Kinetically competing huntingtin aggregation pathways control amyloid polymorphism and properties.

In polyglutamine (polyQ) containing fragments of the Huntington's disease protein huntingtin (htt), the N-terminal 17 amino acid htt(NT) segment serves as the core of α-helical oligomers whose reversible assembly locally concentrates the polyQ segments, thereby facilitating polyQ amyloid nucleation. A variety of aggregation inhibitors have been described that achieve their effects by neutralizing this concentrating function of the htt(NT) segment. In this paper we characterize the nature and limits of this inhibition for three means of suppressing htt(NT)-mediated aggregation.

Intra-arterial therapy for acute stroke: trials and tribulations.

Intra-arterial therapy (IAT) for acute ischemic stroke has undergone great evolution during the past decade. While intra-venous therapy remains the standard of care for eligible patients, there are those patients in whom IV tPA is contraindicated, or those who fail to improve following IV tPA. In those cases, patients with accessible arterial occlusions may benefit from IAT, especially when recanalization can occur within six hours from symptom onset.

Altered angiogenic balance in keloids: a key to therapeutic intervention.

Keloids are manifestations of abnormal wound repair with unresolved clinical complications. An effective therapeutic regimen has not been established for keloids, and current strategies are plagued by problems such as recurrence and side effects. Keloids, being a human-specific dermal fibroproliferative disorder are characterized by an excessive accumulation of extracellular matrix (ECM), thickened basement membrane, unregulated expression of matrix metalloproteases, growth factors, and cytokines.

Incidence of extrinsic compression of the internal jugular vein in unselected patients undergoing CT angiography.

Background And Purpose: Little is known about how commonly the internal jugular vein is compressed by extrinsic structures in the upper neck. The purpose of this paper was to identify the frequency and cause of external compression of the superior segment of the internal jugular vein.

Materials And Methods: Retrospective review of CT angiograms of the neck was performed in 108 consecutive patients.

Endovascular therapy of acute ischemic stroke: report of the Standards of Practice Committee of the Society of NeuroInterventional Surgery.

Objective: To summarize and classify the evidence for the use of endovascular techniques in the treatment of patients with acute ischemic stroke.

Methods: Recommendations previously published by the American Heart Association (AHA) (Guidelines for the early management of adults with ischemic stroke (Circulation 2007) and Scientific statement indications for the performance of intracranial endovascular neurointerventional procedures (Circulation 2009)) were vetted and used as a foundation for the current process. Building on this foundation, a critical review of the literature was performed to evaluate evidence supporting the endovascular treatment of acute ischemic stroke.

Inhibiting the nucleation of amyloid structure in a huntingtin fragment by targeting α-helix-rich oligomeric intermediates.

Although oligomeric intermediates are transiently formed in almost all known amyloid assembly reactions, their mechanistic roles are poorly understood. Recently, we demonstrated a critical role for the 17-amino-acid N-terminus (htt(NT) segment) of huntingtin (htt) in the oligomer-mediated amyloid assembly of htt N-terminal fragments. In this mechanism, the htt(NT) segment forms the α-helix-rich core of the oligomers, leaving much of the polyglutamine (polyQ) segment disordered and solvent-exposed.

Slow amyloid nucleation via α-helix-rich oligomeric intermediates in short polyglutamine-containing huntingtin fragments.

The 17-amino-acid N-terminal segment (htt(NT)) that leads into the polyglutamine (polyQ) segment in the Huntington's disease protein huntingtin (htt) dramatically increases aggregation rates and changes the aggregation mechanism, compared to a simple polyQ peptide of similar length. With polyQ segments near or above the pathological repeat length threshold of about 37, aggregation of htt N-terminal fragments is so rapid that it is difficult to tease out mechanistic details. We describe here the use of very short polyQ repeat lengths in htt N-terminal fragments to slow this disease-associated aggregation.

Reporting standards for angiographic evaluation and endovascular treatment of cerebral arteriovenous malformations.

These guidelines were developed by consensus of a multidisciplinary panel of specialists interested in the evaluation and treatment of patients with arteriovenous malformations (AVMs) of the CNS. The reporting criteria described will serve as a template for trial design and for clinical investigators who wish to report on endovascular therapy of cerebral AVMs. Direct comparison of various treatment paradigms is important to standardization of care, maximization of good treatment outcomes, assessment of new methods and technologies.

Percutaneous sacroplasty.

The recognition of sacral insufficiency fractures continues to be poor, and diagnosis is often delayed resulting in significant morbidity. Percutaneous sacroplasty is an image guided procedure that is safe and potentially effective for treating the pain and disability related to these fractures. Several cohort studies reviewed here report successful outcomes using this procedure, with patients experiencing nearly full pain relief immediately and longitudinally.

Angiographically documented hemorrhagic conversion of a left middle cerebral artery embolic stroke during intra-arterial thrombolysis.

Background And Purpose: The clinical benefits of intra-arterial thrombolysis for ischemic stroke must be weighed against the risks, including hemorrhagic conversion.

Summary Of Case: A case of angiographically documented hemorrhagic conversion of an ischemic stroke during intra-arterial thrombolysis is presented. Discussion focuses on recognition and management of risk factors for hemorrhagic conversion during performance of stroke thrombolysis.

Successful endovascular treatment of a holo-hemispheric cerebral arteriovenous fistula in an infant.

A cerebral arteriovenous fistula (CAVF) is a rare abnormality representing only 4.7% of all cerebral arteriovenous malformations. In this report a unique case is presented of a giant holo-hemispheric CAVF in an infant who presented with congestive heart failure and was successfully treated endovascularly with transarterial and transvenous embolization.

Lysophosphatidic Acid Stimulates the Proliferation of Ovarian Cancer Cells via the gep Proto-Oncogene Gα(12).

Lysophosphatidic acid (LPA), an agonist that activates specific G protein-coupled receptors, is present at an elevated concentration in the serum and ascitic fluid of ovarian cancer patients. Although the increased levels of LPA have been linked to the genesis and progression of different cancers including ovarian carcinomas, the specific signaling conduit utilized by LPA in promoting different aspects of oncogenic growth has not been identified. Here, we show that LPA stimulates both migration and proliferation of ovarian cancer cells.

Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent.

Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.

Alendronate therapy in polyostotic fibrous dysplasia presenting with pathologic fracture.

Polyostotic fibrous dysplasia (PFD) is characterized by developmental failure in the remodeling of primitive bone to mature lamellar bone. PFD presents with bone pain, increased bone fragility, deformities, and fractures. Bisphosphonates are the only agents available for medical management.

Molecular and serum markers in hepatocellular carcinoma: predictive tools for prognosis and recurrence.

With increased understanding of cancer biology, a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis, including angiogenesis, invasion, and metastasis, has been identified. Lately, they are being aggressively evaluated due to challenges involved in establishing early diagnosis, optimizing therapy for cancer inducing hepatotrophic viruses, minimizing the emergence of new tumors, and preventing recurrence after surgical resection or liver transplantation. This comprehensive review examines and critiques the evidence from published manuscripts reporting various tissue and serum biomarkers involved in hepatocellular carcinoma.

The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils.

The 17-residue N-terminus (htt(NT)) directly flanking the polyQ sequence in huntingtin (htt) N-terminal fragments plays a crucial role in initiating and accelerating the aggregation process that is associated with Huntington's disease pathogenesis. Here we report on magic-angle-spinning solid-state NMR studies of the amyloid-like aggregates of an htt N-terminal fragment. We find that the polyQ portion of this peptide exists in a rigid, dehydrated amyloid core that is structurally similar to simpler polyQ fibrils and may contain antiparallel β-sheets.

Critical nucleus size for disease-related polyglutamine aggregation is repeat-length dependent.

Because polyglutamine (polyQ) aggregate formation has been implicated as playing an important role in expanded CAG repeat diseases, it is important to understand the biophysics underlying the initiation of aggregation. Previously, we showed that relatively long polyQ peptides aggregate by nucleated growth polymerization and a monomeric critical nucleus. We show here that over a short range of repeat lengths, from Q(23) to Q(26), the size of the critical nucleus for aggregation increases from monomeric to dimeric to tetrameric.

Assays for studying nucleated aggregation of polyglutamine proteins.

The aggregation of polyglutamine containing protein sequences is implicated in a family of familial neurodegenerative diseases, the expanded CAG repeat diseases. While the cellular aggregation process undoubtedly depends on the flux and local environment of these proteins, their intrinsic physical properties and folding/aggregation propensities must also contribute to their cellular behavior. Here we describe a series of methods for determining mechanistic details of the spontaneous aggregation of polyQ-containing sequences, including the identification and structural examination of aggregation intermediates.

Use of self-expanding intracranial stents in the treatment of acute ischemic stroke.

Conventional endovascular therapy for acute ischemic stroke includes intraarterial pharmacologic thrombolysis with tissue plasminogen activator (TPA) administration with or without mechanical thrombectomy with a variety of devices. The present report describes two cases of stroke refractory to TPA administration in which successful recanalization was accomplished by the use of a self-expanding intracranial stent. Stent-assisted recanalization may be a viable option for patients with acute ischemic stroke refractory to thrombolysis or thrombectomy.

Modeling of blood flow in arterial trees.

Advances in computational methods and medical imaging techniques have enabled accurate simulations of subject-specific blood flows at the level of individual blood cell and in complex arterial networks. While in the past, we were limited to simulations with one arterial bifurcation, the current state-of-the-art is simulations of arterial networks consisting of hundreds of arteries. In this paper, we review the advances in methods for vascular flow simulations in large arterial trees.

Multifocal visual evoked potential recordings in compressive optic neuropathy secondary to pituitary adenoma.

To investigate the effect of pituitary adenoma compressing the optic chiasm on multifocal visual evoked potential (mfVEP) responses and to compare these responses with visual field defects seen on static automated perimetry (SAP). Eight eyes of four subjects (median age, 41.50 years; interquartile range, 33-51 years) who were diagnosed with pituitary adenoma on magnetic resonance imaging (MRI) and seen to have a bitemporal visual field defect on standard automated perimetry (SAP), and twelve age-matched normal subjects (median age, 47.

G(alpha)12/13 inhibition enhances the anticancer effect of bortezomib through PSMB5 downregulation.

Bortezomib is a proteasome inhibitor approved for anticancer therapy. However, variable sensitivity of tumor cells exists in this therapy probably due to differences in the expression of proteasome subunits. G(alpha)(12/13) serves modulators or signal transducers in diverse pathways.