit of large femoral heads in reducing post-operative instability. Ceramic femoral heads may also offer an advantage in reducing polyethylene wear that has been reported in vitro and is starting to become clinically apparent in mid-term clinical outcome studies. Additionally, the risk of taper corrosion at a ceramic femoral head-neck junction is clearly lower than when using a metal femoral head. With improvements in the material properties of both modern ceramic femoral heads and polyethylene acetabular liners that have reduced the risk of mechanical complications, large ceramic heads have gained popularity in recent years.

Wanka L.,Justus Liebig University | Wanka L.,New Hill | Iqbal K.,New Hill | Schreiner P.R.,Justus Liebig University
Chemical Reviews | Year: 2013

The article reviews concentrates on the numerous applications in medicinal chemistry and drug development of adamantane derivatives. The aminoadamantanes are synthetic drugs that have not been inspired by natural products like numerous other drugs. There are, however, also isolates from Nature incorporating an adamantane motif, like 'nature's marvel,' tetrodotoxin. Like amantadine, it also blocks an ion channel, the sodium channel. This potent pharmaceutical activity may be, at least in part, attributed to its rigid dioxaadamantane core. The mutations, in turn, destabilize the closed channel, making it easier to open, which counters the effect of the aminoadamantanes. This model could be advantageous for drug design, because drugs that are larger than hydrated ions do have to overcome a higher energetic barrier to find a binding site inside a pore than to bind to the channel complex from the membrane-facing outside.

Iqbal K.,New Hill
Current Alzheimer research | Year: 2010

Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

Cooper H.J.,New Hill
The bone & joint journal | Year: 2013

Two-stage exchange remains the gold standard for treatment of peri-prosthetic joint infection after total hip replacement (THR). In the first stage, all components and associated cement if present are removed, an aggressive debridement is undertaken including a complete synovectomy, and an antibiotic-loaded cement spacer is put in place. Patients are then treated with six weeks of parenteral antibiotics, followed by an 'antibiotic free period' to help ensure the infection has been eradicated. If the clinical evaluation and serum inflammatory markers suggest the infection has resolved, then the second stage can be completed, which involves removal of the cement spacer, repeat debridement, and placement of a new THR.

Cooper H.J.,New Hill
Orthopedic Clinics of North America | Year: 2014

Corrosion has long been recognized to occur in total hip arthroplasty, but the local effects of this process have only recently become better understood. This article provides an overview of corrosion at modular junctions, and discusses the various etiologic factors for corrosion and the biologic response to metal debris released from this junction. Algorithms are provided for diagnosis and treatment, in accordance with the best available data. © 2014 Elsevier Inc.

Carter G.T.,New Hill
Natural Product Reports | Year: 2011

Although natural products have been marginalized by major pharmaceutical companies over the last 20-30 years, the changing landscape of drug discovery now favors a greatly enhanced role for Nature's privileged structures. Screening for drug leads in phenotypic screens provides the best opportunity to realize the value of natural products. Advances in total synthesis, especially function-oriented syntheses and biosynthetic technologies offer new avenues for the medicinal chemical optimization of biologically active secondary metabolites. Genomic research has given new insights into biosynthetic processes as well as providing evidence that a wealth of unrealized biosynthetic potential remains to be explored. As Pharma strives to develop innovative and highly effective new drugs, natural products will be increasingly valued as sources of novel leads whose further development will be expedited by emerging technologies. © 2011 The Royal Society of Chemistry.

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