bluuebunny/crossref_metadata_2025 huggingface dataset:
Acidosis and Catecholamine Evaluation Following Simulated Law Enforcement “Use of Force” Encounters
Authors: Ho Jeffrey D. , Dawes Donald M. , Nelson Rebecca S. , Lundin Erik J. , Ryan Frank J. , Overton Kenneth G. , Zeiders Adam J. , Miner James R.
Published: July 2010

ACADEMIC EMERGENCY MEDICINE 2010; 17:E60–E68 © 2010 by the Society for Academic Emergency Medicine

Objectives:  Law enforcement authorities are often charged with controlling resisting suspects. These encounters sometimes result in the sudden and unexpected death of the suspect. Drug intoxication, excited delirium syndrome, or excessive uses of force are factors that are often blamed, but sometimes the mechanism of these deaths is not fully understood. It is possible that worsening acidosis or excessive catecholamine release play a part. The objective of this study was to determine the effect on markers of acidosis and catecholamines of various tasks intended to simulate common arrest‐related situations.

Methods:  Subjects were assigned to one of five task groups: 1) a 150‐meter sprint and wall hurdle (simulated flight from arrest); 2) 45 seconds of striking a heavy bag (simulated physical resistance); 3) a 10‐second TASER X26 electronic control device exposure; 4) a fleeing and resistance exercise involving a law enforcement dog (K‐9); or 5) an oleoresin capsicum (OC) exposure to the face and neck. Baseline serum pH, lactate, potassium, troponin I, catecholamines, and creatine kinase (CK) were evaluated. Serum catecholamines, pH, lactate, and potassium were sampled immediately after the task and every 2 minutes for 10 minutes posttask. Vital signs were repeated immediately after the task. Serum CK and troponin I were evaluated again at 24 hours posttask.

Results:  Sixty‐six subjects were enrolled; four did not complete their assigned task. One subject lost the intravenous (IV) access after completing the task and did not have data collected, and one subject only received a 5‐second TASER device exposure and was excluded from the study, leaving 12 subjects in each task group. The greatest changes in acidosis markers occurred in the sprint and heavy bag groups. Catecholamines increased the most in the heavy bag group and the sprint group and increased to a lesser degree in the TASER, OC, and K‐9 groups. Only the sprint group showed an increase in CK at 24 hours. There were no elevations in troponin I in any group, nor any clinically important changes in potassium.

Conclusions:  The simulations of physical resistance and fleeing on foot led to the greatest changes in markers of acidosis and catecholamines. These changes may be contributing or causal mechanisms in sudden custodial arrest‐related deaths (ARDs). This initial work may have implications in guiding applications of force for law enforcement authorities (LEAs) when apprehending resisting subjects.
Autophagy pathways activated in response to PDT contribute to cell resistance against ROS damage
Authors: Dewaele Michael , Martinet Wim , Rubio Noemí , Verfaillie Tom , de Witte Peter A. , Piette Jacques , Agostinis Patrizia
Published: July 2010

Reactive oxygen species (ROS) concurrently instigate apoptosis and autophagy pathways, but the link between these processes remains unclear. Because cytotoxic ROS formation is exploited in anticancer therapy, such as in photodynamic therapy (PDT), a better understanding of the complex interplay between autophagy and apoptosis is urgently required. Previously, we reported that ROS generated by PDT with an endoplasmic reticulum (ER)‐associated sensitizer leads to loss of ER‐Ca2+ homeostasis, ER stress and apoptosis. Here we show that PDT prompted Akt‐mTOR (mammalian target of rapamycin) pathway down‐regulation and stimulated macroautophagy (MA) in cancer and normal cells. Overexpression of the antioxidant enzyme glutathione peroxidase‐4 reversed mTOR down‐regulation and blocked MA progression and apoptosis. Attenuating MA using Atg5 knockdown or 3‐methyladenine, reduced clearance of oxidatively damaged proteins and increased apoptosis, thus revealing a cytoprotective role of MA in PDT. Paradoxically, genetic loss of MA improved clearance of oxidized proteins and reduced photokilling. We found that up‐regulation of chaperone‐mediated autophagy (CMA) in unstressed Atg5−/− cells compensated for MA loss and increased cellular resistance to PDT. CMA‐deficient cells were significantly sensitized to photokilling but were protected against the ER stressor thapsigargin. These results disclose a stress‐specific recruitment of autophagy pathways with cytoprotective function and unravel CMA as the dominant defence mechanism against PDT.
Evaluation of a multifaceted social marketing campaign to increase awareness of and screening for oral cancer in African Americans
Authors: Jedele J.M. , Ismail A.I.
Published: July 2010

Jedele JM, Ismail AI. Evaluation of a multifaceted social marketing campaign to increase awareness of and screening for oral cancer in African Americans. Community Dent Oral Epidemiol 2010; 38: 371–382. © 2010 John Wiley & Sons A/S

Abstract –  Objectives:  A 2‐year social marketing media campaign and community education activities were organized to promote screening for oral cancer in a high‐risk population in Detroit/Wayne County, Michigan. Long‐term goals of the campaign were to reduce the oral cancer death rate, increase the proportion of oral cancers detected at an early stage, and increase the proportion of adults who report having been screened. The intermediate goals of the campaign were to increase awareness of oral cancer and of oral cancer screening. This article presents outcomes related to the intermediate goals of the campaign.

Methods:  The intermediate goals of the campaign were assessed by the number of calls to a toll‐free hotline, which media venues led to calls, number of screenings conducted by the free screening clinic, number of precancers and cancers detected, and the number of sessions conducted, organizations involved, and persons participating in the community education program. The costs per screened case and cancers detected were also evaluated. The media campaign promoted screening using billboards, radio and newspaper ads, and a toll‐free hotline. Culturally relevant messages were developed collaboratively with focus groups representing the target audience. Billboards were placed in highly visible locations around Detroit, Michigan. Sixty‐second messages on the impact of oral cancer and that screening is ‘painless and free’ were aired on radio stations popular with the target audience. Ads displaying the hotline were placed in two local newspapers. Callers to the hotline were scheduled for a free screening with a clinic operated by the project. Referral to an oral surgeon was scheduled if a suspicious lesion was found. Free education sessions were also conducted with community‐based organizations. Costs associated with the campaign and hotline were totaled, and the cost per screening and cancer detected were calculated.

Results:  During the campaign, 1327 radio spots aired; 42 billboards were displayed; two newspaper ads were printed; and 242 education sessions were conducted. The hotline received 1783 calls. The majority of callers reported that their call was prompted by a radio ad (57%). The clinic screened 1020 adults and referred 78 for further examination. Three cancers, two precancers, and 12 benign tumors were detected. The total cost associated with the campaign and toll‐free hotline was $795,898.

Conclusions:  A multifaceted social marketing campaign including radio ads, billboards, and education sessions can effectively target a high‐risk population and that given an outlet could result in a significant number of people getting screened at a relatively low cost.
Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies
Authors: Clos Audra L. , Lasagna‐Reeves Cristian A. , Wagner Richard , Kelly Brent , Jackson George R. , Kayed Rakez
Published: July 2010

Please cite this paper as: Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies. Experimental Dermatology 2010; 19: 904–911.

Abstract:  In the skin, amyloidosis can be found with or without systemic disease. Primary cutaneous amyloidosis defines those amyloidoses restricted to the skin without involvement of other systems. Here, we used conformation‐specific antibodies to characterise both fibrillar and oligomeric amyloid aggregates in the skin from patients with cutaneous amyloidosis. Localised cutaneous amyloidosis with different morphology was reproduced in mice by intra‐dermal (i.d.) and subdermal administration of amyloid‐enhancing factor. Moreover, we demonstrated that conformational antibodies were effective in clearing amyloid deposits caused by localised intra‐lesional injections without the necessity of an immune response. Given the accessibility and amyloid localization in this disease, direct i.d. injections of conformational antibodies could be a convenient and direct method for treatment.
Inhibition of TRPV1 for the treatment of sensitive skin
Authors: Kueper Thomas , Krohn Michael , Haustedt Lars Ole , Hatt Hanns , Schmaus Gerhard , Vielhaber Gabriele
Published: July 2010

Please cite this paper as: Inhibition of TRPV1 for the treatment of sensitive skin. Experimental Dermatology 2010; 19: 980–986.

Abstract:  During the past years, the topic sensitive skin became one of the most important fields in dermatology. The tremendous interest is based on several studies showing that about 50% of the population declares to have sensitive skin. The human thermoreceptor hTRPV1 was previously identified to contribute to this skin condition while facilitating neurogenic inflammation leading to hyperalgesia. Furthermore, skin sensitivity towards capsaicin, a natural activator of TRPV1, was shown to correlate with sensitive skin. In a screening campaign based on recombinant HEK293‐cells stably transfected with hTRPV1, the selective antagonist trans‐4‐tert‐butylcyclohexanol was identified. This antagonist is able to inhibit capsaicin‐induced hTRPV1 activation with an IC50 value of 34 ± 5 μm tested in HEK293‐cells as well as in electrophysiological recordings performed in oocytes expressing hTRPV1. Strikingly, in a clinical study with 30 women using topical treatment with o/w emulsions containing 31.6 ppm capsaicin, we were able to show that 0.4% of this inhibitor significantly reduces capsaicin‐induced burning (P < 0.0001) in vivo. Thus trans‐4‐tert‐butylcyclohexanol has the potential as a novel bioactive for the treatment of sensitive skin.
Controls for trout and char migratory/resident behaviour mainly in stream systems above and below waterfalls/barriers: a multidecadal and broad geographical review
Authors: Northcote T. G.
Published: July 2010

Northcote TG. Controls for trout and char migratory/resident behaviour mainly in stream systems above and below waterfalls/barriers: a multidecadal and broad geographical review. Ecology of Freshwater Fish 2010: 19: 487–509. © 2010 John Wiley & Sons A/S

Abstract – Controls for trout and char migratory and resident behaviour in rivers and streams for above and below natural and man‐made waterfalls/barriers are covered in a multi‐decadal (1950–2000) and wide geographical review (North America, UK, Europe, Japan) that includes reference to over 380 publications. These note 53 for rainbow trout, 61 for cutthroat trout, 104 for brown trout, 47 for bull trout, 41 for brook trout, 35 for Dolly Varden and 42 for white‐spotted char, plus a few general contributions of relevance on some. For each of these species, there has been a major increase in relevant decadal publications since the early 1980s, no doubt in large part because of the upsurge in micro‐genetic methodology for DNA and related technology, coupled with a broadening of interest in stream migratory behaviour of salmonids. Main mechanisms for the control of stream migratory versus resident behaviour appear to cover an interplay among both genetic and environmental factors; in some populations and locations, genetic controls seem to be more important than environmental ones, but in others the reverse. Habitat degradation by various human activities and their introductions of non‐native fish species are becoming causes of reduction in abundance of above and below waterfall stream populations for several of these salmonid species.
Spawning dynamics of American shad (Alosa sapidissima) in the St. Lawrence River, Canada–USA
Authors: Maltais E. , Daigle G. , Colbeck G. , Dodson J. J.
Published: July 2010

Maltais E, Daigle G, Colbeck G, Dodson JJ. Spawning dynamics of American shad (Alosa sapidissima) in the St. Lawrence River, Canada–USA. Ecology of Freshwater Fish 2010: 19: 586–594. © 2010 John Wiley & Sons A/S

Abstract –  The most northerly population of American shad (Alosa sapidissima), located in the St. Lawrence River, is considered vulnerable because of low population abundance and limited spawning habitat located at the upstream extent of the population’s anadromous migration. Here, we aimed to establish the temporal and spatial extent of spawning based on a novel hatch‐date analysis of juveniles. Spawning activity lasted from early May to early July. We found that juveniles captured downstream during the summer hatched later in the year than those captured further upstream. As a result, younger juveniles were distributed somewhat further downstream. In addition, we found significant multimodality in hatch‐date distributions at midstream and downstream sampling stations. Together, these results provide evidence that the 2‐month spawning period involved numerous spawning events that progressed in a downstream direction as the season advanced, rather than being restricted to upstream sites over the spawning season.
Mechanical parameters as predictors of performance in alpine World Cup slalom racing
Authors: Supej M. , Kipp R. , Holmberg H.‐C.
Published: July 2010

The aims of the present study were to develop a method for classifying slalom skiing performance and to examine differences in mechanical parameters. Eighteen elite skiers were recorded with three‐dimensional kinematical measurements and thereafter divided into a higher (HP) and lower performance group, using the ratio between the difference in mechanical energy divided by the mass of the skier and section entrance velocity (Δemech/vin). Moreover, the skiers' velocity (v), acceleration (a), center of mass turn radii (RCM) and skis' turn radii (RAMS), ground reaction forces (GRF) and differential specific mechanical energy [diff(emech)] were calculated. v and diff(emech) were different between the performance groups (P<0.001 and <0.05), while no inter‐group differences in RCM, RAMS, a and GRF were observed. A relationship between RAMS and diff(emech) was demonstrated (r=0.58; P<0.001). The highest GRFs were related to the lowest diff(emech) and a was related to GRF (r=−0.60; P<0.001). The Δemech/vin predicted the performance over short course sections. The HP skiers skied with a higher v and a similar range of diff(emech). We suggest that shortest RAMS and the highest GRFs should be reduced in elite slalom in order to increase performance.
Participation and performance trends in ultra‐triathlons from 1985 to 2009
Authors: Knechtle B. , Knechtle P. , Lepers R.
Published: July 2010

We examined the changes in participation and performance trends in ultra‐triathlons, from the Double Iron (7.6 km swimming, 360 km cycling, 84.4 km running) to the Deca Iron (38 km swimming, 1800 km cycling, 422 km running), between 1985 (first year of a Double Iron) and 2009 (25 years). The mean finish rate for all distances and races was 75.8%. Women accounted for ∼8–10% of the ultra‐triathlons starters. For Double and Triple Iron, the number of finishers per year increased, from 17 to 98 and from 7 to 41, respectively. In the Deca Iron, the finishers per race have remained <20 since the first event was held, up to 2009. Concerning World best performances, the men were ∼19% faster than the women in both the Double and Triple Iron, and ∼30% faster in a Deca Iron. With the increasing length of ultra‐triathlons, the best women became relatively slower compared with the best men. Further investigations are required to understand why this gender difference in total performance time increased with the distance in ultra‐triathlons.
Enhanced dopamine function in DISC1‐L100P mutant mice: implications for schizophrenia
Authors: Lipina T. V. , Niwa M. , Jaaro‐Peled H. , Fletcher P. J. , Seeman P. , Sawa A. , Roder J. C.
Published: July 2010

Significant advances have been made in understanding the role of disrupted‐in‐schizophrenia‐1 (DISC1) in the brain and accumulating findings suggest the possible implication of DISC1 in the regulation of dopamine (DA) function. A mutation in the second exon of DISC1 at L100P leads to the development of schizophrenia‐related behavior in mutant mice (DISC1‐L100P). We investigated here the role of DA in the expression of schizophrenia‐related endophenotypes in the DISC1‐L100P genetic mouse model. The mutated DISC1 resulted in facilitation of the psychostimulant effect of amphetamine in DISC1‐L100P mutant mice assessed in the open field and prepulse inhibition (PPI) tests. Biochemical studies detected a 2.1‐fold increase in the proportion of striatal Dreceptors without significant changes in DA releasein vivoin the striatum of DISC1‐L100P mutants in response to the low dose of amphetamine. The D2receptor antagonist haloperidol reversed the hyperactivity, PPI and latent inhibition (LI) deficits and blocked the psychostimulant effect of amphetamine in DISC1‐L100P mutants. Taken together, our findings show the role of DISC1 in D2‐related pathophysiological mechanism of schizophrenia, linking DISC1 with well‐established DA hypothesis of schizophrenia.
Lmo4 in the nucleus accumbens regulates cocaine sensitivity
Authors: Lasek A. W. , Kapfhamer D. , Kharazia V. , Gesch J. , Giorgetti F. , Heberlein U.
Published: July 2010

An estimated 2 million Americans use cocaine, resulting in large personal and societal costs. Discovery of the genetic factors that contribute to cocaine abuse is important for understanding this complex disease. Previously, mutations in the Drosophila LIM‐only (dLmo) gene were identified because of their increased behavioral sensitivity to cocaine. Here we show that the mammalian homolog Lmo4, which is highly expressed in brain regions implicated in drug addiction, plays a similar role in cocaine‐induced behaviors. Mice with a global reduction in Lmo4 levels show increased sensitivity to the locomotor stimulatory effects of cocaine upon chronic cocaine administration. This effect is reproduced with downregulation of Lmo4 in the nucleus accumbens by RNA interference. Thus, Lmo genes play conserved roles in regulating the behavioral effects of cocaine in invertebrate and mammalian models of drug addiction.
Rebound in the incidence of pneumococcal meningitis in northern France: effect of serotype replacement
Authors: Alexandre C , Dubos F , Courouble C , Pruvost I , Varon E ,   the Hospital Network for Evaluating the Management of Common Childhood Diseases, Martinot A
Published: July 2010

Aim:  To determine whether the recent emergence of nonvaccine pneumococcal serotypes has affected the incidence of pneumococcal meningitis in children a few years after the introduction of the heptavalent pneumococcal conjugate vaccine.

Methods:  We conducted a multicentre retrospective cohort study from 2005 to 2008 in all hospitals with paediatric units in northern France. It included all patients <18 years of age who were admitted for laboratory‐confirmed pneumococcal meningitis during the study period. Data were collected from medical files and laboratory records at each hospital and compared with the regional hospital discharge codes. We assessed global and age‐specific incidence rates of pneumococcal meningitis from 2005 through 2008, compared them with those from the prevaccine era (2000–2002) and evaluated pneumococcal serotypes.

Results:  In all, 41 cases were found during the study period. The incidence rate of pneumococcal meningitis varied from 0.8/100 000 children <18 years in 2005 to 1.8/100 000 children in 2008 (2.2‐fold increase, p = 0.06); and from 1.8 to 11.9/100 000 children <2 years (6.5‐fold increase, p = 0.004). This increase was caused by nonvaccine pneumococcal serotypes.

Conclusion:  The incidence of pneumococcal meningitis in infants has rebounded in northern France during the pneumococcal conjugate vaccine programme, with the emergence of nonvaccine pneumococcal serotypes.
Infliximab therapy in children with Crohn’s disease: a one‐year evaluation of efficacy comparing ‘top‐down’ and ‘step‐up’ strategies
Authors: Kim Mi Jin , Lee Jong Seung , Lee Ji Hyuk , Kim Jae Young , Choe Yon Ho
Published: July 2010

Background:  The aim of this study was to evaluate the efficacy of ‘top‐down’ regimens for the treatment of paediatric Crohn’s disease (CD) and to compare it with the effects of ‘step‐up’ treatment.

Methods:  We evaluated patients treated with ‘top‐down’ and ‘step‐up’ regimens at 8 weeks after the initiation of treatment, with 1 year of follow‐up. Of the 29 patients who received infliximab, 11 cases refractory to conventional therapy were categorized as the ‘step‐up’ group; and 18 cases, with moderate to severe CD, were categorized as the ‘top‐down’ group. Treatment efficacy was assessed by Pediatric Crohn’s Disease Activity Index (PCDAI) scores.

Results:  At 8 weeks, remission was achieved in three of 11 patients in the ‘step‐up’ group and 16 of 18 patients in the ‘top‐down’ group. At 1 year, remission was maintained in five of 11 patients and in 15 of 18 patients, in the ‘step‐up’ and ‘top‐down’ groups, respectively. The serum albumin level, erythrocyte sedimentation rate, PCDAI score and perianal fistula status demonstrated significant improvement in the ‘top‐down’ group.

Conclusion:  In paediatric patients with CD, the infliximab ‘top‐down’ strategy resulted in superior outcomes when compared to the ‘step‐up’ strategy for inducing and maintaining remission at 8 weeks and 1 year posttreatment.
Milk of northern Sudanese mothers whose traditional diet is high in carbohydrate contains low docosahexaenoic acid
Authors: Nyuar KB , Min Y , Ghebremeskel K , Khalil AKH , Elbashir MI , Cawford MA
Published: July 2010

Aim:  The suckling neonates and infants are reliant primarily on the mother for optimal supply of docosahexaenoic acid (DHA). The richest source of preformed DHA is cold‐water oily fish. Although there is paucity of data, existing evidence suggest women with restricted access to these foods have low or marginal DHA status. The aim of the study was to investigate milk fatty acids of Sudanese mothers whose traditional diet is high in carbohydrate and low in fat and gain some insight into the provision of DHA to the suckling offspring.

Methods:  Colostrum (n = 26), transitional (n = 20) and mature (n = 14) milk samples were obtained from Northern Sudanese women (NSW) recruited prior to delivery from Ibrahim Malik and Khartoum Teaching Hospitals.

Results:  The arachidonic acid content of the colostrum (0.87 ± 0.28%) and transitional (0.89 ± 0.29%) and mature (0.48 ± 0.12%) milk of the NSW were broadly comparable with published international values. In contrast, the DHA level (colostrum 0.13 ± 0.07%, transitional 0.13 ± 0.06% and mature milk 0.06 ± 0.05%) was very low.

Conclusion:  The study reveals breast milk of NSW, whose traditional diet is almost devoid of fish and fish products, is unlikely to provide sufficient DHA to support optimal postnatal neuro‐visual development.
The Redox State of Albumin and Serious Cardiovascular Incidence in Hemodialysis Patients
Authors: Terawaki Hiroyuki , Takada Yukie , Era Seiichi , Funakoshi Yoichi , Nakayama Keisuke , Nakayama Masaaki , Ogura Makoto , Ito Sadayoshi , Hosoya Tatsuo
Published: July 2010

Human serum albumin is composed of human mercaptoalbumin (HMA) with cysteine residues having reducing powers and oxidized human non‐mercaptoalbumin. The aim of this study is to clarify whether such redox state of albumin (HSA‐redox) influences the incidence of cardiovascular disease (CVD) in chronic kidney disease patients on regular hemodialysis (HD). We measured HSA‐redox using high‐performance liquid chromatography in 86 anuric HD patients. The association between HSA‐redox and incidental CVD events was evaluated. Twenty patients experienced symptomatic CVD events (16 patients died) at the 2‐year follow‐up. The fraction of HMA (f(HMA)) showed a significantly lower value in patients with CVD than that without CVD, in both pre‐HD (36.5 ± 5.8% and 44.6 ± 9.8%, respectively) and post‐HD (57.2 ± 6.2% and 67.2 ± 7.4%, respectively). The adjusted odds ratio (OR) for the incidental CVD event in patients with pre‐HD f(HMA) < 40% was 5.0 (95% CI; 1.2 to 21.3), and that in patients with post‐HD f(HMA) < 60% was 20.6 (3.2 to 134.7). Likewise, the adjusted OR for the CVD death in patients with pre‐HD f(HMA) < 40% was 2.5 (0.6 to 12.5), and that in patients with post‐HD f(HMA) < 60% was 25.6 (2.5 to 262.8). In conclusion, HSA‐redox is closely related to serious CVD incidence and mortality among HD patients.
Platelet Function, Activation and Apoptosis During and After Apheresis
Authors: Bakry Rania , Sayed Douaa , Galal Hanan , Shaker Sanaa
Published: July 2010

Platelets are known to undergo shape change, activation, release reaction and apoptosis/necrosis during processing and storage. Apheresis may have a deleterious impact on platelet achievability and functional integrity. Platelet concentrates from 50 male volunteers obtained by COBE spectra were screened for platelet activation (CD62 and CD154) and apoptosis (phosphatidylserine detected by Annexin V). Donor samples before separation, during apheresis and at the third day of storage were used as baseline donor samples. Platelet aggregation to adenosine diphosphate (ADP) and collagen was performed. There was a statistically significant increase in the expression of activation markers in two different samples (during separation samples and third day samples). Although the increase in Annexin V expression was not so observable, it showed a significant increase also. There was marked decline in the platelet aggregation. The correlations between the values of CD62, CD154 and Annexin V were detected in baseline samples and increased during separation and at the third day of platelets storage. Correlation between values of platelet aggregation to collagen and Annexin V was relevant only in the baseline samples. No other correlations were encountered between platelet aggregation and markers of activation and apoptosis during apheresis and storage. Initial platelet activation induced by apheresis may have an impact on phosphatidylserine expression with no impact on aggregation function of platelets during storage.
Breaking stress of neutron star crust
Authors: Chugunov A. I. , Horowitz C. J.
Published: July 2010

The breaking stress (the maximum of the stress–strain curve) of neutron star crust is important for neutron star physics including pulsar glitches, emission of gravitational waves from static mountains and flares from star quakes. We perform many molecular dynamic simulations of the breaking stress at different coupling parameters (inverse temperatures) and strain rates. We describe our results with the Zhurkov model of strength. We apply this model to estimate the breaking stress for time-scales ∼1 s–1 yr, which are most important for applications, but much longer than can be directly simulated. At these time-scales, the breaking stress depends strongly on the temperature. For coupling parameter Γ≲ 200 matter breaks at very small stress, if it is applied for a few years. This viscoelastic creep can limit the lifetime of mountains on neutron stars. We also suggest an alternative model of time-scale-independent breaking stress, which can be used to estimate an upper limit on the breaking stress.
Structure‐Based In silico Design of aHigh‐Affinity Dipeptide Inhibitor for Novel Protein Drug Target Shikimate Kinase of Mycobacterium tuberculosis
Authors: Kumar Manoj , Verma Shikha , Sharma Sujata , Srinivasan Alagiri , Singh Tej P. , Kaur Punit
Published: July 2010

Tuberculosis remains one of the most dreaded infectious diseases notwithstanding the availability of a number of anti‐tuberculosis drugs. The recent rise of multidrug‐resistant tuberculosis and its association with HIV infection poses a challenging health concern. Therefore, there exists a pressing requirement to identify novel drug targets and develop new anti‐tuberculosis drugs that will be effective against multidrug‐resistant‐tuberculosis. Shikimate kinase is a novel and attractive drug target as it is vital for the survival of Mycobacterium tuberculosis but is absent in mammals. Hence, inhibitors designed against shikimate kinase will be specific to the pathogen and be least harmful to the host. Till date, no drug candidates are available against this target. The crystal structure of Mycobacterium tuberculosis shikimate kinase complexed with shikimate has been used to identify a dipeptide inhibitor using in silico structure‐based design approach. The designed peptidic inhibitor has a predicted binding affinity of 5.5 nm which is 8000 times better than substrate shikimate and 10 times greater than the best suggested inhibitor. It is potent in both the known open and closed LID conformations of target protein. As small peptides are known to be non‐toxic, this inhibitor could be a lead compound for development of specific anti‐tuberculosis drugs.
Mapping the Druggable Allosteric Space of G‐Protein Coupled Receptors: a Fragment‐Based Molecular Dynamics Approach
Authors: Ivetac Anthony , Andrew McCammon J.
Published: July 2010

To address the problem of specificity in G‐protein coupled receptor (GPCR) drug discovery, there has been tremendous recent interest in allosteric drugs that bind at sites topographically distinct from the orthosteric site. Unfortunately, structure‐based drug design of allosteric GPCR ligands has been frustrated by the paucity of structural data for allosteric binding sites, making a strong case for predictive computational methods. In this work, we map the surfaces of the β1 (β1AR) and β2 (β2AR) adrenergic receptor structures to detect a series of five potentially druggable allosteric sites. We employ the FTMAP algorithm to identify ‘hot spots’ with affinity for a variety of organic probe molecules corresponding to drug fragments. Our work is distinguished by an ensemble‐based approach, whereby we map diverse receptor conformations taken from molecular dynamics (MD) simulations totaling approximately 0.5 μs. Our results reveal distinct pockets formed at both solvent‐exposed and lipid‐exposed cavities, which we interpret in light of experimental data and which may constitute novel targets for GPCR drug discovery. This mapping data can now serve to drive a combination of fragment‐based and virtual screening approaches for the discovery of small molecules that bind at these sites and which may offer highly selective therapies.
A Critical Review of Aspirin in the Secondary Prevention of Noncardioembolic Ischaemic Stroke
Authors: Inzitari Domenico , Piccardi Benedetta , Sarti Cristina
Published: July 2010

Both secondary prevention (such as lifestyle modifications, pharmacotherapy or surgery) and an understanding of the influence of risk factors (including the different aetiologic mechanisms of cerebral ischaemia) play a pivotal role in reducing the burden of recurrent stroke. Regarding the types of preventative treatments available, variations exist across all clinical studies, including differences in target populations (including the type of cerebral ischaemia), risk factors, length of follow-up, drop-out rates and outcomes, which makes translating the results of clinical trials to individual patients difficult. However, with such limitations in mind, this critical albeit nonsystematic review, which compared aspirin with other antiplatelets and in combination with other drugs, showed that the benefit from aspirin treatment is consistently shown in ischaemic stroke, while harms are limited. Furthermore, no definite superiority is apparent across different antiplatelet therapies. Dual antiplatelet regimens may expose to a slight but measurable higher risk of haemorrhagic complications, perhaps in selective groups of patients (i.e. those with severe small-vessel disease or in selective racial groups). Based on our analysis, the indication of aspirin as the first-line choice, also recommended by several acknowledged international or national guidelines, may be confirmed. However, the complex nature of patients at risk of recurrent ischaemic stroke necessitates a comprehensive approach, which should be driven by the primary care physician, whose role is central to successful actions for secondary stroke prevention.
The Concept of the Penumbra: can it be Translated to Stroke Management?
Authors: Heiss Wolf-Dieter
Published: July 2010

The ‘penumbra’ is a concept coined in animal experiments suggesting that functionally impaired tissue can survive and recover if sufficient reperfusion is re-established within a limited time period, which depends on the level of residual flow. In an ischaemic territory, irreversible damage progresses over time from the centre of the most severe flow reduction to the periphery with less disturbed perfusion. This centrifugal progression of irreversible tissue damage is characterised by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusion disturbances. Waves of depolarisations, the peri infarct spreading depressions, inducing activation of ion pumps and liberation of excitatory transmitters play an important role in the drastically increased metabolic demand during reduced oxygen supply causing hypoxic tissue changes and lactacidosis, which further damage the tissue. Positron emission tomography allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction, which can be used to identify regions with a critical reduction in these physiologic variables as indicators of penumbra and irreversible damage within ischaemic territories in animal models and patients with stroke. These positron emission tomography methods require arterial blood sampling and due to the complex logistics involved, are limited for routine application. Therefore, newer tracers were developed for the noninvasive detection of irreversible tissue damage (flumazenil) and of hypoxic tissue changes (fluoromisonidazole). As a widely applicable clinical tool, diffusion/perfusion-weighted magnetic resonance imaging is used; the ‘mismatch’ between perfusion and diffusion changes serves as a surrogate marker of the penumbra. However, in comparative studies of magnetic resonance imaging and positron emission tomography, diffusion-weighted imaging showed a high false-positive rate of irreversible damage, and the perfusion-weighted–diffusion-weighted mismatch overestimated the penumbra as defined by positron emission tomography. Advanced analytical procedures of magnetic resonance imaging data may improve the reliability of these surrogate markers but should be validated with quantitative procedures.
Fibromuscular Dysplasia of Cervical and Intracranial Arteries
Authors: Touzé Emmanuel , Oppenheim Catherine , Trystram Denis , Nokam Ghislain , Pasquini Marta , Alamowitch Sonia , Hervé Dominique , Garnier Pierre , Mousseaux Elie , Plouin Pierre-François
Published: July 2010

Fibromuscular dysplasia is an uncommon, segmental, nonatherosclerotic arterial disease of unknown aetiology. The disease primarily affects women and involves intermediate-sized arteries in many areas of the body, including cervical and intracranial arteries. Although often asymptomatic, fibromuscular dysplasia can also be associated with spontaneous dissection, severe stenosis that compromises the distal circulation, or intracranial aneurysm, and is therefore responsible for cerebral ischaemia or subarachnoid haemorrhage. Fibro-muscular dysplasia affects middle and distal portions of the internal carotid and vertebral arteries, and occasionally, intracranial arteries. Several pathological and angiographic patterns exist. The most frequent pathological type is medial fibromuscular dysplasia, which is associated with the ‘string of beads' angiographic pattern. Unifocal lesions are less common and can be associated with several pathological subtypes. The pathophysiology of the disease is widely unknown. Fibromuscular dysplasia may in fact result from various causes and reflect a non-specific response to different insults. The poor knowledge of the natural history and the lack of randomised trials that compared the different treatment options do not allow any satisfactory judgement to be made regarding the need for or the efficacy of any treatment.
Evaluation of Long-Term Upregulation of Calbindin D28K as a Preventive Approach for Ischaemic Stroke
Authors: Freimann Florian B. , Crome Olaf , Shevtsova Zinayida , Bähr Mathias , Kügler Sebastian
Published: July 2010

Buffering of intracellular calcium peaks following an acute ischaemic stroke protects neurons from necrotic and apoptotic cell death. However, the need for on-demand delivery of protective agents due to the short therapeutic window in stroke therapy makes it difficult to apply a calcium-buffering strategy in patients. We investigated the effects of a preventive upregulation of the calcium-binding protein Calbindin D28K as a potential approach for patients at a high risk of ischaemic stroke. We overexpressed Calbindin D28K in the striatal and cortical region in mice using an adeno-associated viral vector (AAV) for 12 weeks, and then assessed neuroprotective effects after MCAO. In contrast to studies showing a neuroprotective effect of shortly induced Calbindin D28K overexpression, we found no increased survival of neurons overexpressing Calbindin D28K for 12 weeks. We suggest that neuronal calcium metabolism adapts to higher Calbindin D28K levels after long-term overexpression. This potentially preventive approach to protect from ischaemic stroke does not have clinical applicability.
The Urico-Ictus Study, a Phase 3 Study of Combined Treatment with Uric Acid and rtPA Administered Intravenously in Acute Ischaemic Stroke Patients within the First 4.5 H of Onset of Symptoms
Authors: Amaro Sergio , Cánovas David , Castellanos Mar , Gállego Jaime , Martí-Fàbregas Joan , Segura Tomás , Chamorro Ángel
Published: July 2010

Rationale

Oxidative stress is a major contributor to brain damage in patients with ischaemic stroke. Uric acid (UA) is a potent endogenous antioxidant molecule. In experimental ischaemia in rats, the exogenous administration of uric acid is neuroprotective and enhances the effect of rtPA. Moreover, in acute stroke patients receiving rtPA within 3 h of stroke onset, the intravenous administration of uric acid is safe, prevents an early decline in uric acid levels and reduces an early increase in oxidative stress markers and in active matrix metalloproteinase nine levels.

Aim

To determine whether the combined treatment with uric acid and rtPA is superior to rtPA alone in terms of clinical efficacy in acute ischaemic stroke patients treated within the first 4.5 h of onset of symptoms.

Study design

Multicentre, interventional, randomised, double-blind and vehicle-controlled efficacy study with parallel assignment (1:1). Estimated enrolment: 420 patients over 3 years, starting in January 2010. Treatment arms included patients will receive a single intravenous infusion of 1 g of UA dissolved in a vehicle (500 ml of 0.1% lithium carbonate and 5% mannitol) ( n = 210) or vehicle alone ( n = 210). Inclusion and exclusion criteria: the study will include patients older than 18 years, treated with rtPA within the first 4.5 h of clinical onset and with a baseline National Institute of Health Stroke Scale score >6 and <25 and a modified Rankin Scale score ≤ 2 before the ischaemic event. Patients with renal insufficiency, gout or asymptomatic hiperuricaemia treated with allopurinol will be excluded.

Study outcomes

The primary outcome measure is the proportion of patients achieving an modified Rankin Scale of 0 to 1 at 3 months after treatment or two in those patients with a prior qualifying modified Rankin Scale of 2. Secondary outcome measures include the final infarction volume measured at 72 h and the proportion of patients with symptomatic intracranial haemorrhage (≥ 4 points of increase in the National Institute of Health Stroke Scale score).
Effect of Strengthening Exercise in Addition to Task-Specific Gait Training after Stroke: a Randomised Trial
Authors: Scianni Aline , Teixeira-Salmela Luci F. , Ada Louise
Published: July 2010

Rationale

Gait deficits contribute considerably to functional disability after stroke, and the regaining of walking ability is a major goal in most stroke rehabilitation programmes. Evidence suggests that muscular strengthening exercises after stroke can improve strength and activity. Additionally, task-related practice performed at high intensities may enhance walking competency in people with stroke. However, there is insufficient evidence to conclude which approach is most effective.

Aim

This study will test the hypothesis that task-specific walking training plus targeted strength training is superior to task-specific walking training alone in improving strength, motor co-ordination, quality of independent walking, and participation in acute stroke patients.

Design

This trial is a prospective, randomised clinical trial. People after stroke who are living at home and attending outpatient clinics will be randomly allocated into either an experimental or a control group. The experimental group will undertake task-specific walking training, plus targeted strength training three times per week over 10 weeks, while the control group will only undertake task-specific walking training. At baseline, after 10 weeks of intervention and 4 weeks after the cessation of the interventions, allocation-blinded researchers will collect outcome measures.

Study outcomes

Primary outcomes will be measured for levels of impairment (strength and co-ordination), activity (quality of walking), and participation (quality of life). Secondary outcomes will be the minimal clinically important differences of lower limb strength, motor co-ordination, and gait speed.
ORIGINAL ARTICLE: The relationship between patients’ perception of the effects of neurofibromatosis type 2 and the domains of the Short Form‐36
Authors: Neary W.J. , Hillier V.F. , Flute T. , Stephens S.D.G. , Ramsden R.T. , Evans D.G.R.
Published: July 2010

Clin. Otolaryngol. 2010, 35, 291–299

Objectives:  To investigate the relationship between those issues concerning quality of life in patients with neurofibromatosis type 2 (NF2) as identified by the closed set NF2 questionnaire and the eight norm‐based measures and the physical component summary (PCS) and mental component summary (MCS) scores of the Short Form‐36 (SF‐36) Questionnaire.

Design:  Postal questionnaire study.

Setting:  Questionnaires sent to subjects’ home addresses.

Participants:  Eighty‐seven adult subjects under the care of the Manchester Multidisciplinary NF2 Clinic were invited to participate.

Main outcome measures:  Sixty‐two (71%) completed sets of closed set NF2 questionnaires and SF‐36 questionnaires were returned.

Results:  Subjects with NF2 scored less than the norm of 50 on both the physical component summary and mental component summary scores and the eight individual norm‐based measures of the Short Form‐36 questionnaire. Correlations (using Kendall’s tau) were examined between patients’ perceptions of their severity of difficulty with the following activities and the eight norm‐based measures and the physical component summary and mental component summary scores of the Short Form‐36 questionnaire: Communicating with spouse/significant other (N = 61). The correlation coefficients were significant at the 0.01 level for the mental component summary score, together with three of the norm‐based scores [vitality (VT), social functioning and role emotional]. Social communication (N = 62). All 10 correlations were significant at the 0.01 or 0.001 level. Balance (N = 59). All 10 correlations were highly significant at the P < 0.001 level. Hearing difficulties (N = 61). All correlations were significant at either the 0.01 level or less apart from the mental component summary score and three of the norm‐based scores (role physical, VT and mental health). Mood change (N = 61). All correlations were significant at the 0.01 level or less, apart from one norm‐based score (role physical).

Conclusions:  The Short Form‐36 questionnaire has allowed us to relate patients’ perceptions of their difficulties, as identified by the closed set NF2 questionnaire, to the physical and mental domains measured by this validated and widely used scale, and has provided further insight into areas of functioning affected by NF2.
Neuromedin U is necessary for normal gastrointestinal motility and is regulated by serotonin
Authors: Nakashima Yoshiki , Ida Takanori , Sato Takahiro , Nakamura Yuki , Takahashi Tomoko , Mori Kenji , Miyazato Mikiya , Kangawa Kenji , Kusukawa Jingo , Kojima Masayasu
Published: July 2010

Neuromedin U (NMU) was originally isolated from porcine spinal cord and shown to be distributed in numerous tissues, including the gastrointestinal tract. However, little is known about the role of NMU in the regulation of gastrointestinal functions. We established a radioimmunoassay system that is exceptionally specific for mouse NMU and found high NMU content in the gastrointestinal tract, particularly in the Auerbach's and Meissner's plexi, suggesting a possible role of NMU in gastrointestinal motility. NMU promoted small intestinal transit, and NMU deficiency resulted in lowered intestinal motility rate and diminished the effect of serotonin‐induced defecation and diarrhea. These results indicate that NMU promotes intestinal transit and maintains intestinal homeostasis.
Insights into the evolution of proglucagon‐derived peptides and receptors in fish and amphibians
Authors: Ng Stephanie Y. L. , Lee Leo T. O. , Chow Billy K. C.
Published: July 2010

Glucagon and the glucagon‐like peptides (GLP‐1 and GLP‐2) share a common evolutionary origin and are triplication products of an ancestral glucagon exon. In mammals, a standard scenario is found where only a single proglucagon‐derived peptide set exists. However, fish and amphibians have either multiple proglucagon genes or exons that are likely resultant of duplication events. Through phylogenetic analysis and examination of their respective functions, the proglucagon ligand‐receptor pairs are believed to have evolved independently before acquiring specificity for one another. This review will provide a comprehensive overview of current knowledge of proglucagon‐derived peptides and receptors, with particular focus on fish and amphibian species.
Phylogenetic aspects of gonadotropin‐inhibitory hormone and its homologs in vertebrates
Authors: Tsutsui Kazuyoshi
Published: July 2010

The decapeptide gonadotropin‐releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion in vertebrates, but a hypothalamic neuropeptide inhibiting gonadotropin secretion was, until recently, unknown in vertebrates. In 2000, we discovered a novel hypothalamic dodecapeptide that inhibits gonadotropin release in quail and termed it gonadotropin‐inhibitory hormone (GnIH). GnIH acts on the pituitary and GnRH neurons in the hypothalamus via a novel G protein‐coupled receptor for GnIH to inhibit gonadal development and maintenance by decreasing gonadotropin release and synthesis. The pineal hormone melatonin is a key factor controlling GnIH neural function. Because GnIH exists and functions in several avian species, GnIH is considered to be a new key neuropeptide controlling avian reproduction. After the discovery of GnIH in birds, the presence of GnIH homologs has been demonstrated in other vertebrates from fish to humans. Interestingly, mammalian GnIH homologs also act to inhibit reproduction by decreasing gonadotropin release in several mammalian species. It is concluded that GnIH and GnIH homologs act to inhibit gonadotropin release in higher vertebrates.