bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment with the vascular disrupting agent combretastatin is associated with impaired AQP2 trafficking and increased urine output
Authors: Bohn Anja B. , Nørregaard Rikke , Stødkilde Lene , Wang Yan , Bertelsen Lotte B. , Fenton Robert A. , Matchkov Vladimir V. , Bouzinova Elena V. , Horsman Michael R. , Frøkiær Jørgen , Stødkilde-Jørgensen Hans
Published: May 2012

Combretastatin A-4 disodium phosphate (CA4P) is a vascular disrupting agent known to mediate its effects primarily on tumor blood vessels. CA4P has previously been shown to induce a significant increase in mean arterial blood pressure and in hemoglobin concentration in mice. In the present study, we examined whether this is associated with a general leakage of water into certain tissues or with changes in renal water handling. Munich-Wistar rats received either CA4P (30 mg/kg body wt) or saline intraperitoneally as a bolus injection. One hour later, hemoglobin concentration and mean blood pressure increased significantly. MRI showed no significant changes in tissue water content following CA4P administration. However, urine output and salt excretion increased 1 h after CA4P treatment, without changes in urinary and medullary osmolality. Aquaporin 2 (AQP2) mRNA levels in kidney inner medulla did not change 1 h after CA4P treatment, but semiquantitative confocal laser-scanning microscopy analysis demonstrated a decrease in phosphorylated AQP2 (pS256-AQP2) apical distribution within the collecting ducts of CA4P-treated rats compared with the characteristic apical localization in control rats. Furthermore, we demonstrated that CA4P cause disruption of microtubules and a weaker apical labeling of pS256-AQP2 in collecting duct principal cells within 1 h. In conclusion, our data indicate that water escapes from the vascular system after CA4P treatment, and it may take place primarily through a renal mechanism. The CA4P-mediated increase in urine output seems to be a local effect in the collecting ducts due to reduced AQP2 trafficking to the apical plasma membrane.
Tissue kallikrein activation of the epithelial Na channel
Authors: Patel Ankit B. , Chao Julie , Palmer Lawrence G.
Published: May 2012

Epithelial Na Channels (ENaC) are responsible for the apical entry of Na+in a number of different epithelia including the renal connecting tubule and cortical collecting duct. Proteolytic cleavage of γ-ENaC by serine proteases, including trypsin, furin, elastase, and prostasin, has been shown to increase channel activity. Here, we investigate the ability of another serine protease, tissue kallikrein, to regulate ENaC. We show that excretion of tissue kallikrein, which is secreted into the lumen of the connecting tubule, is stimulated following 5 days of a high-K+or low-Na+diet in rats. Urinary proteins reconstituted in a low-Na buffer activated amiloride-sensitive currents ( INa) in ENaC-expressing oocytes, suggesting an endogenous urinary protease can activate ENaC. We next tested whether tissue kallikrein can directly cleave and activate ENaC. When rat ENaC-expressing oocytes were exposed to purified tissue kallikrein from rat urine (RTK), ENaC currents increased threefold in both the presence and absence of a soybean trypsin inhibitor (SBTI). RTK and trypsin both decreased the apparent molecular mass of cleaved cell-surface γ-ENaC, while immunodepleted RTK produced no shift in apparent molecular mass, demonstrating the specificity of the tissue kallikrein. A decreased effect of RTK on Xenopus ENaC, which has variations in the putative prostasin cleavage sites in γ-ENaC, suggests these sites are important in RTK activation of ENaC. Mutating the prostasin site in mouse γ-ENaC (γRKRK186QQQQ) abolished ENaC activation and cleavage by RTK while wild-type mouse ENaC was activated and cleaved similar to that of the rat. We conclude that tissue kallikrein can be a physiologically relevant regulator of ENaC activity.
Mitochondrial aquaporin-8 in renal proximal tubule cells: evidence for a role in the response to metabolic acidosis
Authors: Molinas Sara M. , Trumper Laura , Marinelli Raúl A.
Published: May 2012

Mitochondrial ammonia synthesis in proximal tubules and its urinary excretion are key components of the renal response to maintain acid-base balance during metabolic acidosis. Since aquaporin-8 (AQP8) facilitates transport of ammonia and is localized in inner mitochondrial membrane (IMM) of renal proximal cells, we hypothesized that AQP8-facilitated mitochondrial ammonia transport in these cells plays a role in the response to acidosis. We evaluated whether mitochondrial AQP8 (mtAQP8) knockdown by RNA interference is able to impair ammonia excretion in the human renal proximal tubule cell line, HK-2. By RT-PCR and immunoblotting, we found that AQP8 is expressed in these cells and is localized in IMM. HK-2 cells were transfected with short-interfering RNA targeting human AQP8. After 48 h, the levels of mtAQP8 protein decreased by 53% ( P < 0.05). mtAQP8 knockdown decreased the rate of ammonia released into culture medium in cells grown at pH 7.4 (−31%, P < 0.05) as well as in cells exposed to acid (−90%, P < 0.05). We also evaluated mtAQP8 protein expression in HK-2 cells exposed to acidic medium. After 48 h, upregulation of mtAQP8 (+74%, P < 0.05) was observed, together with higher ammonia excretion rate (+73%, P < 0.05). In vivo studies in NH4Cl-loaded rats showed that mtAQP8 protein expression was also upregulated after 7 days of acidosis in renal cortex (+51%, P < 0.05). These data suggest that mtAQP8 plays an important role in the adaptive response of proximal tubule to acidosis possibly facilitating mitochondrial ammonia transport.
Split-belt walking: adaptation differences between young and older adults
Authors: Bruijn Sjoerd M. , Van Impe Annouchka , Duysens Jacques , Swinnen Stephan P.
Published: May 2012

Human walking is highly adaptable, which allows us to walk under different circumstances. With aging, the probability of falling increases, which may partially be due to a decreased ability of older adults to adapt the gait pattern to the needs of the environment. The literature on visuomotor adaptations during reaching suggests, however, that older adults have little problems in adapting their motor behavior. Nevertheless, it may be that adaptation during a more complex task like gait is compromised by aging. In this study, we investigated the ability of young ( n = 8) and older ( n = 12) adults to adapt their gait pattern to novel constraints with a split-belt paradigm. Findings revealed that older adults adapted less and more slowly to split-belt walking and showed fewer aftereffects than young adults. While young adults showed a fast adjustment of the relative time spent in swing for each leg older adults failed to do so, but instead they were very fast in manipulating swing speed differences between the two legs. We suggest that these changes in adaptability of gait due to aging stem from a mild degradation of cortico-cerebellar pathways (reduced adaptability) and cerebral structures (decreased ability to change gait cycle timing). However, an alternative interpretation may be that the observed reduced adaptation is a compensatory strategy in view of the instability induced by the split-belt paradigm.
Influence of the behavioral goal and environmental obstacles on rapid feedback responses
Authors: Nashed Joseph Y. , Crevecoeur Frédéric , Scott Stephen H.
Published: May 2012

The motor system must consider a variety of environmental factors when executing voluntary motor actions, such as the shape of the goal or the possible presence of intervening obstacles. It remains unknown whether rapid feedback responses to mechanical perturbations also consider these factors. Our first experiment quantified how feedback corrections were altered by target shape, which was either a circular dot or a bar. Unperturbed movements to each target were qualitatively similar on average but with greater dispersion of end point positions when reaching to the bar. On random trials, multijoint torque perturbations deviated the hand left or right. When reaching to a circular target, perturbations elicited corrective movements that were directed straight to the location of the target. In contrast, corrective movements when reaching to a bar were redirected to other locations along the bar axis. Our second experiment quantified whether the presence of obstacles could interfere with feedback corrections. We found that hand trajectories after the perturbations were altered to avoid obstacles in the environment. Importantly, changes in muscle activity reflecting the different target shapes (bar vs. dot) or the presence of obstacles were observed in as little as 70 ms. Such changes in motor responses were qualitatively consistent with simulations based on optimal feedback control. Taken together, these results highlight that long-latency motor responses consider spatial properties of the goal and environment.
Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)
Authors: Ratia M. , Giménez-Llort L. , Camps P. , Muñoz-Torrero D. , Pérez B. , Clos M.V. , Badia A.
Published: May 2012

Background: Different studies have established that cholinergic neurodegeneration could be a major pathological feature of Alzheimer’s disease (AD). Thus, enhancement of the central cholinergic neurotransmission has been regarded as one of the most promising strategies for the symptomatic treatment of AD, mainly by means of reversible acetylcholinesterase inhibitors (AChEIs). The cognitive-enhancing properties of both huprine X, a new AChEI, and the structurally related huperzine A, as well as their effects on the regulation of several neurochemical processes related to AD have been studied in triple transgenic mice (3xTg-AD). Methods: Seven-month-old homozygous 3xTg-AD male mice, which received chronic intraperitoneal treatment with either saline, huprine X (0.12 µmol·kg–1) or huperzine A (0.8 µmol·kg–1) were subjected to a battery of behavioural tests after 3 weeks of treatment and thereafter the brains were dissected to study the neurochemical effects induced by the two AChEIs. Results: Treatments with huprine X and huperzine A improved learning and memory in the Morris water maze and some indicators of emotionality without inducing important adverse effects. Moreover, huprine X and huperzine A activate protein kinase C/mitogen-activated protein kinase pathway signalling, α-secretases (ADAM 10 and TACE) and increase the fraction of phospho-glycogen synthase kinase 3-β. Conclusion: Results obtained herein using a sample of 3xTg-AD animals strongly suggest that the treatment with the two AChEIs not only improves the cognitive performance of the animals but also induces some neurochemical changes that could contribute to the beneficial effects observed.
The Translational Role of Diffusion Tensor Image Analysis in Animal Models of Developmental Pathologies
Authors: Oguz Ipek , McMurray Matthew S. , Styner Martin , Johns Josephine M.
Published: May 2012

Diffusion tensor magnetic resonance imaging (DTI) has proven itself a powerful technique for clinical investigation of the neurobiological targets and mechanisms underlying developmental pathologies. The success of DTI in clinical studies has demonstrated its great potential for understanding translational animal models of clinical disorders, and preclinical animal researchers are beginning to embrace this new technology to study developmental pathologies. In animal models, genetics can be effectively controlled, drugs consistently administered, subject compliance ensured, and image acquisition times dramatically increased to reduce between-subject variability and improve image quality. When pairing these strengths with the many positive attributes of DTI, such as the ability to investigate microstructural brain organization and connectivity, it becomes possible to delve deeper into the study of both normal and abnormal development. The purpose of this review is to provide new preclinical investigators with an introductory source of information about the analysis of data resulting from small animal DTI studies to facilitate the translation of these studies to clinical data. In addition to an in-depth review of translational analysis techniques, we present a number of relevant clinical and animal studies using DTI to investigate developmental insults in order to further illustrate techniques and to highlight where small animal DTI could potentially provide a wealth of translational data to inform clinical researchers.
Update on the Management of Hypertension for Secondary Stroke Prevention
Authors: Castilla-Guerra Luis , Fernández-Moreno María del Carmen
Published: May 2012

High blood pressure (BP) is the strongest risk factor for stroke. It is estimated that almost 50% of strokes may be attributable to hypertension. Both diastolic and isolated systolic hypertension are important predictors of primary or recurrent strokes, and even minor decreases in BP can reduce the risk of stroke. While the primary prevention of stroke through the treatment of hypertension is well established, the issue of lowering BP after a stroke has been uncertain, particularly since this might worsen cerebral perfusion if autoregulation remains chronically damaged or severe carotid artery stenosis is present. Furthermore, there is substantial evidence to support BP lowering for prevention of a first stroke; however, few trials have focused on antihypertensive therapy for recurrent stroke prevention. In fact, currently, BP management in patients with strokes remains problematic, and questions such as the choice of antihypertensive drug and by how much to reduce BP are yet to be resolved. Recently, the American Heart Association and American Stroke Association published updated guidelines for recurrent stroke prevention, and new recommendations on BP management have been included. Our review presents the most recent evidence on the management of hypertension in patients who have had a stroke.
Increased Vascular Contractility and Oxidative Stress in β2-Adrenoceptor Knockout Mice: The Role of NADPH Oxidase
Authors: Davel A.P. , Ceravolo G.S. , Wenceslau C.F. , Carvalho M.H.C. , Brum P.C. , Rossoni L.V.
Published: May 2012

Background/Aims: β2-adrenoceptor (β2-AR) activation induces smooth muscle relaxation and endothelium-derived nitric oxide (NO) release. However, whether endogenous basal β2-AR activity controls vascular redox status and NO bioavailability is unclear. Thus, we aimed to evaluate vascular reactivity in mice lacking functional β2-AR (β2KO), focusing on the role of NO and superoxide anion. Methods and Results: Isolated thoracic aortas from β2KO and wild-type mice (WT) were studied. β2KO aortas exhibited an enhanced contractile response to phenylephrine compared to WT. Endothelial removal and L-NAME incubation increased phenylephrine-induced contraction, abolishing the differences between β2KO and WT mice. Basal NO availability was reduced in aortas from β2KO mice. Incubation of β2KO aortas with superoxide dismutase or NADPH inhibitor apocynin restored the enhanced contractile response to phenylephrine to WT levels. β2KO aortas exhibited oxidative stress detected by enhanced dihydroethidium fluorescence, which was normalized by apocynin. Protein expression of eNOS was reduced, while p47phox expression was enhanced in β2KO aortas. Conclusions: The present results demonstrate for the first time that enhanced NADPH-derived superoxide anion production is associated with reduced NO bioavailability in aortas of β2KO mice. This study extends the knowledge of the relevance of the endogenous activity of β2-AR to the maintenance of the vascular physiology.
Esteem 2 Middle Ear Implant: Our Experience
Authors: Gerard J.M. , Thill M.P. , Chantrain G. , Gersdorff M. , Deggouj N.
Published: May 2012

Introduction: The Esteem is a totally implantable hearing system that uses piezoelectric technology. It is indicated in case of moderate to severe stable sensorineural hearing loss with a minimum discrimination score of 60% and a middle ear which is anatomically and functionally intact. Its two components (sensor and driver) are positioned and fixed in the mastoid cavity and coupled respectively to the incus body and capitulum with cement. Study Design: Retrospective study. Settings: Tertiary referral center. Materials and Methods: Pure-tone average (PTA) gain in the implanted ear was calculated at 1, 2, and 4 KHz, word recognition score (WRS) gain at 50 dB SPL, and average WRS (AWRS) gain at 40, 55, and 70 dB SPL. WRS was also evaluated in silence and noise. All patients were asked to fill in the abbreviated profile of hearing aid benefit (APHAB) questionnaire pre- and postoperatively as well as an Esteem questionnaire. Results: Thirteen patients received implants between May 2008 and April 2010. Five minor complications occurred (1 temporary partial facial palsy, 1 secondary healing difficulty, and 3 revision surgeries for poor and deteriorating functional results and progressive gain loss after use of a heart defibrillator). Two patients (15%) suffered major complications and their implants had to be removed 4 months postoperatively because of a Staphylococcus aureus wound infection. One patient underwent reimplantation 6 months later. Mean PTA gain was 25 ± 11 dB, mean WRS gain at 50 dB SPL was 64 ± 33%, and mean AWRS gain was 40 ± 20%. WRS in silence and with a signal-noise ratio of 10, 0, and –5 dB was 91 ± 11, 85 ± 14, 71 ± 19, and 64 ± 30%, respectively. The APHAB questionnaire revealed 84% of satisfaction improvement compared to the previous classic hearing aid. Conclusion: The totally implantable hearing device Esteem 2 can offer good functional and satisfaction results. Careful selection of patients is required, however, based on hearing tests, exclusion of middle ear ventilation problems, and CAT-scan middle ear anatomy. Specific surgical training and experience are also needed. The implant is safe and only associated with classic auditory implant complications.
Natural Exceptions to Normal Gonad Development in Mammals
Authors: Jiménez R. , Barrionuevo F.J. , Burgos M.
Published: May 2012

Gonads are the only organs with 2 possible developmental pathways, testis or ovary. A consequence of this unique feature is that mutations in genes controlling gonad development give rise not only to gonadal malformation or dysfunction but also to frequent cases of sex reversal, including XY females, XX males and intersexes. Most of our current knowledge on mammalian sex determination, the genetic process by which the gonadal primordia are committed to differentiate as either testes or ovaries, has derived mainly from the study of sex-reversed mice obtained by direct genetic manipulation. However, there are also numerous cases of natural exceptions to normal gonad development which have been described in a variety of mammals, including both domestic and wild species. Here, we review the most relevant cases of: (1) natural, non-induced sex reversal and intersexuality described in laboratory rodents, including Sxr and B6-YDOM mice; (2) sex reversal in domestic animals, including freemartinism in bovids and pigs, XX sex reversal in pigs, goats and dogs, XY sex reversal in the horse, and sex chromosome chimerism and sex reversal in the cat, and (3) sex reversal in wild mammals, including the generalised true hermaphroditism described in talpid moles, XY sex reversal in Akodon, Microtus and Dicrostonyx species, males lacking a Y chromosome and SRY in Ellobius lutescens, the X* chromosome of Myopus schisticolor, and sex chromosome mosaicism and X0 females in Microtus oregoni. These studies are necessary to elucidate particular aspects of mammalian gonad development in some instances and to understand how the genetic mechanisms controlling gonad development have evolved.
Comparative Molecular Cytogenetics in Cetartiodactyla
Authors: Rubes J. , Musilova P. , Kopecna O. , Kubickova S. , Cernohorska H. , Kulemsina A.I.
Published: May 2012

Cetartiodactyla comprises Artiodactyla (even-toed ungulates) and Cetacea (whales, dolphins and porpoises). Artiodactyla is a large taxon represented by about 200 living species ranked in 10 families. Cetacea are classified into 13 families with almost 80 species. Many publications concerning karyotypic relationships in Cetartiodactyla have been published in previous decades. Formerly, the karyotypes of closely related species were compared by chromosome banding. Introduction of molecular cytogenetic methods facilitated comparative mapping between species with highly rearranged karyotypes and distantly related species. Such information is a prerequisite for the understanding of karyotypic phylogeny and the reconstruction of the karyotypes of common ancestors. This study summarizes the data on chromosome evolution in Cetartiodactyla, mainly derived from molecular cytogenetic studies. Traditionally, phylogenetic relationships of most groups have been estimated using morphological data. However, the results of some molecular studies of mammalian phylogeny are discordant with traditional conceptions of phylogeny. Cetartiodactyls provide several examples of incongruence between traditional morphological and molecular data. Such cases of conflict include the relationships of the major clades of artiodactyls, the relationships among the extant families of the suborder Ruminantia or the phylogeny of the family Bovidae. The most unexpected aspect of the molecular phylogeny was the recognition that Cetacea is a deeply nested member of Artiodactyla. The largest living order of terrestrial hoofed mammals is the even-toed hoofed mammals, or Artiodactyla. The artiodactyls are composed of over 190 living species including pigs, peccaries, hippos, camels, llamas, deer, pronghorns, giraffes, sheep, goats, cattle and antelopes. Cetacea is an order of wholly aquatic mammals, which include whales, dolphins and porpoises. Cetartiodactyla has become the generally accepted name for the clade containing both of these orders.
Systems of Care for ST-Segment–Elevation Myocardial Infarction: A Report From the American Heart Association’s
Mission: Lifeline
Authors: Jollis James G. , Granger Christopher B. , Henry Timothy D. , Antman Elliott M. , Berger Peter B. , Moyer Peter H. , Pratt Franklin D. , Rokos Ivan C. , Acuña Anna R. , Roettig Mayme Lou , Jacobs Alice K.
Published: May 2012

Background—

National guidelines call for participation in systems to rapidly diagnose and treat ST-segment–elevation myocardial infarction (STEMI). In order to characterize currently implemented STEMI reperfusion systems and identify practices common to system organization, the American Heart Association surveyed existing systems throughout the United States.

Methods and Results—

A STEMI system was defined as an integrated group of separate entities focused on reperfusion therapy for STEMI within a geographic region that included at least 1 hospital that performs percutaneous coronary intervention and at least 1 emergency medical service agency. Systems meeting this definition were invited to participate in a survey of 42 questions based on expert panel opinion and knowledge of existing systems. Data were collected through the American Heart Association
Mission: Lifeline
website.

Between April 2008 and January 2010, 381 unique systems involving 899 percutaneous coronary intervention hospitals in 47 states responded to the survey, of which 255 systems (67%) involved urban regions. The predominant funding sources for STEMI systems were percutaneous coronary intervention hospitals (n = 320, 84%) and /or cardiology practices (n = 88, 23%). Predominant system characteristics identified by the survey included: STEMI patient acceptance at percutaneous coronary intervention hospital regardless of bed availability (N = 346, 97%); single phone call activation of catheterization laboratory (N = 335, 92%); emergency department physician activation of laboratory without cardiology consultation (N = 318, 87%); data registry participation (N = 311, 84%); and prehospital activation of the laboratory through emergency department notification without cardiology notification (N = 297, 78%). The most common barriers to system implementation were hospital (n = 139, 37%) and cardiology group competition (n = 81, 21%) and emergency medical services transport and finances (n = 99, 26%).

Conclusions—

This survey broadly describes the organizational characteristics of collaborative efforts by hospitals and emergency medical services to provide timely reperfusion in the United States. These findings serve as a benchmark for existing systems and should help guide healthcare teams in the process of organizing care for patients with STEMI.
Low-Dose Physical Activity Attenuates Cardiovascular Disease Mortality in Men and Women With Clustered Metabolic Risk Factors
Authors: Hamer Mark , Stamatakis Emmanuel
Published: May 2012

Background—

Physical activity may ameliorate the health hazards of metabolic disorders but evidence is inconclusive, and estimates of the minimal threshold for protection remain unknown.

Methods and Results—

The sample comprised 23 747 men and women (aged 54.1 ± 12.7 years [mean±SD], 45.2% men) without a known history of cardiovascular disease at baseline who were drawn from the Health Survey for England and the Scottish Health Survey. Based on blood pressure, high-density lipoprotein cholesterol, diabetes, waist circumference, and low-grade inflammation (C-reactive protein ≥ 3 mg/L), participants were classified as metabolically healthy (zero or one metabolic abnormality) or unhealthy (≥ 2 metabolic abnormalities). Self-reported physical activity was assessed at baseline. Cox proportional hazards models were used to examine the association of clustered metabolic risk and physical activity with mortality, controlling for age, sex, smoking, socioeconomic group, cardiovascular disease medication, and self-rated health. Over 7.0 ± 3.0 years follow-up, there were 2264 all-cause and 717 cardiovascular disease deaths, respectively. A physical activity threshold of at least one to 2 sessions per week was found to provide protection against mortality. Compared with active/metabolically healthy, the active with clustered metabolic abnormalities were not at elevated risk of cardiovascular disease (hazard ratio, 0.82; 95% CI, 0.54 –1.26) or all-cause mortality (hazard ratio, 1.11; 95% CI, 0.89 –1.39), although their inactive counterparts were at elevated risk of cardiovascular disease (hazard ratio, 1.41; 95% CI, 1.05 –1.91) and all-cause mortality (hazard ratio, 1.50; 95% CI, 1.27–1.78).

Conclusions—

The risk of cardiovascular disease associated with poor metabolic health is substantially lower among those who are physically active. At minimum, a weekly bout of moderate to vigorous physical activity is protective in men and women with clustered metabolic abnormalities.
Gene Regulatory Networks in Cardiac Conduction System Development
Authors: Munshi Nikhil V.
Published: May 2012

The cardiac conduction system is a specialized tract of myocardial cells responsible for maintaining normal cardiac rhythm. Given its critical role in coordinating cardiac performance, a detailed analysis of the molecular mechanisms underlying conduction system formation should inform our understanding of arrhythmia pathophysiology and affect the development of novel therapeutic strategies. Historically, the ability to distinguish cells of the conduction system from neighboring working myocytes presented a major technical challenge for performing comprehensive mechanistic studies. Early lineage tracing experiments suggested that conduction cells derive from cardiomyocyte precursors, and these claims have been substantiated by using more contemporary approaches. However, regional specialization of conduction cells adds an additional layer of complexity to this system, and it appears that different components of the conduction system utilize unique modes of developmental formation. The identification of numerous transcription factors and their downstream target genes involved in regional differentiation of the conduction system has provided insight into how lineage commitment is achieved. Furthermore, by adopting cutting-edge genetic techniques in combination with sophisticated phenotyping capabilities, investigators have made substantial progress in delineating the regulatory networks that orchestrate conduction system formation and their role in cardiac rhythm and physiology. This review describes the connectivity of these gene regulatory networks in cardiac conduction system development and discusses how they provide a foundation for understanding normal and pathological human cardiac rhythms.
Modulation of Training by Single-Session Transcranial Direct Current Stimulation to the Intact Motor Cortex Enhances Motor Skill Acquisition of the Paretic Hand
Authors: Zimerman Máximo , Heise Kirstin F. , Hoppe Julia , Cohen Leonardo G. , Gerloff Christian , Hummel Friedhelm C.
Published: May 2012

Background and Purpose—

Mechanisms of skill learning are paramount components for stroke recovery. Recent noninvasive brain stimulation studies demonstrated that decreasing activity in the contralesional motor cortex might be beneficial, providing transient functional improvements after stroke. The more crucial question, however, is whether this intervention can also enhance the acquisition of complex motor tasks, yielding longer-lasting functional improvements. In the present study, we tested the capacity of cathodal transcranial direct current stimulation (tDCS) applied over the contralesional motor cortex during training to enhance the acquisition and retention of complex sequential finger movements of the paretic hand.

Method—

Twelve well-recovered chronic patients with subcortical stroke attended 2 training sessions during which either cathodal tDCS or a sham intervention were applied to the contralesional motor cortex in a double-blind, crossover design. Two different motor sequences, matched for their degree of complexity, were tested in a counterbalanced order during as well as 90 minutes and 24 hours after the intervention. Potential underlying mechanisms were evaluated with transcranial magnetic stimulation.

Results—

tDCS facilitated the acquisition of a new motor skill compared with sham stimulation (
P
=0.04) yielding better task retention results. A significant correlation was observed between the tDCS-induced improvement during training and the tDCS-induced changes of intracortical inhibition (
R
2
=0.63).

Conclusions—

These results indicate that tDCS is a promising tool to improve not only motor behavior, but also procedural learning. They further underline the potential of noninvasive brain stimulation as an adjuvant treatment for long-term recovery, at least in patients with mild functional impairment after stroke.
Which Risk Factors Are More Associated With Ischemic Stroke Than Intracerebral Hemorrhage in Patients With Atrial Fibrillation?
Authors: McGrath Emer R. , Kapral Moira K. , Fang Jiming , Eikelboom John W. , Conghaile Aengus ó , Canavan Michelle , O'Donnell Martin J.
Published: May 2012

Background and Purpose—

The decision to prescribe oral anticoagulant therapy in patients with atrial fibrillation is based on an assessment of the competing risks of ischemic stroke and major bleeding, of which intracerebral hemorrhage (ICH) is the most important type. We sought to determine the comparative importance of risk factors for ischemic stroke and ICH in patients with acute stroke and atrial fibrillation with particular emphasis on risk factors common to both stroke types.

Methods—

Consecutive patients with acute ischemic stroke or ICH and atrial fibrillation included in the Registry of the Canadian Stroke Network constituted the cohort. Multivariable logistic regression analysis was used to determine the association between baseline risk factors and presentation with ICH versus ischemic stroke. Risk factors included: (1) those previously reported to be risk factors for both ischemic stroke and major bleeding (particularly ICH) (“shared” risk factors, including age, alcohol, hypertension, diabetes mellitus, renal impairment, prior stroke/transient ischemic attack and preadmission dementia); and (2) other risk factors associated with either stroke subtype alone.

Results—

A total of 3197 patients presented with atrial fibrillation and acute stroke, of which 12.2% presented with ICH. Of the “shared” risk factors, age (OR, 1.19; 95% CI, 1.06–1.34 per decade) and prior stroke/transient ischemic attack (OR, 1.45; 95% CI, 1.12–1.87) were more associated with ischemic stroke than ICH, whereas a history of hypertension (OR, 0.89; 95% CI, 0.68–1.17), diabetes mellitus (OR 1.23; 95% CI, 0.92–1.64), renal impairment (OR, 1.28; 95% CI, 0.95–1.71), and alcohol intake were not more strongly associated with either stroke subtype.

Conclusion—

Of the risk factors known to be associated with both ischemic stroke and ICH in patients with atrial fibrillation, we found that none had a stronger association with ICH. Older age was more strongly associated with ischemic stroke than ICH.
Cotton Mather Brings Isaac Watts's Hymns to America; or, How to Perform a Hymn without Singing It
Authors: Phillips Christopher N.
Published: May 2012

This essay reconstructs Cotton Mather's efforts to introduce Isaac Watts's hymns into New England print culture using sermon pamphlets and family prayer guides. These forms framed hymns as read rather than sung texts, but they also enabled the performance of hymns as expressions of personal faith during the Great Awakening.
Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry
Authors: Baudo Francesco , Collins Peter , Huth-Kühne Angela , Lévesque Hervé , Marco Pascual , Nemes László , Pellegrini Fabio , Tengborn Lilian , Knoebl Paul
Published: May 2012

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).
Embryonic Birthdate of Hypothalamic Leptin-Activated Neurons in Mice
Authors: Ishii Yuko , Bouret Sebastien G.
Published: May 2012

The hypothalamus plays a critical role in the regulation of energy balance. Neuroanatomical and mouse genetic data have defined a core circuitry in the hypothalamus that mediates many of the effects of leptin on feeding and energy balance regulation. The present study used 5-bromo-2′-deoxyuridine (a marker of dividing cells) and a neuronal marker to systematically examine neurogenesis in the mouse embryonic hypothalamus, particularly the birth of neurons that relay leptin signaling. The vast majority of neurons in hypothalamic nuclei known to control energy balance is generated between embryonic days (E) 12 and E16, with a sharp peak of neurogenesis occurring on E12. Neurons in the dorsomedial and paraventricular nuclei and the lateral hypothalamic area are born between E12 and E14. The arcuate and ventromedial nuclei exhibit a relatively longer neurogenic period. Many neurons in these nuclei are born on E12, but some neurons are generated as late as E16. We also examined the birth of leptin-activated cells by coupling the 5-bromo-2′-deoxyuridine staining with cFos immunohistochemistry. Remarkably, the majority of leptin-activated cells in the adult hypothalamus were also born during a discrete developmental window on E12. These results provide new insight into the development of hypothalamic neurons that control feeding and identify important developmental periods when alterations in the intrauterine environment may affect hypothalamic neurogenesis and produce long-term consequences on hypothalamic cell numbers.
Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development
Authors: Lange Clemens A. K. , Luhmann Ulrich F. O. , Mowat Freya M. , Georgiadis Anastasios , West Emma L. , Abrahams Sabu , Sayed Haroon , Powner Michael B. , Fruttiger Marcus , Smith Alexander J. , Sowden Jane C. , Maxwell Patrick H. , Ali Robin R. , Bainbridge James W. B.
Published: May 2012

Molecular oxygen is essential for the development, growth and survival of multicellular organisms. Hypoxic microenvironments and oxygen gradients are generated physiologically during embryogenesis and organogenesis. In the eye, oxygen plays a crucial role in both physiological vascular development and common blinding diseases. The retinal pigment epithelium (RPE) is a monolayer of cells essential for normal ocular development and in the mature retina provides support for overlying photoreceptors and their vascular supply. Hypoxia at the level of the RPE is closely implicated in pathogenesis of age-related macular degeneration. Adaptive tissue responses to hypoxia are orchestrated by sophisticated oxygen sensing mechanisms. In particular, the von Hippel-Lindau tumour suppressor protein (pVhl) controls hypoxia-inducible transcription factor (HIF)-mediated adaptation. However, the role of Vhl/Hif1a in the RPE in the development of the eye and its vasculature is unknown. In this study we explored the function of Vhl and Hif1a in the developing RPE using a tissue-specific conditional-knockout approach. We found that deletion of Vhl in the RPE results in RPE apoptosis, aniridia and microphthalmia. Increased levels of Hif1a, Hif2a, Epo and Vegf are associated with a highly disorganised retinal vasculature, chorioretinal anastomoses and the persistence of embryonic vascular structures into adulthood. Additional inactivation of Hif1a in the RPE rescues the RPE morphology, aniridia, microphthalmia and anterior vasoproliferation, but does not rescue retinal vasoproliferation. These data demonstrate that Vhl-dependent regulation of Hif1a in the RPE is essential for normal RPE and iris development, ocular growth and vascular development in the anterior chamber, whereas Vhl-dependent regulation of other downstream pathways is crucial for normal development and maintenance of the retinal vasculature.
In vitro generation of mature dopamine neurons by decreasing and delaying the expression of exogenous Nurr1
Authors: Park Chang-Hwan , Lim Mi-Sun , Rhee Yong-Hee , Yi Sang-Hoon , Kim Boe-Kyoung , Shim Jae-Won , Kim Yong Ho , Jung Sung Jun , Lee Sang-Hun
Published: May 2012

Neural stem/progenitor cell (NSC/NPC) cultures can be a source of dopamine (DA) neurons for experimental and transplantation purposes. Nurr1, a steroid receptor transcription factor, can overcome the limitations associated with differentiation of cultured NPCs into DA neurons. However, forced Nurr1 expression in NPC cultures generates non-neuronal and/or immature DA cells. We show here that the Nurr1 level and period of expression crucially affect the differentiation and maturation of Nurr1-induced DA neurons. Mature DA neurons were generated by manipulating Nurr1 expression patterns to resemble those in the developing midbrain.
Hyperproliferation of mitotically active germ cells due to defective anti-Müllerian hormone signaling mediates sex reversal in medaka
Authors: Nakamura Shuhei , Watakabe Ikuko , Nishimura Toshiya , Picard Jean-Yves , Toyoda Atsushi , Taniguchi Yoshihito , di Clemente Nathalie , Tanaka Minoru
Published: May 2012

The function of AMH (Anti-Müllerian hormone), a phylogenetically ancient member of the TGFβ family of proteins, in lower vertebrates is largely unknown. Previously, we have shown that the gene encoding the type II anti-Müllerian hormone receptor, amhrII, is responsible for excessive germ cell proliferation and male-to-female sex reversal in the medaka hotei mutant. In this study, functional analyses in cultured cells and of other amhrII mutant alleles indicate that lack of AMH signaling causes the hotei phenotype. BrdU incorporation experiments identified the existence of both quiescent and mitotically active germ cells among the self-renewing, type I population of germ cells in the developing gonad. AMH signaling acts in supporting cells to promote the proliferation of mitotically active germ cells but does not trigger quiescent germ cells to proliferate in the developing gonad. Furthermore, we show that the male-to-female sex reversal phenotype in hotei mutants is not a direct consequence of AMH signaling in supporting cells, but is instead mediated by germ cells. Our data demonstrate that interfollicular AMH signaling regulates proliferation at a specific stage of germ cell development, and that this regulation is crucial for the proper manifestation of gonadal sex directed by sex determination genes.
Distinct developmental origins and regulatory mechanisms for GABAergic neurons associated with dopaminergic nuclei in the ventral mesodiencephalic region
Authors: Achim Kaia , Peltopuro Paula , Lahti Laura , Li James , Salminen Marjo , Partanen Juha
Published: May 2012

GABAergic neurons in the ventral mesodiencephalic region are highly important for the function of dopaminergic pathways that regulate multiple aspects of behavior. However, development of these neurons is poorly understood. We recently showed that molecular regulation of differentiation of the GABAergic neurons associated with the dopaminergic nuclei in the ventral midbrain (VTA and SNpr) is distinct from the rest of midbrain, but the reason for this difference remained elusive. Here, we have analyzed the developmental origin of the VTA and SNpr GABAergic neurons by genetic fate mapping. We demonstrate that the majority of these GABAergic neurons originate outside the midbrain, from rhombomere 1, and move into the ventral midbrain only as postmitotic neuronal precursors. We further show that Gata2, Gata3 and Tal1 define a subpopulation of GABAergic precursors in ventral rhombomere 1. A failure in GABAergic neuron differentiation in this region correlates with loss of VTA and SNpr GABAergic neurons in Tal1 mutant mice. In contrast to midbrain, GABAergic neurons of the anterior SNpr in the diencephalon are not derived from the rhombomere 1. These results suggest unique migratory pathways for the precursors of important GABAergic neuron subpopulations, and provide the basis for understanding diversity within midbrain GABAergic neurons.
Development of Biosensing Devices and Systems Using Micro/Nanoelectrodes
Authors: Matsue Tomokazu
Published: May 2012

This article presents an overview of the recent progress made by our group in the development of bioelectrochemical devices and systems. The topics include intra- and extracellular measurements for the characterization of cellular functions, scanning electrochemical microscopy (SECM) with a probe-type micro/nanoelectrode, characterization of localized enzymes and membranes with SECM, characterization of live cells with SECM, high-resolution SECM systems for biological applications, cellular chips and devices for biosensing, cellular devices based on detection of gene expression, addressable micro/nanoelectrode arrays for multipoint measurements, and bioimaging microfluidic devices and dielectrophoretic devices with microelectrodes.
α-MoO3 Hollow Nanospheres as an Anode Material for Li-Ion Batteries
Authors: Sasidharan Manickam , Gunawardhana Nanda , Noma Hiroaki , Yoshio Masaki , Nakashima Kenichi
Published: May 2012

α-MoO3 hollow nanospheres have been synthesized using a soft template of polymeric micelles with core–shell–corona architecture. Poly(styrene-block-[3-(methacryloylamino)propyl]trimethylammonium chloride-block-ethylene oxide) micelles (PS–PMAPTAC–PEO) with cationic shell block effectively produce core/shell composite particles through electrostatic interaction with anionic MoO42− precursor. Transmission electron microscope (TEM) images of α-MoO3 have confirmed the hollow structure with an average outer diameter of 42 ± 2; the hollow cavity diameter was found to be 23 ± 1 nm. The molybdenum trioxide hollow nanospheres were investigated as anode materials for lithium intercalation in a Li-ion battery (LIBs). The nanostructured electrode delivers high discharge capacity of 263 mA h g−1 for the first cycle at a rate of 0.3 C. The capacity retention of MoO3 hollow nanospheres is 2.2 times higher than that of dense MoO3 particles. Interestingly, the hollow particle based electrodes maintain structural integrity even after subjecting to a high current density 2000 mA g−1 (10 C) and show good electrode stability vis-à-vis cycling performance. The enhanced electrochemical behavior is attributed to hollow particles with thin shell domain that facilitates fast lithium diffusion kinetics.
Collective Interactions of Molecules with an Interfacial Solid
Authors: Kaneko Katsumi , Itoh Tsutomu , Fujimori Toshihiko
Published: May 2012

Confinement of molecules in nanoscale pores of an interfacial solid such as single wall carbon nanotubes of which all component carbon atoms are exposed to the interface with gas phase induces collective phenomena; the confinement effect is interpreted by the interaction potential theory. The nanoconfinement effect gives rise to in-pore phase anomalies for NO, H2O, CCl4, superhigh-pressure effect, hydrophobic to hydrophilic transformation for carbon, and a marked quantum molecular sieving. The confinement of KI in the nanotube space below 0.1 MPa produces high-pressure-phase KI above 1.9 GPa. Water molecules gain hydrophilicity with cluster formation in order to accommodate in the hydrophobic carbon spaces. The subnanometer quantum fluctuation for H2 and D2 gives rise to a marked quantum molecular sieving effect in nanoscale pores. The Cu-based porous coordination polymer crystals can detect the surrounding stimuli such as CO2 pressure change to vary the crystal lattice, accompanying gate adsorption.
Synthesis of π-Conjugated Two Generation Dendrimer Composed of p-Phenylenevinylene Dendron and Triphenylamine Surface Group
Authors: Mizusaki Masanobu , Yamada Yuichiro , Obara Satoru , Tada Kentaro
Published: May 2012

π-Conjugated two generation dendrimer composed of p-phenylenevinylene dendron and triphenylamine surface group was synthesized via a convergent route. The dendrimer shows high solubility in organic solvents and fluorescence emission resulting from the p-phenylenevinylene site.
Nonadditive Substituent Effects on Expanding Prestrained C–C Bond in Crystal: X-ray Analyses on Unsymmetrically Substituted Tetraarylpyracenes Prepared by a Flow Microreactor Method
Authors: Suzuki Takanori , Uchimura Yasuto , Ishigaki Yusuke , Takeda Takashi , Katoono Ryo , Kawai Hidetoshi , Fujiwara Kenshu , Nagaki Aiichiro , Yoshida Jun-ichi
Published: May 2012

Based on space integration using a flow microreactor system, the title unsymmetrically substituted pyracenes with an extremely long C–C bond [1.714(2)–1.739(4) Å] are readily accessible, whose structures demonstrate nonadditive substituent effects on expanding the polyarylated C1–C2 bond in crystal. The bond lengths rather exhibit correlation with the eclipsing degree of the Csp3–Csp3 bond, which is more affected by the intermolecular factors such as crystal packing.