bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation
Authors: Hupp Sabrina , Ribes Sandra , Seele Jana , Bischoff Carolin , Förtsch Christina , Maier Elke , Benz Roland , Mitchell Timothy J , Nau Roland , Iliev Asparouh I
Published: September 2017

Background and Purpose

Streptococcus pneumoniae is the most common cause of bacterial meningitis in adults and is characterized by high lethality and substantial cognitive disabilities in survivors. Here, we have studied the capacity of an established therapeutic agent, magnesium, to improve survival in pneumococcal meningitis by modulating the neurological effects of the major pneumococcal pathogenic factor, pneumolysin.

Experimental Approach

We used mixed primary glial and acute brain slice cultures, pneumolysin injection in infant rats, a mouse meningitis model and complementary approaches such as Western blot, a black lipid bilayer conductance assay and live imaging of primary glial cells.

Key Results

Treatment with therapeutic concentrations of magnesium chloride (500 mg·kg−1 in animals and 2 mM in cultures) prevented pneumolysin‐induced brain swelling and tissue remodelling both in brain slices and in animal models. In contrast to other divalent ions, which diminish the membrane binding of pneumolysin in non‐therapeutic concentrations, magnesium delayed toxin‐driven pore formation without affecting its membrane binding or the conductance profile of its pores. Finally, magnesium prolonged the survival and improved clinical condition of mice with pneumococcal meningitis, in the absence of antibiotic treatment.

Conclusions and Implications

Magnesium is a well‐established and safe therapeutic agent that has demonstrated capacity for attenuating pneumolysin‐triggered pathogenic effects on the brain. The improved animal survival and clinical condition in the meningitis model identifies magnesium as a promising candidate for adjunctive treatment of pneumococcal meningitis, together with antibiotic therapy.
INNER‐CITY REVITALIZATION IN CANADA: A VANCOUVER CASE STUDY
Authors: LEY DAVID
Published: September 2017

The phenomenon of inner‐city revitalization has recently stimulated attention in a number of advanced nations. The argument is extended to the Canadian city through a discussion of the housing market in Vancouver's inner neighbourhoods. The problem of the erosion of modestly priced accommodation in the inner city is emphasized, suggesting that present trends may reinstitute a zone of privilege adjacent to the downtown core, substantially modifying the residential morphology and land use models inherited from the industrial city.

Le phénomène de la revivification de l' intérieur urbain, depuis peu, attire l'attention dans certains pays avancés. L'exposé en vient au case de la ville canadienne par une discussion du marché de l'habitation des quartiers centraux de Vancouver. Le problème de l'érosion du logement de prix abordable est mis en relief. Les tendances actuelles se mblent évoluer vers le rétablissement d'une zone privilégiée adjacente au centre ville, modifiant sensiblement la morphologie résidentielle et les modéles d'utilisation du sol hérités de la ville industrielle.
Memory and Executive Functioning in 12‐Year‐Old Children With a History of Institutional Rearing
Authors: Bick Johanna , Zeanah Charles H. , Fox Nathan A. , Nelson Charles A.
Published: September 2017

We examined visual recognition memory and executive functioning (spatial working memory [SWM], spatial planning, rule learning, and attention shifting) in 12‐year‐olds (n = 150) who participated in the Bucharest Early Intervention Project, a randomized controlled trial of foster care for institutionally reared children. Similar to prior reports at 8 years of age, institutionally reared children showed significant deficits in visual recognition memory and SWM. Deficits in attention shifting and rule learning were also apparent at this time point. These data suggest that early experiences continue to shape the development of memory, learning, and executive functioning processes in preadolescence, which may explain broader cognitive and learning difficulties commonly associated with severe early life neglect.
Meta‐analysis of accuracy of intraocular lens power calculation formulas in short eyes
Authors: Wang Qiwei , Jiang Wu , Lin Tiao , Wu Xiaohang , Lin Haotian , Chen Weirong
Published: September 2017

Importance

Intraocular lens (IOL) power selection is a critical factor affecting visual outcome after IOL implantation in short eyes. Many formulas have been developed to achieve a precise prediction of the IOL power. However, controversy regarding the accuracy remains.

Background

To investigate the accuracy of different IOL power calculation formulas in short eyes.

Design

Meta‐analysis.

Participants

Patients with the axial length of eyes less than 22 mm from previously reported studies.

Methods

A comprehensive search in Pubmed, EMBASE, Cochrane Data Base of Systematic Reviews and the Cochrane Central Register of Controlled Trials was conducted by October 2016. We assessed the methodological quality using a modified QUADAS‐2 tool and performed analysis on weighted mean differences of mean absolute errors (MAE) among different formulas.

Main Outcomes Measures

The between‐group difference of MAE was evaluated with weighted mean difference and 95% confidence intervals.

Results

Ten observational studies, involving 1161 eyes, were enrolled to compare six formulas: Haigis, Holladay 2, Hoffer Q, Holladay 1, SRK/T and SRK II. Among them, the Holladay 2 introduced the smallest overall MAE (0.496D) without statistical significance. The difference of MAE is statistically significant between Haigis and Hoffer Q (mean difference = −0.07D, P = 0.003), Haigis and SRK/T (mean difference = −0.07D, P = 0.009), Haigis and SRK II (mean difference = −0.41D, P = 0.01). For publication bias and small‐study effect, neither funnel plot nor egger's test detected statistical finding.

Conclusion and Relevance

The overall evidence from the studies confirmed the superiority of Haigis over Hoffer Q, SRK/T and SRK II in prediction IOL power in short eyes.
The Translational Science Benefits Model: A New Framework for Assessing the Health and Societal Benefits of Clinical and Translational Sciences
Authors: Luke Douglas A. , Sarli Cathy C. , Suiter Amy M. , Carothers Bobbi J. , Combs Todd B. , Allen Jae L. , Beers Courtney E. , Evanoff Bradley A.
Published: September 2017

We report the development of the Translational Science Benefits Model (TSBM), a framework designed to support institutional assessment of clinical and translational research outcomes to measure clinical and community health impacts beyond bibliometric measures. The TSBM includes 30 specific and potentially measurable indicators that reflect benefits that accrue from clinical and translational science research such as products, system characteristics, or activities. Development of the TSBM was based on literature review, a modified Delphi method, and in‐house expert panel feedback. Three case studies illustrate the feasibility and face validity of the TSBM for identification of clinical and community health impacts that result from translational science activities. Future plans for the TSBM include further pilot testing and a resource library that will be freely available for evaluators, translational scientists, and academic institutions who wish to implement the TSBM framework in their own evaluation efforts.
Impact of cardiac resynchronization therapy on mitral valve apparatus geometry and clinical outcomes in patients with secondary mitral regurgitation
Authors: Mihos Christos G. , Yucel Evin , Capoulade Romain , Orencole Mary P. , Upadhyay Gaurav A. , Santana Orlando , Singh Jagmeet P. , Picard Michael H.
Published: September 2017

Background

Cardiac resynchronization therapy (CRT) may improve secondary mitral regurgitation (MR) in patients with cardiomyopathy. The effects on mitral valve (MV) and left ventricular (LV) geometry, however, have not been clearly defined.

Methods

Between 2009 and 2012, 229 CRT implants were performed at a single academic center. Seventy‐one had ≥mild MR at baseline and serial echocardiography, without subsequent MV intervention. The pre‐CRT and follow‐up echocardiograms were retrospectively reviewed for (1) MV and LV geometry measurements; (2) MR grade; and (3) LV remodeling indices.

Results

The mean age was 67 ± 15 years, and the cardiomyopathy was ischemic in 37 (52%). At a mean follow‐up of 4.0 ± 1.9 years, there were significant improvements in LV ejection fraction and size, MR grade, MV tenting area and anterior leaflet tethering angle, and end‐systolic interpapillary muscle distance (IPMD), and reductions in moderate‐to‐severe or severe MR (27% vs 15%; P = .04) and New York Heart Association functional class III/IV symptoms (83% vs 41%; P < .001). Multivariable analysis revealed the pre‐CRT MV tenting height (OR 1.25, 95% CI 1.01–1.56; P = .04) and end‐systolic IPMD (OR 1.14, 95% CI 0.99–1.32; P = .08) as independently associated with moderate or greater MR at follow‐up. Finally, at 5 years post‐CRT implantation, the estimated survival and freedom from LV assist device or cardiac transplantation was 61%.

Conclusions

CRT results in favorable effects on MV and LV geometry and decreases the prevalence of moderate‐to‐severe or severe MR and heart failure symptoms. The pre‐CRT MV tenting height and IPMD are independently associated with persistent MR at follow‐up.
The epidemiology of mandibular fractures in Caracas, Venezuela: Incidence and its combination patterns
Authors: Amarista Rojas Félix J. , Bordoy Soto María A. , Cachazo Morelba , Dopazo Juan R. , Vélez Henrique
Published: September 2017

Background/Aim

As reported in the literature by several authors, there is a great variation between countries in terms of etiology and patterns of mandibular fractures. The aim of this study was to determine the incidence of mandibular fractures at the Oral and Maxillofacial Surgery Unit, “Dr. Domingo Luciani” Hospital, Venezuela, during the period January 2010 to March 2013.

Materials and Methods

A retrospective study was conducted to assess the etiology of trauma, age group, gender, anatomic distribution of injury, and combination patterns by reviewing patients records.

Results

There were 334 patients with 522 mandibular fractures averaging 1.56 fractures per patient. Eighty‐five percent of the patients were males with an overall male: female ratio of 6.15:1. The highest occurrence of trauma was in the 20–29 years (43.4%) age group. The etiology most frequently observed was motorcycle traffic accidents in 94 patients (28.1%), and the parasymphysis region was the most common location with 144 (27.6%) fractures. Almost half (48.8%) of the injuries were combined mandibular fractures with 29 different combinations, and the most common was a mandibular body fracture + parasymphysis fracture (22.1%).

Conclusion

Mandibular fracture is a common facial injury with variable incidence and etiology across gender and age range. The findings of this study are similar to other studies and provide important clinical information that will assist in the treatment planning of these types of injuries.
Oral‐maxillofacial trauma of a geriatric population in a super‐ageing country
Authors: Ito Ryohei , Kubota Kosei , Inui Akinari , Nakagawa Hiroshi , Kon Takao , Narita Norihiko , Tamura Yoshihiro , Oyama Toshiaki , Satake Anna , Furudate Ken , Kobayashi Wataru
Published: September 2017

Background/Aim

World population has been ageing, and oral‐maxillofacial trauma of geriatric population is expected to increase. The aim of this study was to analyse the characteristic features of oral‐maxillofacial trauma in the geriatric population.

Materials and Methods

Data from 127 patients aged 65 years old or older, who were treated for oral‐maxillofacial trauma at the Department of Oral and Maxillofacial Surgery, Hirosaki University, from 2000 to 2014, were retrospectively analysed. The data from 292 patients aged 20‐64 years were used as a comparison.

Results

Oral‐maxillofacial trauma in the geriatric population had been increasing over 15‐year period. The male to female ratio was 1.05:1 in the older group and 2.3:1 in the younger group. In the older group, 117 patients (92.1%) had one or more underlying systemic diseases, and 16 (12.6%) had suffered injuries in association with acute medical disorders. The most common injuries in the older group were bone fractures (46.5%). The ratio of fractures in the older group was lower than in the younger group (69.2%). Trauma in the older group most frequently occurred because of falls from a standing height or lower (52.0%), and the mandible was the most common site of fracture (74.6%). A conservative form of treatment for maxillofacial fractures was most commonly (86.4%) chosen for the older group, whilst surgical treatment was most commonly in the younger group (55.0%).

Conclusion

Oral‐maxillofacial trauma in the geriatric population shows characteristic features in terms of aetiology, patterns and treatment modalities.
Healing of soft tissue lacerations in diabetic‐induced rats
Authors: Alzoubi Fawaz , Joseph Bobby , Andersson Lars
Published: September 2017

Background/Aim

Prevalence and incidence of diabetes are increasing and many dental trauma patients today have diabetes. The implications of delayed wound healing, associated with diabetes mellitus, on oral mucosal wound healing have not been investigated extensively. The aim of this study was to investigate the implications of diabetes mellitus on the cellular, vascular, and fibroblastic changes induced by laceration on the oral mucosa of Wistar rats.

Materials and Methods

Sixteen female Wistar rats were randomly assigned into two groups: 1. Experimental Streptozotocin‐induced diabetic group (8 rats). 2. Control group (8 rats). A standardized laceration injury was induced from the corner of the mouth to the mid‐check penetrating through dermal and oral mucosal contaminated by saliva. Samples were taken from the rats after sacrificing them on days 1,3,7, and 10. Inflammation was evaluated both qualitatively and quantitatively. Two investigators evaluated samples in a blinded manner.

Results

Histology reports indicated delayed wound healing patterns in diabetic rats through days 1, 3, 7, and 10 when compared to controls. Inflammation was also noted to be consistently present more often in diabetic rats. Furthermore, polymorphonuclear cell count was consistently higher in diabetic rats.

Conclusion

The results suggest that oral mucosa wound healing is delayed in diabetic Wistar rats compared to non‐diabetic rats in terms of wound closure, angiogenesis, and polymorphonuclear cells number. Furthermore, it is also suggested that wound healing is impaired both in the early and late stages of soft tissue wound healing.
Novel mutations in Thai patients with glanzmann thrombasthenia
Authors: Ittiwut Rungnapa , Suchartlikitwong Pintip , Kittikalayawong Yaowaree , Ittiwut Chupong , Prasopsanti Karan , Sosothikul Darintr , Shotelersuk Vorasuk , Suphapeetiporn Kanya
Published: September 2017

Objectives

Glanzmann thrombasthenia (GT) is an autosomal recessive platelet disorder, caused by defects of the platelet integrin αIIbβ3 (GPIIb/IIIa) resulting from pathogenic mutations in either ITGA2B or ITGB3. It is characterized by spontaneous mucocutaneous bleeding. The molecular features of GT in Thailand have not been identified.

This study aimed to determine the clinical and molecular features of unrelated Thai patients with GT.

Methods

Four patients with clinically suspected GT were recruited at the Division of Pediatric Hematology/Oncology, King Chulalongkorn Memorial Hospital. The diagnosis was based on clinical and hematological parameters as well as genetic analysis. Whole exome sequencing (WES) was performed in all cases.

Results

Of the four patients studied, the median age at first suspicion of GT was 2.5 years. All presented with severe bleeding symptoms (WHO bleeding scale 3). Flow cytometry to assess the surface GPIIb/IIIa complex showed reduced expression. By WES, we successfully identified seven mutant alleles in ITGA2B. One alteration, the c.2915dup (p.Leu973Alafs*63), was detected in two unrelated families. One patient was homozygous for the c.617T>A (p.Val206Asp). Of the five different mutations, three have never been previously described. These include a missense, c.617T>A (p.Val206Asp), a deletion, c.1524_1533del (p.Gln508Hisfs*3), and a nonsense, c.2344C>T (p.Arg782Ter).

Conclusion

This study reported three novel mutations expanding the genotypic spectrum of ITGA2B causing GT.
Effect of reduced‐intensity conditioning and the risk of late‐onset non‐infectious pulmonary complications in pediatric patients
Authors: Nagasawa Masayuki , Mitsuiki Noriko , Aoki Yuki , Ono Toshiaki , Isoda Takeshi , Imai Kohsuke , Takagi Masatoshi , Kajiwara Michiko , Kanegane Hirokazu , Morio Tomohiro
Published: September 2017

Objective

Late‐onset non‐infectious pulmonary complications (LONIPCs) contribute to higher morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Therefore, we investigated the risk factors of LONIPCs in pediatric patients.

Method

Between 2001 and 2011, 74 pediatric patients (range, 7 months to 22.7 years old; median 6.5 years old), including 29 with a primary immunodeficiency, underwent 80 allo‐HSCTs at our institution. Sixty‐seven patients who survived more than 3 months after allo‐HSCT were analyzed retrospectively. The median follow‐up period was 1 973 days (range, 126‐5 145 days).

Results

Nine patients (13.4%) developed LONIPCs between 90 and 3 578 days after allo‐HSCT. A myeloablative conditioning (MAC) regimen and chronic GVHD were determined as significant risk factors of LONIPCs. None of 18 patients who received the reduced‐intensity conditioning (RIC) regimen developed LONIPCs, although there was no difference in overall survival between the MAC and RIC regimen. Notably, two immunodeficient patients who received busulfan‐based MAC regimen under 2 years old developed LONIPC with no history of chronic GVHD after 5 years and 10 years from SCT, respectively, suggesting the direct toxicity of busulfan.

Conclusion

Our study's findings indicate that the RIC regimen reduces the risk of LONIPCs in pediatric patients.
Trial‐by‐trial co‐variation of pre‐stimulusEEGalpha power and visuospatial bias reflects a mixture of stochastic and deterministic effects
Authors: Benwell Christopher S. Y. , Keitel Christian , Harvey Monika , Gross Joachim , Thut Gregor
Published: September 2017

Human perception of perithreshold stimuli critically depends on oscillatoryEEGactivity prior to stimulus onset. However, it remains unclear exactly which aspects of perception are shaped by this pre‐stimulus activity and what role stochastic (trial‐by‐trial) variability plays in driving these relationships. We employed a novel jackknife approach to link single‐trial variability in oscillatory activity to psychometric measures from a task that requires judgement of the relative length of two line segments (the landmark task). The results provide evidence that pre‐stimulus alpha fluctuations influence perceptual bias. Importantly, a mediation analysis showed that this relationship is partially driven by long‐term (deterministic) alpha changes over time, highlighting the need to account for sources of trial‐by‐trial variability when interpretingEEGpredictors of perception. These results provide fundamental insight into the nature of the effects of ongoing oscillatory activity on perception. The jackknife approach we implemented may serve to identify and investigate neural signatures of perceptual relevance in more detail.
Homogeneous processing in the striatal direct and indirect pathways: single body part sensitive type IIb neurons may express either dopamine receptor D1 or D2
Authors: Coffey Kevin R. , Nader Miles , Bawa Jasmeet , West Mark O.
Published: September 2017

Striatal medium spiny projection neurons (MSNs) output through two diverging circuits, the ‘direct and indirect pathways’ which originate from minimally overlapping populations of MSNs expressing either the dopamine receptor D1 or the dopamine receptor D2. One modern theory of direct and indirect pathway function proposes that activation of direct pathway MSNs facilitates output of desired motor programs, while activation of indirect pathway MSNs inhibits competing motor programs. A separate theory suggests that coordinated timing or synchrony of the direct and indirect pathways is critical for the execution of refined movements. These hypotheses are made testable by a common type of striatal neuron known as type IIb MSNs. Clusters of these MSNs exhibit phasic increases in firing rate related to sensorimotor activity of single body parts. If these MSNs were to reside in only the direct pathway, evidence would be provided that D1 MSNs are ‘motor program’ specific, which would lend credence to the ‘competing motor programs’ hypothesis. However, if type IIb MSNs reside in both pathways, evidence would be provided for the ‘coordinated timing or synchrony’ hypothesis. Our results show that type IIb neurons may express either D1 or D2. This evidence supports the theory that the coordinated timing or synchrony of the direct and indirect pathways is critical for refined movements. We also propose a model in which the direct and indirect pathways act as a differentiator circuit, providing a possible mechanism by which coordinated activity of D1 and D2 neurons may output meaningful somatosensorimotor information to downstream structures.
The involvement of centralized and distributed processes in sub‐second time interval adaptation: an ERP investigation of apparent motion
Authors: Kaya Utku , Yildirim Fazilet Zeynep , Kafaligonul Hulusi
Published: September 2017

Accumulating evidence suggests that the timing of brief stationary sounds affects visual motion perception. Recent studies have shown that auditory time interval can alter apparent motion perception not only through concurrent stimulation but also through brief adaptation. The adaptation after‐effects for auditory time intervals was found to be similar to those for visual time intervals, suggesting the involvement of a central timing mechanism. To understand the nature of cortical processes underlying such after‐effects, we adapted observers to different time intervals using either brief sounds or visual flashes and examined the evoked activity to the subsequently presented visual apparent motion. Both auditory and visual time interval adaptation led to significant changes in the ERPs elicited by the apparent motion. However, the changes induced by each modality were in the opposite direction. Also, they mainly occurred in different time windows and clustered over distinct scalp sites. The effects of auditory time interval adaptation were centred over parietal and parieto‐central electrodes while the visual adaptation effects were mostly over occipital and parieto‐occipital regions. Moreover, the changes were much more salient when sounds were used during the adaptation phase. Taken together, our findings within the context of visual motion point to auditory dominance in the temporal domain and highlight the distinct nature of the sensory processes involved in auditory and visual time interval adaptation.
Unveiling neural coupling within the sensorimotor system: directionality and nonlinearity
Authors: Yang Yuan , Dewald Julius P. A. , van der Helm Frans C. T. , Schouten Alfred C.
Published: September 2017

Neural coupling between the central nervous system and the periphery is essential for the neural control of movement. Corticomuscular coherence is a popular linear technique to assess synchronised oscillatory activity in the sensorimotor system. This oscillatory coupling originates from ascending somatosensory feedback and descending motor commands. However, corticomuscular coherence cannot separate this bidirectionality. Furthermore, the sensorimotor system is nonlinear, resulting in cross‐frequency coupling. Cross‐frequency oscillations cannot be assessed nor exploited by linear measures. Here, we emphasise the need of novel coupling measures, which provide directionality and acknowledge nonlinearity, to unveil neural coupling in the sensorimotor system. We highlight recent advances in the field and argue that assessing directionality and nonlinearity of neural coupling will break new ground in the study of the control of movement in healthy and neurologically impaired individuals.
Beta‐band oscillations during passive listening to metronome sounds reflect improved timing representation after short‐term musical training in healthy older adults
Authors: Fujioka Takako , Ross Bernhard
Published: September 2017

Sub‐second time intervals in musical rhythms provide predictive cues about future events to performers and listeners through an internalized representation of timing. While the acuity of automatic, sub‐second timing as well as cognitively controlled, supra‐second timing declines with ageing, musical experts are less affected. This study investigated the influence of piano training on temporal processing abilities in older adults using behavioural and neuronal correlates. We hypothesized that neuroplastic changes in beta networks, caused by training in sensorimotor coordination with timing processing, can be assessed even in the absence of movement. Behavioural performance of internal timing stability was assessed with synchronization–continuation finger‐tapping paradigms. Magnetoencephalography (MEG) was recorded from older adults before and after one month of one‐on‐one training. For neural measures of automatic timing processing, we focused on beta oscillations (13–30 Hz) during passive listening to metronome beats. Periodic beta‐band modulations in older adults before training were similar to previous findings in young listeners at a beat interval of 800 ms. After training, behavioural performance for continuation tapping was improved and accompanied by an increased range of beat‐induced beta modulation, compared to participants who did not receive training. Beta changes were observed in the caudate, auditory, sensorimotor and premotor cortices, parietal lobe, cerebellum and medial prefrontal cortex, suggesting that increased resources are involved in timing processing and goal‐oriented monitoring as well as reward‐based sensorimotor learning.
Systolic blood pressure targets, diastolic J curve and cuff artefact in blood pressure measurement: a note of caution
Authors: Spence J. D.
Published: September 2017

Click here to view the accompanying paper in this volume.
Characterization of isolated amyloid myopathy
Authors: Liewluck T. , Milone M.
Published: September 2017

Background and purpose

Amyloid myopathy frequently occurs in the setting of systemic amyloidosis and less commonly in isolation (isolated amyloid myopathy). Anoctaminopathy‐5 and dysferlinopathy were recently recognized as causes of isolated amyloid myopathy. The present study aimed to characterize the isolated amyloid myopathy and to compare it with amyloid myopathy associated with systemic amyloidosis.

Methods

We searched the Muscle Laboratory database to identify patients with pathologically confirmed amyloid myopathy seen in neurology clinics between January 1998 and September 2016. Patients with monoclonal gammopathy, peripheral neuropathy, organomegaly or symptoms or pathologic evidence of amyloid deposition outside skeletal muscle were classified as having systemic amyloidosis‐associated myopathy.

Results

Fifty‐two patients were identified, including 14 with isolated amyloid myopathy (eight anoctaminopathy‐5, two dysferlinopathy and four genetically unknown) and 38 with systemic amyloidosis (32 immunoglobulin light‐chain amyloidosis, four familial amyloid polyneuropathy and two senile systemic amyloidosis). Compared with patients with systemic amyloidosis, patients with isolated amyloid myopathy had a younger age of onset (median, 41.5 vs. 65 years), no dysphagia (0% vs. 26%) or weight loss (0% vs. 26%), but more frequent calf atrophy (57% vs. 0%), small collections of inflammatory cells on muscle biopsy (43% vs. 0%) and asymptomatic hyperCKemia at onset (21% vs. 0%). All patients with isolated amyloid myopathy had creatine kinase (CK) values >2.5 times the upper limit of normal.

Conclusions

Isolated amyloid myopathy accounts for 27% of patients with amyloid myopathy, mostly due to anoctaminopathy‐5. There are various clinical and laboratory parameters that can help to differentiate isolated amyloid myopathy from systemic amyloidosis.
Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta‐analysis
Authors: Iftikhar I. H. , Alghothani L. , Trotti L. M.
Published: September 2017

To synthesize evidence from available randomized controlled trials (RCT) to compare the efficacies of dopaminergic drugs (pramipexole, ropinirole and rotigotine) and α‐2‐δ ligands (gabapentin enacarbil and pregabalin) for the treatment of restless legs syndrome (RLS). We searched PubMed for all eligible RCTs. Network meta‐analysis using frequentist methodology with random effect models was performed for mean changes in scores on the International RLS Study Group Rating Scale (IRLS) and for responder rates on Clinical Global Impressions‐Improvement (CGI‐I); analyzed as odds ratio (OR). Network meta‐analysis of mean changes in IRLS data from 35 studies with 7333 participants showed that all treatments, in specific gabapentin enacarbil, followed by pregabalin and rotigotine were superior to placebo [mean reduction in IRLS scores: −5.31 (−6.74 to −3.87), −5.20 (−6.91 to −3.49), 5.17 (3.73–6.61), respectively] but there were no significant differences between active treatments. Network meta‐analysis of 5137 participants from 24 studies showed that gabapentin enacarbil and rotigotine were associated with the highest CGI‐I response rates [ORs: 5.68; (95% CI, 4.14–7.21); and 4.68 (2.87–6.49), compared to placebo, respectively]. No significant inter‐treatment differences exist, except for that between gabapentin enacarbil and ropinirole. Based on IRLS scores and CGI‐I response rates, while gabapentin enacarbil, pregabalin and rotigotine stand out as the most efficacious of all examined drugs, it is noteworthy that no significant inter‐treatment differences exist, except for that between gabapentin enacarbil and ropiniriole (for CGI‐I response rates).
Intravenous thrombolysis for patients with in‐hospital stroke onset: propensity‐matched analysis from the Safe Implementation of Treatments in Stroke‐East registry
Authors: Tsivgoulis G. , Katsanos A. H. , Kadlecová P. , Czlonkowska A. , Kobayashi A. , Brozman M. , Švigelj V. , Csiba L. , Fekete K. , Kõrv J. , Demarin V. , Vilionskis A. , Jatuzis D. , Krespi Y. , Karapanayiotides T. , Giannopoulos S. , Mikulik R.
Published: September 2017

Background and purpose

Recent cross‐sectional study data suggest that intravenous thrombolysis (IVT) in patients with in‐hospital stroke (IHS) onset is associated with unfavorable functional outcomes at hospital discharge and in‐hospital mortality compared to patients with out‐of‐hospital stroke (OHS) onset treated with IVT. We sought to compare outcomes between IVT‐treated patients with IHS and OHS by analysing propensity‐score‐matched data from the Safe Implementation of Treatments in Stroke‐East registry.

Methods

We compared the following outcomes for all propensity‐score‐matched patients: (i) symptomatic intracranial hemorrhage defined with the safe implementation of thrombolysis in stroke‐monitoring study criteria, (ii) favorable functional outcome defined as a modified Rankin Scale (mRS) score of 0–1 at 3 months, (iii) functional independence defined as an mRS score of 0–2 at 3 months and (iv) 3‐month mortality.

Results

Out of a total of 19 077 IVT‐treated patients with acute ischaemic stroke, 196 patients with IHS were matched to 5124 patients with OHS, with no differences in all baseline characteristics (P > 0.1). Patients with IHS had longer door‐to‐needle [90 (interquartile range, IQR, 60–140) vs. 65 (IQR, 47–95) min, P < 0.001] and door‐to‐imaging [40 (IQR, 20–90) vs. 24 (IQR, 15–35) min, P < 0.001] times compared with patients with OHS. No differences were detected in the rates of symptomatic intracranial hemorrhage (1.6% vs. 1.9%, P = 0.756), favorable functional outcome (46.4% vs. 42.3%, P = 0.257), functional independence (60.7% vs. 60.0%, P = 0.447) and mortality (14.3% vs. 15.1%, P = 0.764). The distribution of 3‐month mRS scores was similar in the two groups (P = 0.273).

Conclusions

Our findings underline the safety and efficacy of IVT for IHS. They also underscore the potential of reducing in‐hospital delays for timely tissue plasminogen activator delivery in patients with IHS.
A novel missense mutation in AIFM1 results in axonal polyneuropathy and misassembly of OXPHOS complexes
Authors: Hu B. , Wang M. , Castoro R. , Simmons M. , Dortch R. , Yawn R. , Li J.
Published: September 2017

Background and purpose

Apoptosis‐inducing factor mitochondrion‐associated‐1 (AIFM1) in mitochondria has captured a great deal of attention due to its well‐described function in apoptosis. Mutations in AIFM1 have resulted in multiple clinical phenotypes, including X‐linked Charcot–Marie–Tooth disease type 4. These syndromes usually involve multiple locations within the nervous system and/or multiple organs. This study describes a novel missense mutation in AIFM1 and its associated peripheral nerve disease.

Methods

Patients with AIFM1 mutation were characterized clinically, electrophysiologically, genetically and by magnetic resonance imaging. The fibroblasts were isolated from the patients to study mitochondrial OXPHOS complexes.

Results

We identified a family with a novel missense mutation (Phe210Leu) in AIFM1 who developed an isolated late‐onset axonal polyneuropathy in which the central nervous system and other organs were spared. Interestingly, this Phe210Leu mutation resulted in abnormal assembly of mitochondrial complex I and III, and failed to disrupt AIFM1 binding with mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the patients’ cells. Deficiency of either AIFM1 or MIA40 is known to impair the assembly of mitochondrial complex I and IV. However, levels of both AIFM1 and MIA40 were unchanged.

Conclusions

Phe210Leu mutation in AIFM1 induces an axonal polyneuropathy that might be contributed by the misassembly of mitochondrial complex I and III. This misassembly appears to be independent of the traditional mechanism via AIFM1/MIA40 deficiency.
CD8+ lineage dendritic cells determine adaptive immune responses to inflammasome activation upon sterile skin injury
Authors: Chakraborty Rituparna , Chandra Janin , Cui Shuai , Tolley Lynn , Cooper Matthew A. , Kendall Mark , Frazer Ian H.
Published: September 2017

The molecular links between sterile inflammation and induction of adaptive immunity have not been fully identified. Here, we examine how damage‐associated molecular patterns (DAMPs), as opposed to pathogen‐associated molecules (PAMPs), regulate the immune response to non–self‐antigens presented at the site of a physical injury. Heat applied briefly to the skin invokes sterile inflammation, characterized by local cell death and caspase‐1 activation without demonstrably disrupting skin integrity. Co‐delivery of ovalbumin (OVA) with heat injury induces OVA‐specific CD8+ T‐cell responses, and this is dependent on caspase‐1 activation and MyD88 signalling. Using Id2flox/flox‐CD11cCre+ mice, we demonstrate that CD8+ lineage DCs are required to induce OVA‐specific CD8+ T‐cell responses following heat injury. Consistent with this observation, intradermal administration of CD8+ lineage DCs but not CD11b+ lineage DCs restores priming of CD8+ T‐cell responses in Casp‐1−/− mice. Thus, we conclude that a sterile injury induces CD8+ T‐cell immune responses to local antigen through caspase‐1 activation and requires CD8+ lineage DCs, a finding of significance for immunotherapy and for the pathogenesis of autoimmunity.
House dust mite allergens Der f and Der p induce IL‐31 production by blood‐derived T cells from atopic dermatitis patients
Authors: Szegedi Krisztina , van Lier Amanda , Res Pieter C. , Chielie Saskia , Bos Jan D. , Kezic Sanja , Middelkamp‐Hup Maritza A. , Luiten Rosalie M.
Published: September 2017

Aero‐allergens, such as house dust mite (HDM), have been suggested to play a role in the initiation of atopic dermatitis (AD)‐related skin inflammation. Here, we analysed the proliferation and the cytokine expression of blood‐derived T cells from AD and healthy individuals upon HDM‐allergen stimulation. The proliferating cells from healthy individuals and AD patients had a significantly different, distinct cytokine profile: in AD blood, we found increased frequencies of HDM‐reactive IL‐31‐producing T cells, as well as a decreased Th1/Th2 and Tc1/Tc2 ratio, suggesting that allergen‐specific T cells in blood of chronic AD patients are subject to pre‐existent Th2‐Tc2 and “Th31‐Tc31” programming.
Evidence for a contributory role of a xenogeneic immune response in experimental epidermolysis bullosa acquisita
Authors: Niebuhr Markus , Kasperkiewicz Michael , Maass Sebastian , Hauenschild Eva , Bieber Katja , Ludwig Ralf J. , Westermann Jürgen , Kalies Kathrin
Published: September 2017

Autoimmune diseases affect a large fraction of the population in Western countries. To elucidate the underlying causes, autoantibody transfer‐induced mouse models have been established that greatly contributed to the understanding of the pathophysiology of these diseases. However, the role of a potentially co‐occurring murine xenogeneic immune response to commonly utilized rabbit anti‐mouse IgG remains poorly understood. Using the established rabbit anti‐mouse type VII collagen (COL7) IgG‐induced mouse model of the mucocutaneous blistering disorder epidermolysis bullosa acquisita (EBA), we found in this study a profound T‐ and B‐cell response along with an altered cytokine expression profile in draining lymph nodes of mice injected with the xenogeneic IgG. This was associated with the formation of circulating and skin‐bound mouse anti‐rabbit IgG in wild‐type but not CD154‐deficient or B‐cell‐deficient JHT mice challenged with pathogenic rabbit IgG. Development of EBA skin lesions was attenuated in the two mouse strains lacking a B‐cell response at later observation time points, but was not affected in mice treated with the T‐cell trafficking blocker FTY720. Collectively, our results implicate a host's xenoreactive immune response to rabbit anti‐mouse COL7 IgG, a confounding effect that may contribute to immune complex‐driven inflammation and tissue damage in this antibody transfer‐induced EBA mouse model, especially at later time points. In this regard, it may be recommended to finish the evaluation of results obtained by experiments employing antibody‐transferred mouse models within the first 2 weeks after the pathogenic antibody injection.
Human tissue inhibitor of metalloproteinases‐1 improved wound healing in diabetes through its anti‐apoptotic effect
Authors: Lao Guojuan , Ren Meng , Wang Xiaoyi , Zhang Jinglu , Huang Yanrui , Liu Dan , Luo Hengcong , Yang Chuan , Yan Li
Published: September 2017

Impaired wound healing accompanies severe cell apoptosis in diabetic patients. Tissue inhibitor of metalloproteinases‐1 (TIMP‐1) was known to have effects on promoting growth and anti‐apoptosis for cells. We aimed to determine the actual levels of TIMP‐1 and cell apoptosis in: (i) the biopsies of diabetic and non‐diabetic foot tissue and (ii) the human fibroblasts with or without treatments of advanced glycation end‐products (AGEs). Next, we aimed to determine the improved levels of cell apoptosis and wound healing after the treatments of either active protein of TIMP‐1 or in vivo expression of gene therapy vector‐mediated TIMP‐1 in both the human fibroblasts and the animal model of diabetic rats. The levels of TIMP‐1 were significantly reduced in diabetic skin tissues and in AGEs‐treated fibroblasts. Both AGEs‐treated cells were effectively protected from apoptosis by active protein of TIMP‐1 at appropriate dose level. So did the induced in vivo TIMP‐1 expression after gene delivery. Similar effects were also found on the significant improvement of impaired wound healing in diabetic rats. We concluded that TIMP‐1 improved wound healing through its anti‐apoptotic effect. Treatments with either active protein TIMP‐1 or TIMP‐1 gene therapy delivered in local wound sites may be used as a strategy for accelerating diabetic wound healing.
Paracrine crosstalk between endothelial cells and melanocytes through clusterin to inhibit pigmentation
Authors: Kim Misun , Lee Jiun , Park Tae Jun , Kang Hee Young
Published: September 2017

Cutaneous vasculature systems play a role in regulating skin pigmentation. We analysed RNA sequencing data to identify novel antimelanogenic factors secreted from endothelial cells and found that one of the secreted factors, clusterin, is highly expressed by HDMECs. To investigate the paracrine effect of clusterin from HDMECs on the regulation of melanogenesis, HDMECs were infected with clusterin or sh‐clusterin lentivirus and the HDMEC‐derived conditioned media were used to treat normal human melanocytes. It was found that HDMEC‐derived clusterin inhibits melanogenesis through MITF/tyrosinase downregulation. The findings here suggest that HDMECs secrete copious amounts of clusterin and that the clusterin is a factor contributing to the inhibitory effect of endothelial cells on melanogenesis via paracrine crosstalk between endothelial cells and melanocytes.
Atropinic (anticholinergic) burden in antipsychotic‐treated patients
Authors: Montastruc François , Benevent Justine , Touafchia Anthony , Chebane Leila , Araujo Mélanie , Guitton‐Bondon Emmanuelle , Durrieu Geneviève , Arbus Christophe , Schmitt Laurent , Begaud Bernard , Montastruc Jean‐Louis
Published: September 2017

Antipsychotic drugs possess side atropinic (anticholinergic) properties that may induce several adverse drug reactions (ADRs), such as memory loss or cognitive impairment. The aim of this study was to investigate anticholinergic burden in patients treated with antipsychotic drugs. All ADR reports including at least one antipsychotic and registered between 2000 and 2015 in the Midi‐Pyrénées PharmacoVigilance Database were extracted and analyzed using the Anticholinergic Duran's list. The primary objective of this cross‐sectional study was to calculate anticholinergic burden in antipsychotic‐treated patients; the secondary one was to investigate associated factors. Among the 1948 reports, the average number of atropinic drugs per report was 2.4 ± 1.4. At least one atropinic drug was found in 59.4% of reports (1158), in addition to antipsychotic drugs. The mean anticholinergic burden per report was 3.9 ± 2.9. A value ≥3 was found in 61.7% of the reports. A significant association between anticholinergic burden, age, and male gender of patients was found. The mean value of anticholinergic burden remained stable during the study period. This study showed high values of anticholinergic burden in patients receiving antipsychotics. Thus, considering the potential noxious clinical impact of atropinic properties on cognitive functions, an appropriate approach should be used to reduce prescription of antipsychotics with a high anticholinergic burden but also coprescription of other frequently associated atropinic drugs, such as antiparkinsonians, H1 antihistamines, or imipraminic antidepressants in these patients.
Energetic solutions of Rock Sandpipers to harsh winter conditions rely on prey quality
Authors: Ruthrauff Daniel R. , Dekinga Anne , Gill Robert E. , Piersma Theunis
Published: September 2017

Rock SandpipersCalidris ptilocnemishave the most northerly non‐breeding distribution of any shorebird in the Pacific Basin (upper Cook Inlet, Alaska; 61°N, 151°W). In terms of freezing temperatures, persistent winds and pervasive ice, this site is the harshest used by shorebirds during winter. We integrated physiological, metabolic, behavioural and environmental aspects of the non‐breeding ecology of Rock Sandpipers at the northern extent of their range to determine the relative importance of these factors in facilitating their unique non‐breeding ecology. Not surprisingly, estimated daily energetic demands were greatest during January, the coldest period of winter. These estimates were greatest for foraging birds, and exceeded basal metabolic rates by a factor of 6.5, a scope of increase that approaches the maximum sustained rate of energetic output by shorebirds during periods of migration, but far exceeds these periods in duration. We assessed the quality of their primary prey, the bivalveMacoma balthica, to determine the daily foraging duration required by Rock Sandpipers to satisfy such energetic demands. Based on size‐specific estimates ofM. balthicaquality, Rock Sandpipers require over 13 h/day of foraging time in upper Cook Inlet in January, even when feeding on the highest quality prey. This range approaches the average daily duration of mudflat availability in this region (c. 18 h), a maximum value that annually decreases due to the accumulation of shore‐fast ice. Rock Sandpipers are likely to maximize access to foraging sites by following the exposure of ice‐free mudflats across the upper Cook Inlet region and by selecting smaller, higher qualityM. balthicato minimize foraging times. Ultimately, this unusual non‐breeding ecology relies on the high quality of their prey resources. Compared with other sites across their range,M. balthicafrom upper Cook Inlet have relatively light shells, potentially the result of the region's depauperate invertebrate predator community. Given the delicate balance between environmental and prey conditions that currently make Cook Inlet a viable wintering area for Rock Sandpipers, small variations in these variables may affect the suitability of the site in the future.