CyPLOS: a new family of synthetic ionophores

The ion transport properties of a new family of synthetic ionophores based on cyclic phosphate-linked oligosaccharide (CyPLOS) macrocycles are described

Effects of balloon injury on neointimal hyperplasia in steptozotocin-induced diabetes and in hyperinsulinemic nondiabetic pancreatic islet-transplanted rats.

BACKGROUND: The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown. METHODS AND RESULTS: Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H-ras-negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed. CONCLUSIONS: In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals

Low affinity PEGylated hemoglobin from Trematomus bernacchii, a model for hemoglobin-based blood substitutes

<p>Abstract</p> <p>Background</p> <p>Conjugation of human and animal hemoglobins with polyethylene glycol has been widely explored as a means to develop blood substitutes, a novel pharmaceutical class to be used in surgery or emergency medicine. However, PEGylation of human hemoglobin led to products with significantly different oxygen binding properties with respect to the unmodified tetramer and high NO dioxygenase reactivity, known causes of toxicity. These recent findings call for the biotechnological development of stable, low-affinity PEGylated hemoglobins with low NO dioxygenase reactivity.</p> <p>Results</p> <p>To investigate the effects of PEGylation on protein structure and function, we compared the PEGylation products of human hemoglobin and <it>Trematomus bernacchii </it>hemoglobin, a natural variant endowed with a remarkably low oxygen affinity and high tetramer stability. We show that extension arm facilitated PEGylation chemistry based on the reaction of <it>T. bernacchii </it>hemoglobin with 2-iminothiolane and maleimido-functionalyzed polyethylene glycol (MW 5000 Da) leads to a tetraPEGylated product, more homogeneous than the corresponding derivative of human hemoglobin. PEGylated <it>T. bernacchii </it>hemoglobin largely retains the low affinity of the unmodified tetramer, with a p50 50 times higher than PEGylated human hemoglobin. Moreover, it is still sensitive to protons and the allosteric effector ATP, indicating the retention of allosteric regulation. It is also 10-fold less reactive towards nitrogen monoxide than PEGylated human hemoglobin.</p> <p>Conclusions</p> <p>These results indicate that PEGylated hemoglobins, provided that a suitable starting hemoglobin variant is chosen, can cover a wide range of oxygen-binding properties, potentially meeting the functional requirements of blood substitutes in terms of oxygen affinity, tetramer stability and NO dioxygenase reactivity.</p

Medical therapy for patients with subclinical and clinical carotid atherosclerosis

The management of carotid artery disease includes both modifications in life style as well treatment of vascular risk factors. However, strict risk factor modification, including improved antihypertensive therapy, lipid management, smoking cessation, and antiplatelet therapy, promise for reducing the vascular event rate in patients with carotid atherosclerosis. The best medical management for stroke prevention was highlighted in clinical practice guidelines issued jointly in 2006 by the American Heart Association and the American Stroke Association, and co-sponsored by the Council on Cardiovascular Radiology and Intervention and the American Academy of Neurology. Lowering blood pressure to a target below 120/80 mm Hg by life style interventions and antihypertensive treatment. Glucose control to near-normoglycemic levels (target hemoglobin A1C ≤7%) is recommended among diabetics to reduce micro-vascular complications and, with lesser certainty, macrovascular complications. The primary objective of this review is to summarize the current evidence and standards for the advanced diagnostic and management strategies used in asymptomatic and symptomatic patients with carotid atherosclerosis

Diagnostic contribution of Magnetic Resonance Imaging in an atypical presentation of Motor Neuron Disease

Motor neuron disease (MND) is a neurodegenerative disease determining progressive and relentless motor deterioration involving both upper and lower motor neurons (UMN and LMN); several variants at onset are described. Here we describe a case of MND presenting as pure spastic monoparesis in which magnetic resonance imaging (MRI) gave a substantial contribution in confirming the diagnosis and assessing the severity of UMN involvement. An isolated pyramidal syndrome, with complete absence of LMN signs, is a rare phenotype in the context of MND (less than 4% of total cases), especially if restricted to only one limb. Several other elements made this case an unusual presentation of MND: the late age of onset (8th decade), the subacute evolution of symptoms (raising the suspicion of an ischemic or inflammatory, rather than degenerative, etiology), the patient’s past medical history (achalasia, erythema nodosum), the increase of inflammatory indices. Conventional MRI showed no focal lesions that could explain the clinical features; therefore, we used advanced MR sequences. Diffusion tensor imaging (DTI) evaluation evidenced bilateral impairment of corticospinal tract (CST) diffusion metrics, with clear right-left asymmetry, pointing to a neurodegenerative etiology, which clinically appeared less likely at that time. Magnetic resonance spectroscopy (MRS) showed a significant reduction of NAA/Cho + Cr ratio in the motor cortex (MC), further supporting the hypothesis of UMN degeneration. In conclusion, in this particular case of MND, whose nosographic framing has not been fully defined, advanced MRI techniques with DTI and MRS proved to be of great usefulness in confirming a diffuse UMN involvement, possibly at a more advanced stage than its clinical expression

Erectile Dysfunction as a Predictor of Cardiovascular Events and Death in Diabetic Patients With Angiographically Proven Asymptomatic Coronary Artery Disease A Potential Protective Role for Statins and 5-Phosphodiesterase Inhibitors

ObjectivesWe sought to investigate whether erectile dysfunction (ED) is a predictor of future cardiovascular events and death in diabetic patients with silent coronary artery disease (CAD) and whether there are predictors of cardiovascular events and death among CAD diabetic patients with ED.BackgroundCase-control studies showed that ED is associated with CAD in diabetic patients, but no prospective study is available.MethodsType 2 diabetic men (n = 291) with silent CAD angiographically documented were recruited. Erectile dysfunction was assessed by the International Index Erectile Function-5 questionnaire.ResultsDuring a follow-up period of 47.2 ± 21.8 months (range 4 to 82 months), 49 patients experienced major adverse cardiac events (MACE). The difference in ED prevalence between patients with and those without MACE was significant (61.2% vs. 36.4%; p = 0.001). Cox regression analysis showed that ED predicted MACE (hazard ratio [HR] 2.1; 95% confidence interval [CI] 1.6 to 2.6; p < 0.001). Among patients with CAD and ED, the Kaplan-Meier method showed that the statin (Mantel log-rank test: 3.921; p = 0.048) and 5-phosphodiesterase (5-PDE) inhibitor use (Mantel log-rank test: 4.608; p = 0.032) were associated with a lower rate of MACE. Cox regression analysis showed that statin use (HR 0.66; 95% CI 0.46 to 0.97; p = 0.036) reduced MACE. Treatment with 5-PDE inhibitors did not enter the model, but its p value was very near to the significant level (HR 0.68; 95% CI 0.46 to 1.01; p = 0.056).ConclusionsOur data first show that ED is a powerful predictor of cardiovascular morbidity and mortality in diabetic patients with silent CAD and that the treatment with statins and 5-PDE inhibitors might reduce the occurrence of MACE among CAD diabetic patients with ED

EVOLUTIONARY ADAPTATIONS IN ANTARCTIC FISH: THE OXYGEN-TRANSPORT SYSTEM

Understanding molecular adaptations evolved in response to environmental temperature changes is essential, because temperature affects the kinetic energy of molecules and modifies molecular interactions, macromolecular stability/functioning and membrane features. Environmental oxygen availability may also play an important role in the evolution of polar marine organisms, as suggested by the physiological and biochemical strategies adopted by these organisms to acquire, deliver and scavenge oxygen.This review summarises the current knowledge on the structure and function of hemoglobins of fish living in Antarctic habitats. The variety of adaptations underlying the ability of Antarctic fish to survive at temperatures permanently close to freezing is unique among teleosts. The dominant perciform suborder Notothenioidei affords an excellent study group for elaborating the evolution of biochemical adaptation to temperature. The availability of notothenioid taxa living in a wide range of latitudes (Antarctic, sub-Antarctic, and temperate regions) offers a remarkable opportunity to study the physiological and biochemical characters gained and, conversely, lost in response to cold and to reconstruct the likely evolutionary events modulating the ability to carry oxygen in freezing habitats. Although oxygen can be transported in freely dissolved form most animals rely on one or more protein carriers to deliver it to the respiring tissues. Compared to temperate and tropical species, high-Antarctic notothenioids have evolved reduced hemoglobin concentration/multiplicity. The Antarctic family Channichthyidae (the notothenioid crown group) is devoid of hemoglobin. All extant icefish species lack hemoglobin and many have lost myoglobin expression. In these species, oxygen delivery to tissues occurs by transport of the gas physically dissolved in the plasma.ADAPTACIONES EVOLUTIVAS EN PECES ANTÁRTICOS: EL SISTEMA DE TRANSPORTE DE OXÍGENO. Comprender las adaptaciones moleculares que han evolucionado en respuesta a los cambios de temperatura del medio ambiente es esencial, porque la temperatura afecta la energía cinética de las moléculas y  modiica  las  interacciones  moleculares,  la  estabilidad  de  las  macromoleculares,  sus  características  y  el funcionamiento de la membrana. La disponibilidad de oxígeno ambiental desempeña un papel importante en la evolución de los organismos marinos polares, como se evidencia en las estrategias isiológicas y bioquímicas adoptadas  por  estos  organismos  para  adquirir,  gastar  y  usar  oxígeno.  Esta  revisión  resume  el  conocimiento actual sobre la estructura y función de la hemoglobina de los peces que viven en hábitats antárticos. La amplia variedad de adaptaciones que permiten que los peces antárticos tengan la capacidad para sobrevivir de forma permanente en temperaturas cerca de la congelación es única entre los teleósteos. El suborden Notothenioidei, perteneciente a los Perciformes, es un excelente grupo para el estudio de la evolución y adaptación bioquímica a la temperatura. La gran variedad de taxones de nototénidos que viven en una amplia variedad de latitudes (Antártida, sub-antárticas, y las regiones templadas) ofrece una oportunidad extraordinaria para estudiar las características  isiológicas  y  bioquímicas  adquiridas  y  perdidas  por  este  grupo  en  respuesta  al  frío,  además de la posibilidad de reconstruir  los eventos más probables que direccionaron la evolución de la capacidad de transportar oxígeno en hábitats polares. Aunque el oxígeno puede ser transportado en su forma libre disuelta, la mayoría de los animales dependen de una o más proteínas para entregarlo a los tejidos para la respiración. En comparación con especies de zonas templadas y tropicales, los nototenoideos de la alta Antártida han evolucionado reduciendo la concentración y multiplicidad de hemoglobina. La familia antártica Channichthyidae (el grupo con corona de los Nototénidos) carece de la hemoglobina. Todas las especies de peces existentes que viven en el hielo carecen de hemoglobina y muchas han perdido la expresión de la mioglobina. En estas especies, el aporte de oxígeno a los tejidos se produce por el transporte del gas físicamente disuelto en el plasma. Palabras clave: Antártida; adaptaciones al frio; evolución; hemoglobina.ADAPTAÇÕES EVOLUTIVAS EM PEIXES ANTÁTRTICOS: O SISTEMA DE TRANSPORTE DE OXIGÊNIO.  Compreender as adaptações moleculares envolvidas na resposta às mudanças na temperatura  ambiental  é  essencial,  pois  a  temperatura  afeta  a  energia  cinética  das  moléculas  e  modiica  as interações moleculares, a estabilidade/funcionamento das macromoléculas e as características da membrana. A disponibilidade de oxigênio no ambiente pode também ter um importante papel na evolução dos organismos marinhos polares, como indicado pelas estratégias isiológicas e bioquímicas adotadas por estes organismos para adquirir, transportar e trocar oxigênio.   Esta revisão resume o conhecimento atual da estrutura e funcionamento das hemoglobinas de peixes que ocorrem em ambientes Antárticos. A diversidade de adaptações que sustentam a habilidade de peixes antárticos sobreviverem em temperaturas permanentemente próximas do congelamento é  única  entre  os  teleósteos.  A  dominante  sub-ordem  Perciforme  Notothenioidei  apresenta-se  como  um excelente  grupo  de  estudo  para  melhorar  o  conhecimento  sobre  a  evolução  das  adaptações  bioquímicas  à temperatura. A ocorrência de nototenióides em uma ampla variedade de latitudes (Antártica, sub-Antártica e regiões temperadas) oferece uma oportunidade notável para estudar as características isiológicas e bioquímicas obtidas  e,  por  outro  lado,  perdidas  em  resposta  ao  frio,  além  de  tornar  possível  a  reconstrução  dos  eventos evolutivos  que  provavelmente  modularam  a  habilidade  desses  peixes  de  transportar  oxigênio  em  ambientes extremamente frios. Embora  o  oxigênio  possa  ser  transportado  livremente  na  sua  forma  dissolvida,  a  maioria  dos  animais depende de um ou mais tipos de proteínas carreadoras para entregar o oxigênio aos tecidos. Quando comparadas às  espécies  temperadas  e  tropicais,  os  nototenióides  da  região Antártica,  propriamente  dita,  desenvolveram reduzida  concentração/multiplicidade  de  hemoglobinas.  A  família  de  peixes  Antárticos  Channichthyidae (crown group  nototenióide)  não  apresenta  hemoglobina.  Todas  as  espécies  de iceish  (peixes-do-gelo)  não possuem hemoglobinas e muitas também não produzem mioglobinas. Nessas espécies, o transporte de oxigênio aos tecidos ocorre através do gás isicamente dissolvido no plasma. Palavras-chave: Antártica; adaptações ao frio; evolução; hemoglobina

Single-agent rituximab is an effective salvage therapy in pretreated patients with hairy cell leukemia

No abstract availabl

Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD