The novel 5-lipoxygenase inhibitor ABT-761 attenuates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage

OBJECTIVE: Eicosanoids have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). Leukotrienes, 5-hydroxyperoxyeicosatetraenoic acid, and 5-hydroxyeicosatetraenoic acid are part of this group of substances, resulting from the 5-lipoxygenase activity on arachidonic acid metabolism. This study examined the effects of ABT-761, a new 5-lipoxygenase inhibitor, on cerebral vasospasm in an in vivo rabbit model of SAH. METHODS: A total of 48 rabbits were assigned to one of six groups: SAH + placebo (n = 8), SAH + ABT-761 20 mg/kg (n = 8), SAH + ABT-761 30 mg/kg (n = 8), control + placebo (n = 8), control + ABT-761 20 mg/kg (n = 8), and control + ABT-761 30 mg/kg (n = 8). Drug administration was initiated 30 minutes after induction of SAH and repeated 24 hours later. The animals were killed 48 hours after SAH, using the perfusion-fixation method. The cross sectional areas of basilar artery histological sections were measured by an investigator blinded to the treatment groups of the individual samples. RESULTS: In placebo-treated animals, the average luminal cross sectional area of the basilar artery was reduced by 68% after SAH as compared with controls (P < 0.0001). After SAH, the vasospastic response was attenuated in animals treated with 20 or 30 mg/kg representing a 28 or 35% reduction, respectively (P = 0.0011 and P = 0.0038). CONCLUSION: The results demonstrated that ABT-761 is effective in attenuating experimental cerebral vasospasm, indicating that this new drug represents a potential therapeutic agent for the treatment of vasospasm after SAH

Full recovery of a 13-year-old boy with pediatric Ramsay Hunt syndrome using a shorter course of aciclovir and steroid at lower doses: a case report

<p>Abstract</p> <p>Introduction</p> <p>Reports on children with Ramsay Hunt syndrome are limited in the literature, resulting in uncertainty regarding the clinical manifestations and outcome of this syndrome. Treatment for Ramsay Hunt syndrome is usually with antivirals, although there is no evidence for beneficial effect on the outcome of Ramsay Hunt syndrome in adults (insufficient data on children exists). Here, we report a case of Ramsay Hunt syndrome occurring in a child who inadvertently received a lower dose of aciclovir and steroid administered for shorter than is usual. Our patient made a full recovery.</p> <p>Case presentation</p> <p>A 13-year-old African boy presented to our out-patients department with an inability to move the right side of his face for one week. He had previously been seen by the doctor on call, who prescribed aciclovir 200 mg three times per day and prednisone 20 mg once daily, both orally for five days, with a working diagnosis of Bell's palsy. After commencement of aciclovir-prednisone, while at home, our patient had headache, malaise, altered taste, vomiting after feeds, a ringing sound in his right ear as well as earache and ear itchiness. Additionally, he developed numerous fluid-filled pimples on his right ear. On presentation, a physical examination revealed a right-sided lower motor neuron facial nerve palsy and a healing rash on the right pinna. On direct questioning, our patient admitted having had chicken pox about three months previously. Based on the history and physical examination, Ramsay Hunt syndrome was diagnosed. Our patient was lost to follow-up until 11 months after the onset of illness; at this time, his facial nerve function was normal.</p> <p>Conclusions</p> <p>This case report documents the clinical manifestations and outcome of pediatric Ramsay Hunt syndrome; a condition with few case reports in the literature. In addition, our patient made a full recovery despite inadvertently receiving a lower dose of aciclovir and steroid administered for shorter than is usual.</p

Evidence for distinct coastal and offshore communities of bottlenose dolphins in the north east Atlantic.

Bottlenose dolphin stock structure in the northeast Atlantic remains poorly understood. However, fine scale photo-id data have shown that populations can comprise multiple overlapping social communities. These social communities form structural elements of bottlenose dolphin (Tursiops truncatus) [corrected] populations, reflecting specific ecological and behavioural adaptations to local habitats. We investigated the social structure of bottlenose dolphins in the waters of northwest Ireland and present evidence for distinct inshore and offshore social communities. Individuals of the inshore community had a coastal distribution restricted to waters within 3 km from shore. These animals exhibited a cohesive, fission-fusion social organisation, with repeated resightings within the research area, within a larger coastal home range. The offshore community comprised one or more distinct groups, found significantly further offshore (>4 km) than the inshore animals. In addition, dorsal fin scarring patterns differed significantly between inshore and offshore communities with individuals of the offshore community having more distinctly marked dorsal fins. Specifically, almost half of the individuals in the offshore community (48%) had characteristic stereotyped damage to the tip of the dorsal fin, rarely recorded in the inshore community (7%). We propose that this characteristic is likely due to interactions with pelagic fisheries. Social segregation and scarring differences found here indicate that the distinct communities are likely to be spatially and behaviourally segregated. Together with recent genetic evidence of distinct offshore and coastal population structures, this provides evidence for bottlenose dolphin inshore/offshore community differentiation in the northeast Atlantic. We recommend that social communities should be considered as fundamental units for the management and conservation of bottlenose dolphins and their habitat specialisations

Classification of Ventricular Septal Defects for the Eleventh Iteration of the International Classification of Diseases—Striving for Consensus: A Report From the International Society for Nomenclature of Paediatric and Congenital Heart Disease

The definition and classification of ventricular septal defects have been fraught with controversy. The International Society for Nomenclature of Paediatric and Congenital Heart Disease is a group of international specialists in pediatric cardiology, cardiac surgery, cardiac morphology, and cardiac pathology that has met annually for the past 9 years in an effort to unify by consensus the divergent approaches to describe ventricular septal defects. These efforts have culminated in acceptance of the classification system by the World Health Organization into the 11th Iteration of the International Classification of Diseases. The scheme to categorize a ventricular septal defect uses both its location and the structures along its borders, thereby bridging the two most popular and disparate classification approaches and providing a common language for describing each phenotype. Although the first-order terms are based on the geographic categories of central perimembranous, inlet, trabecular muscular, and outlet defects, inlet and outlet defects are further characterized by descriptors that incorporate the borders of the defect, namely the perimembranous, muscular, and juxta-arterial types. The Society recognizes that it is equally valid to classify these defects by geography or borders, so the emphasis in this system is on the second-order terms that incorporate both geography and borders to describe each phenotype. The unified terminology should help the medical community describe with better precision all types of ventricular septal defects

LKB1 Destabilizes Microtubules in Myoblasts and Contributes to Myoblast Differentiation

Background: Skeletal muscle myoblast differentiation and fusion into multinucleate myotubes is associated with dramatic cytoskeletal changes. We find that microtubules in differentiated myotubes are highly stabilized, but premature microtubule stabilization blocks differentiation. Factors responsible for microtubule destabilization in myoblasts have not been identified. Findings: We find that a transient decrease in microtubule stabilization early during myoblast differentiation precedes the ultimate microtubule stabilization seen in differentiated myotubes. We report a role for the serine-threonine kinase LKB1 in both microtubule destabilization and myoblast differentiation. LKB1 overexpression reduced microtubule elongation in a Nocodazole washout assay, and LKB1 RNAi increased it, showing LKB1 destabilizes microtubule assembly in myoblasts. LKB1 levels and activity increased during myoblast differentiation, along with activation of the known LKB1 substrates AMPactivated protein kinase (AMPK) and microtubule affinity regulating kinases (MARKs). LKB1 overexpression accelerated differentiation, whereas RNAi impaired it. Conclusions: Reduced microtubule stability precedes myoblast differentiation and the associated ultimate microtubule stabilization seen in myotubes. LKB1 plays a positive role in microtubule destabilization in myoblasts and in myoblast differentiation. This work suggests a model by which LKB1-induced microtubule destabilization facilitates the cytoskeleta

Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin. Copyright: © 2014 Milutinovic et al

Proliferation of Hydroelectric Dams in the Andean Amazon and Implications for Andes-Amazon Connectivity

Due to rising energy demands and abundant untapped potential, hydropower projects are rapidly increasing in the Neotropics. This is especially true in the wet and rugged Andean Amazon, where regional governments are prioritizing new hydroelectric dams as the centerpiece of long-term energy plans. However, the current planning for hydropower lacks adequate regional and basin-scale assessment of potential ecological impacts. This lack of strategic planning is particularly problematic given the intimate link between the Andes and Amazonian flood plain, together one of the most species rich zones on Earth. We examined the potential ecological impacts, in terms of river connectivity and forest loss, of the planned proliferation of hydroelectric dams across all Andean tributaries of the Amazon River. Considering data on the full portfolios of existing and planned dams, along with data on roads and transmission line systems, we developed a new conceptual framework to estimate the relative impacts of all planned dams. There are plans for 151 new dams greater than 2 MW over the next 20 years, more than a 300% increase. These dams would include five of the six major Andean tributaries of the Amazon. Our ecological impact analysis classified 47% of the potential new dams as high impact and just 19% as low impact. Sixty percent of the dams would cause the first major break in connectivity between protected Andean headwaters and the lowland Amazon. More than 80% would drive deforestation due to new roads, transmission lines, or inundation. We conclude with a discussion of three major policy implications of these findings. 1) There is a critical need for further strategic regional and basin scale evaluation of dams. 2) There is an urgent need for a strategic plan to maintain Andes-Amazon connectivity. 3) Reconsideration of hydropower as a low-impact energy source in the Neotropics

Uptake Rate of Cationic Mitochondrial Inhibitor MKT-077 Determines Cellular Oxygen Consumption Change in Carcinoma Cells

<div><h3>Objective</h3><p>Since tumor radiation response is oxygen-dependent, radiosensitivity can be enhanced by increasing tumor oxygenation. Theoretically, inhibiting cellular oxygen consumption is the most efficient way to increase oxygen levels. The cationic, rhodacyanine dye-analog MKT-077 inhibits mitochondrial respiration and could be an effective metabolic inhibitor. However, the relationship between cellular MKT-077 uptake and metabolic inhibition is unknown. We hypothesized that rat and human mammary carcinoma cells would take up MKT-077, causing a decrease in oxygen metabolism related to drug uptake.</p> <h3>Methods</h3><p>R3230Ac rat breast adenocarcinoma cells were exposed to MKT-077. Cellular MKT-077 concentration was quantified using spectroscopy, and oxygen consumption was measured using polarographic electrodes. MKT-077 uptake kinetics were modeled by accounting for uptake due to both the concentration and potential gradients across the plasma and mitochondrial membranes. These kinetic parameters were used to model the relationship between MKT-077 uptake and metabolic inhibition. MKT-077-induced changes in oxygen consumption were also characterized in MDA-MB231 human breast carcinoma cells.</p> <h3>Results</h3><p>Cells took up MKT-077 with a time constant of ∼1 hr, and modeling showed that over 90% of intracellular MKT-077 was bound or sequestered, likely by the mitochondria. The uptake resulted in a rapid decrease in oxygen consumption, with a time constant of ∼30 minutes. Surprisingly the change in oxygen consumption was proportional to uptake rate, not cellular concentration. MKT-077 proved a potent metabolic inhibitor, with dose-dependent decreases of 45–73% (p = 0.003).</p> <h3>Conclusions</h3><p>MKT-077 caused an uptake rate-dependent decrease in cellular metabolism, suggesting potential efficacy for increasing tumor oxygen levels and radiosensitivity <em>in vivo</em>.</p> </div