bluuebunny/crossref_metadata_2025 huggingface dataset:
Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: a comprehensive Argentine study of inhibitor risks
Authors: Rossetti L. C. , Szurkalo I. , Radic C. P. , Abelleyro M. M. , Primiani L. , Neme D. , Candela M. , Bianco R. P. , de Tezanos Pinto M. , Larripa I. B. , De Brasi C. D.
Published: March 2013

Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor‐positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe‐HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del‐frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype–specific inhibitor risks [OR; prevalence (CI)] in severe‐HA patients classifying a high‐risk group including multi‐exon deletions [3.66; 55% (19–100)], Inv22 [1.8; 24% (19–100)] and nonsense in FVIII‐LCh [1.2; 21% (7–59)]; an average risk group including single‐exon deletions, indel frameshifts and nonsense‐HCh; and a low‐risk group represented by missense defects [0.14; 3% (0.6–11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor‐predisposing factors related to FVIII product exposure were found in age‐ and F8 genotype–stratified populations of severe‐HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation‐specific inhibitor risks than the HA database and other published series. This case‐specific information will help in designing fitted therapies and follow‐up protocols in Argentina.
The benefits of exercise for patients with haemophilia and recommendations for safe and effective physical activity
Authors: Negrier C. , Seuser A. , Forsyth A. , Lobet S. , Llinas A. , Rosas M. , Heijnen L.
Published: March 2013

Most health care professionals involved in the management of people with haemophilia (PWH) believe that exercise is beneficial and its practice is widely encouraged. This article aims to demonstrate that appropriate exercise (adapted to the special needs of the individual PWH) may be beneficial for all PWH through improved physical, psychosocial and medical status. Based on evidence gathered from the literature, many PWH, particularly those using long‐term prophylaxis or exhibiting a mild/moderate bleeding phenotype, are as active as their healthy peers. PWH experience the same benefits of exercise as the general population, being physically healthier than if sedentary and enjoying a higher quality of life (QoL) through social inclusion and higher self‐esteem. PWH can also gain physically from increased muscle strength, joint health, balance and flexibility achieved through physiotherapy, physical activity, exercise and sport. Conversely, very little data exist on activity levels of PWH in countries with limited resources. However, regarding specific exercise recommendations in PWH, there is a lack of randomized clinical trials, and consequently formal, evidence‐based guidelines have not been produced. Based on published evidence from this review of the literature, together with the clinical experience of the authors, a series of recommendations for the safe participation of PWH in regular physical activities, exercises and sport are now proposed. In summary, we believe that appropriately modified programmes can potentially allow all PWH to experience the physical and psychosocial benefits of being physically active which may ultimately lead to an improved QoL.
Radioactive synovectomy with 90yttrium and 153samarium hydroxyapatite in haemophilic joints: preliminary study on radiation safety
Authors: Thomas S. , Mendes J. D. , Souza S. A. , Lorenzato C. S. , Assi P. E. , Pacheco L. R. L. , Gabriel M. B. , Bordim A. , Gutfilen B. , da Fonseca L. M. B.
Published: March 2013

Most countries still do not achieve 1 IU of factor VIII/capita sufficient for survival. Although primary prophylaxis prevents synovitis, is not universally used. Chronic synovitis is treated with arthroscopy at expense of considerable amount of coagulation factors, and specialized surgeons. Radioactive synovectomy (RS) is a minimally invasive and cost effective alternative to arthroscopy, often considered first the option for persistent synovitis. Even without established causation with cancer, RS is avoided by some, due to this concern. We aim contributing to the understanding of RS safety regarding malignancy, presenting a large number of treated patients, and a single case of cancer. Three centres in Brazil applied RS with 90Yttrium Citrate, 90Yttrium hydroxyapatite or 153Samarium hydroxyapatite in haemophilic joints and performed a survey addressing cancer in these patients. Four hundred and eighty eight patients (ages 3–51) received 1–3 RS (total 842) and follow‐up was 6 months to 9 years. One patient aged 14 years presented Ewing sarcoma, 11 months after RS. The tumour was treated successfully with surgery and chemotherapy. Causality of cancer by RS is improbable in this case. Accordingly, latency here is far below minimum 5–10 years for radio‐induction of solid tumours. Moreover, ES is not a typically radio‐induced tumour, even at high doses. In agreement with others, though recognizing limitations, this study suggests RS is safe regarding cancer induction. Synovitis is a known burden for patients. The decision of making reasonable usage of RS should be outweighed with the risks of leaving synovitis untreated.
Long‐term trends in the composition of aphidophagous coccinellid communities in Central Europe
Authors: Honek Alois , Martinkova Zdenka , Kindlmann Pavel , Ameixa Olga M. C. C. , Dixon Anthony F. G.
Published: March 2013

Coccinellids (Coleoptera: Coccinellidae) provide important ecosystem services as biocontrol agents in contributing to the regulation of key agricultural pests. It is generally accepted that biodiversity of native coccinellid communities has been declining during recent decades. Here, we present the results of a long‐term study of coccinellid communities and report an attempt to determine whether recent changes in land use have affected their composition.

Coccinellids were sampled in cereal crops, on wild herbaceous plants and deciduous trees during two periods (1976–1983 and 2002–2010).

There are similar species‐rich communities of coccinellids on trees and wild herbaceous plants (average numbers of species 3.18 and 3.06, respectively) and a poorer community on cereals (2.63). Only a few species, associated with particular types of vegetation, differed in their absolute abundance in the first and second period. There was no obvious cause of this variation in abundance. Diversity of coccinellid communities was higher in the second than in the first period (Shannon‐Wiener index 1.32 and 1.14 respectively), although the number of individuals was lower (average catch per sampling session 10.0 and 18.6 individuals respectively).

Over the 35 years of this study, the compositions of the communities remained essentially similar with the numbers of particular species more closely correlated in the two periods on cereals (R2 = 0.97) than on herbaceous plants (R2 = 0.74) and trees (R2 = 0.67).
Gastrocnemius Tendon Strain in a Dog Treated With Autologous Mesenchymal Stem Cells and a Custom Orthosis
Authors: Case J. Brad , Palmer Ross , Valdes‐Martinez Alex , Egger Erick L. , Haussler Kevin K.
Published: March 2013

Objective

To report clinical findings and outcome in a dog with gastrocnemius tendon strain treated with autologous mesenchymal stem cells and a custom orthosis.

Study Design

Clinical report.

Animal

A 4‐year‐old spayed female Border Collie.

Methods

Bone‐marrow derived, autologous mesenchymal stem cells were transplanted into the tendon core lesion. A custom, progressive, dynamic orthosis was fit to the tarsus. Serial orthopedic examinations and ultrasonography as well as long‐term force‐plate gait analysis were utilized for follow up.

Results

Lameness subjectively resolved and peak vertical force increased from 43% to 92% of the contralateral pelvic limb. Serial ultrasonographic examinations revealed improved but incomplete restoration of normal linear fiber pattern of the gastrocnemius tendon.

Conclusions

Findings suggest that autologous mesenchymal stem cell transplantation with custom, progressive, dynamic orthosis may be a viable, minimally invasive technique for treatment of calcaneal tendon injuries in dogs.
Chromatin remodelling initiation in spermatids: differences among human males
Authors: de Vries M. , Ramos L. , Lacroix R. , D'Hauwers K. , Hendriks J.C.M. , Kremer J.A.M. , van der Vlag J. , de Boer P.
Published: March 2013

During the last phase of spermatogenesis, called spermiogenesis, the nucleosome‐based chromatin structure is replaced by a protamine‐based DNA packaging. Not much is known about the chromatin remodelling involved in humans and animals. Here, we have investigated initiation of chromatin remodelling over seven probands of which five were diagnosed with non‐obstructive azoospermia (NOA) and two with obstructive azoospermia (OA) (failed vaso‐vasostomy patients with proven fertility prior to vasectomy, Johnsen scores ≥9). Chromatin remodelling was studied evaluating the presence of nucleosomes, histone H3, pre‐protamine 2 and protamine 1. This approach was feasible since the local initiation of nucleosome eviction in the sub acrosomal domain, which was visible in alkaline nuclear spread preparations. The patterns of nucleosome and H3 loss were largely congruent. Nucleus wide incorporation of protamine 1 could already be observed at the late round spermatid stage. Both for nucleosome loss and for protamine 1 incorporation, there was distinct variation within and between probands. This did not relate to the efficiency of sperm production per meiocyte. Pre‐protamine 2 was always confined to the subacrosomal domain, confirming the role of this area in chromatin remodelling.
The prognostic role of the new entity butterfly‐like facial rash and cutaneous findings in patients with crimean congo haemorrhagic fever
Authors: Pancar G.S. , Duygu F. , Kalkan G.
Published: March 2013

Background

Crimean Congo Haemorrhagic Fever (CCHF) is a deadly fever caused by Nairovirus (family Bunyaviridae). It is an important public health problem in hyperendemic regions with a high mortality rate. There have been many studies on cutaneous findings in other viral infections, however, our knowledge is limited regarding CCHF. The aim of this study was to evaluate the cutaneous manifestations of CCHF and their relationship with mortality.

Methods

Patients who were diagnosed CCHF between April 1 and September 1, 2011 were enrolled in this study. Dermatologic examination and laboratory analysis were obtained during hospitalization.

Results

A new entity that is first reported in this study as a butterfly‐like facial rash was recognized in 76 patients (42.9%). It was not correlated with mortality but could coexist with other dermatological signs of CCHF. The major outcome was the increased mortality rate with other cutaneous findings (especially ecchymosis, purpura and petechia) (P < 0.01). While 12 deceased individuals had one or more skin findings, only one patient died without any cutaneous manifestations. Mortality rate was higher in patients with purpura than the patients with pethesia. The statistically significant correlation was observed between cutaneous manifestations and elevation of aspartate aminotransferase (AST) levels (P = 0.009). Platelet levels were lower in patients with cutaneous involvement (P < 0.01). No statistically significant relationship was found between cutaneous findings and alanine aminotransferase (ALT), white blood cell (WBC), Haemoglobin (Hb), creatinine kinase (CK) and lactate dehydrogenase (LDH) levels.

Limitations

Histopathologic examination of facial rash could not be done because of haemostatic failure.

Conclusion

The results of this study confirm that cutaneous findings can be a clue regarding the prognosis of the patients with CCHF. Physicians should be aware that CCHF may present with a butterfly‐like rash on the face.
Water availability and population origin affect the expression of the tradeoff between reproduction and growth in Plantago coronopus
Authors: Hansen C. F. , García M. B. , Ehlers B. K.
Published: March 2013

Investment in reproduction and growth represent a classic tradeoff with implication for life history evolution. The local environment can play a major role in the magnitude and evolutionary consequences of such a tradeoff. Here, we examined the investment in reproductive and vegetative tissue in 40 maternal half‐sib families from four different populations of the herb Plantago coronopus growing in either a dry or wet greenhouse environment. Plants originated from populations with an annual or a perennial life form, with annuals prevailing in drier habitats with greater seasonal variation in both temperature and precipitation. We found that water availability affected the expression of the tradeoff (both phenotypic and genetic) between reproduction and growth, being most accentuated under dry condition. However, populations responded very differently to water treatments. Plants from annual populations showed a similar response to drought condition with little variation among maternal families, suggesting a history of selection favouring genotypes with high allocation to reproduction when water availability is low. Plants from annual populations also expressed the highest level of plasticity. For the perennial populations, one showed a large variation among maternal families in resource allocation and expressed significant negative genetic correlations between reproductive and vegetative biomass under drought. The other perennial population showed less variation in response to treatment and had trait values similar to those of the annuals, although it was significantly less plastic. We stress the importance of considering intraspecific variation in response to environmental change such as drought, as conspecific plants exhibited very different abilities and strategies to respond to high versus low water availability even among geographically close populations.
Late Quaternary climatic vegetational shifts in an ecological transition zone of northern Madagascar: insights from genetic analyses of two endemic rodent species
Authors: Rakotoarisoa J.‐E. , Raheriarisena M. , Goodman S. M.
Published: March 2013

The Loky‐Manambato region, located in northern Madagascar, is a biotically rich contact zone between different forest biomes. Local current forest cover is composed of both humid and dry formations, which show elevational stratification. A recent phylogeographical study of a regional dry forest rodent, Eliurus carletoni (subfamily Nesomyinae), found genetic evidence of forest contractions between 18 750 and 7500 years BP, which based on extrapolation of the pollen subfossil record, was thought to be associated with an expansion of local humid forests. Herein, we conduct a genetic test of this hypothesis and focused on populations on two neighbouring massifs of forest‐dependent rodent species, one associated with low‐elevation dry forests (E. carletoni) and the other with higher elevation humid forests (Eliurus tanala). Using mitochondrial markers and a combination of traditional and coalescent‐based phylogeographical, historical demographic and population genetic methods, we found evidence of historical connections between populations of E. tanala. Adjacent populations of E. carletoni and E. tanala exhibit opposite historical demographic patterns, and for both, evidence suggests that historical demographic events occurred within the last 25 000 years BP. These findings strongly support the proposed late Quaternary shifts in the floristic composition of the Loky‐Manambato region.
Apolipoprotein E ε4 Allele Interacts with Sex and Cognitive Status to Influence All‐Cause and Cause‐Specific Mortality in U.S. Older Adults
Authors: Beydoun May A. , Beydoun Hind A. , Kaufman Jay S. , An Yang , Resnick Susan M. , O'Brien Richard , Ferrucci Luigi , Zonderman Alan B.
Published: March 2013

Objectives

To confirm associations of apolipoprotein E (ApoE) ε4 carrier status, sex, and time‐dependent cognitive status with mortality risk and to investigate these joint effects of these associations in a cohort of community‐dwelling U.S. adults.

Design

Prospective cohort study.

Setting

The Baltimore Longitudinal Study of Aging (BLSA).

Participants

Of 3,047 BLSA participants aged 17 to 98 at first visit (60.1% male), 1,704 with complete ApoE genotype data were included, of whom 1,461 aged 50 and older with one or more visits were eligible.

Measurements

Time to death from all, cardiovascular, and noncardiovascular causes.

Results

Probability of survival was lower for ApoE ε4 carriers, particularly those who were older. A Cox proportional hazards model for all‐cause mortality yielded a hazard ratio (HR) for ApoE ε4 carrier versus noncarriers of 1.31 (95% confidence interval (CI) = 1.02–1.68). This association was also found for cardiovascular mortality. Time‐dependent all‐cause dementia (HR = 1.73, 95% CI = 1.33–2.26) and mild cognitive impairment (HR = 1.95, 95% CI = 1.42–2.67) increased all‐cause mortality risk, associations that were also detected for noncardiovascular mortality. When individuals were free of cognitive impairment, a dose‐response relationship with ε4 alleles was found for all‐cause mortality (HR = 1.40, 95% CI = 0.94–2.07 for 1 ε4; HR = 2.61, 95% CI = 1.12–6.07 for 2 ε4). After onset of Alzheimer's disease (AD), carrying only one ε4 allele resulted in an approximately 77% greater all‐cause mortality risk than in noncarriers. ApoE ε4 carrier status increased all‐cause mortality risk in men and interacted with time‐dependent AD to increase the risk of this outcome (relative excess risk due to interaction = 2.15, 95% CI = 1.22–3.07).

Conclusion

ApoE ε4 carrier status was found to increase all‐cause and cardiovascular mortality risks and interacted with sex and time‐dependent AD status to affect all‐cause mortality.
Scoring of sweat losses in exercised horses – a pilot study
Authors: Zeyner A. , Romanowski K. , Vernunft A. , Harris P. , Kienzle E.
Published: March 2013

Based on a series of exercise tests which included the estimation of sweat losses, this article proposes a novel sweat scoring system for exercising horses. This provides a practical estimate of individual animal exercise‐induced sweat losses, based on visible appearance of sweat on the coat after work, which takes into account the effect of various influencing factors. In terms of accuracy and flexibility, the score seems to provide advantages over estimates based on current general recommendations from reference books. Additional studies are needed to validate this scoring system and its use under more diverse situations.
Soil characteristics determine microhabitat selection of the fossorial amphisbaenian Trogonophis wiegmanni
Authors: Martín J. , López P. , García L. V.
Published: March 2013

Amphisbaenians are reptiles specialized for a fossorial lifestyle, which may limit their opportunities for microhabitat selection in comparison with epigeal reptiles. We hypothesized that, given the fossorial habits of amphisbaenians, a detailed analysis of the physical and chemical properties of the soil may reveal their patterns of habitat use. We investigated microhabitat and soil use by a population of the amphisbaenian Trogonophis wiegmanni from the Chafarinas Islands (North‐West Africa) and compared them with those available in the habitat. Results showed that some soil physical and chemical characteristics determined microhabitat use by T. wiegmanni. Amphisbaenians selected soils that were relatively sandy, basic, carbonated and shallow, having a high cover of medium‐sized rocks, whereas they avoided marine salinized, more acid and deeper heavy‐textured soils (i.e. with percentages of silt comparatively high), and those covered mainly by small rocks. No differences were found between soils with and without influence of seabird colonies, although this was the main driver of soil chemical variations in these Islands. Vegetation cover per se did not seem to have a direct influence on microhabitat use. We discuss how energetic costs of burrowing and the direct and indirect influences of soil chemical properties could explain these patterns of habitat use.
Expression and function of the Transforming Growth Factor‐b system in the human and rat enteric nervous system
Authors: Hagl C. , Schäfer K.‐H. , Hellwig I. , Barrenschee M. , Harde J. , Holtmann M. , Porschek S. , Egberts J.‐H. , Becker T. , Wedel T. , Böttner M.
Published: March 2013

Background

Transforming growth factor‐betas (TGF‐bs) are pleiotropic growth factors exerting neurotrophic functions upon various neuronal populations of the central nervous system. In contrast, the role of TGF‐b isoforms in the enteric nervous system (ENS) is largely unknown. We therefore analyzed the gene expression pattern of the TGF‐b system in the human colon and in rat myenteric plexus, and smooth muscle cell cultures and determined the effect of TGF‐b isoforms on neuronal differentiation.

Methods

Human colonic samples as well as cultured rat myenteric plexus, and smooth muscle cells were assessed for mRNA expression levels of the TGF‐b system (TGF‐b1‐3, TbR‐1‐3) by qPCR. The colonic wall was separated into mucosa and tunica muscularis and enteric ganglia were isolated by laser microdissection (LMD) to allow site‐specific gene expression analysis. Effects of TGF‐b isoforms on neurite outgrowth and branching pattern of cultured myenteric neurons were monitored.

Key Results

mRNA expression of the TGF‐b system was detected in all compartments of the human colonic wall as well as in LMD‐isolated myenteric ganglia. Cultured myenteric neurons and smooth muscle cells of rat intestine also showed mRNA expression of all ligands and receptors. Transforming growth factor‐b2 treatment increased neurite length and branching pattern in cultured myenteric neurons.

Conclusions & Inferences

The TGF‐b system is abundantly expressed in the human and rat ENS arguing for an auto‐/paracrine function of this system on enteric neurons. Transforming growth factor‐b2 promotes neuronal differentiation and plasticity characterizing this molecule as a relevant neurotrophic factor for the ENS.
Inpp4b is a novel negative modulator of osteoclast differentiation and a prognostic locus for human osteoporosis
Authors: Vacher Jean
Published: March 2013

Inositol polyphosphate 4‐phosphatase type II (Inpp4b) is a novel negative modulator of osteoclast differentiation and a prognostic locus for human osteoporosis. This short overview summarizes some of the cellular, molecular, and crosstalk signaling mechanisms that control osteoclast and osteoblast differentiation and activation.
Rules of engagement: distinct functions for the four class I PI3K catalytic isoforms in immunity
Authors: Okkenhaug Klaus
Published: March 2013

Mammalian cells can express up to four different class I phosphatidylinositide 3‐kinase (PI3K) isoforms, each of which is engaged by tyrosine kinases or G protein–coupled receptors (GPCRs) to generate the second messenger signaling molecule PtdIns(3,4,5)P3 (PIP3). The p110α and p110β isoforms are relatively widely expressed, whereas p110γ and p110δ are more highly expressed in cells of the immune system than in other cell types. Nevertheless, each of the four class I PI3Ks have been shown to participate in the orchestration of the signaling events that lead to immune cell development and control of gene expression, skewing toward individual cell lineage subsets and proliferation.
Challenges in the clinical development of PI3K inhibitors
Authors: Massacesi Cristian , di Tomaso Emmanuelle , Fretault Nathalie , Hirawat Samit
Published: March 2013

The PI3K/Akt/mTOR pathway is one of the most frequently dysregulated signaling pathways in cancer and an important target for drug development. PI3K signaling plays a fundamental role in tumorigenesis, governing cell proliferation, survival, motility, and angiogenesis. Activation of the pathway is frequently observed in a variety of tumor types and can occur through several mechanisms. These mechanisms include (but are not limited to) upregulated signaling via the aberrant activation of receptors upstream of PI3K, amplification or gain‐of‐function mutations in the PIK3CA gene encoding the p110α catalytic subunit of PI3K, and inactivation of PTEN through mutation, deletion, or epigenetic silencing. PI3K pathway activation may occur as part of primary tumorigenesis, or as an adaptive response (via molecular alterations or increased phosphorylation of pathway components) that may lead to resistance to anticancer therapies. A range of PI3K inhibitors are being investigated for the treatment of different types of cancer; broad clinical development plans require a flexible yet well‐structured approach to clinical trial design.
Hypoxia, energy balance and obesity: from pathophysiological mechanisms to new treatment strategies
Authors: Kayser B. , Verges S.
Published: March 2013

High altitude exposure is often accompanied by weight loss. Postulated mechanisms are a reduction of nutritional energy intake, a reduction of intestinal energy uptake from impaired intestinal function and increased energy expenditure. Beyond the field of altitude, there are good reasons for renewed interest in the relationship between hypoxia and energy balance. The increasing prevalence of obesity and associated comorbidities represent a major health concern. Obesity is frequently associated with sleep disorders leading to intermittent systemic hypoxia with deleterious cardiovascular and metabolic consequences. Hypoxic regions may be present within hypertrophic white adipose tissue leading to chronic systemic inflammation. Among the increasing number of people commuting to altitude for work or leisure, obesity is a risk factor for acute mountain sickness. Paradoxically, exposure to intermittent hypoxia might be considered as a means to lose body mass and to improve metabolic risk factors. Daytime exposure to intermittent hypoxia has been used to treat hypertension in former Soviet Union countries and is now being experimented elsewhere. Such intermittent hypoxic exposure at rest or during exercise may lead to improvement in body composition and health status with improved exercise tolerance, metabolism and systemic arterial pressure. Future research should confirm whether hypoxic training could be a new treatment strategy for weight loss and comorbidities in obese subjects and elucidate the underlying mechanisms and signalling pathways.
Incidence of difficult bag‐mask ventilation in children: a prospective observational study
Authors: Valois‐Gómez Teresa , Oofuvong Maliwan , Auer Grant , Coffin Donna , Loetwiriyakul Witthaya , Correa José A.
Published: March 2013

Background

Difficult airway (DA), including difficult bag‐mask ventilation (DBMV), and difficult intubation (DI) is an important challenge for the pediatric anesthesiologist. While expected DBMV can be successfully managed with appropriate equipment and personnel, unexpected DBMV relies on the resources available and the experience of the anesthesiologist at the time of the emergency. The incidence and risk factors of unexpected DA in otherwise healthy children, including DBMV among pediatric patients are not known. The aim of this study was to expand the scientific knowledge of unexpected DBMV among pediatric patients.

Methods

Patients between the ages of 0 and 8 years, undergoing elective surgery requiring bag‐mask ventilation BMV and intubation at the Montreal Children's Hospital were recruited in this prospective observational study. Data on the incidence of DBMV and risk factors were collected over a 3‐year period.

Results

In a sample of 484 children, the incidence of unexpected difficult BMV was 6.6% (95% CI [4.6, 9.2]). The incidence of expected DA among the screened patients (N = 4865) was 0.5% (95% CI [0.3, 0.7]). In a logistic regression analysis, age (OR 0.98; 95%CI [0.97, 0.99]), undergoing otolaryngology (ENT) surgery (OR 2.92; 95% CI [1.08, 7.95]) and use of neuromuscular blocking agents (OR 3.49; 95%CI [1.50–8.11]) were independently associated with DBMV. The incidence of DI was 1.2%. No association between DBMV and DI was found (Fisher's exact test, P = 1.0).

Conclusions

This is the first published report of the incidence of unexpected DBMV among healthy pediatric patients.
Systematic Review and Meta‐Analysis of Pharmacological Therapies for Painful Diabetic Peripheral Neuropathy
Authors: Snedecor Sonya J. , Sudharshan Lavanya , Cappelleri Joseph C. , Sadosky Alesia , Mehta Sonam , Botteman Marc
Published: March 2013

Background

Painful diabetic peripheral neuropathy (pDPN) is prevalent among persons with diabetes and increases over time. Published guidelines recommend a number of medications to treat this condition providing clinicians with a variety of treatment options. This study provides a comprehensive systematic review and meta‐analysis of published pharmacologic therapies for pDPN.

Methods

The published literature was systematically searched to identify randomized, controlled trials of all available pharmacologic treatments for pDPN (recommended or nonrecommended) reporting predefined efficacy and safety outcomes. Bayesian fixed‐effect mixed treatment comparison methods were used to assess relative therapeutic efficacy and harms.

Results

Data from 58 studies including 29 interventions and 11,883 patients were analyzed. Pain reduction over that of placebo on the 11‐point numeric rating scale ranged from −3.29 for sodium valproate (95% credible interval [CrI] = [−4.21, −2.36]) to 1.67 for Sativex (−0.47, 0.60). Estimates for most treatments were clustered between 0 and −1.5 and were associated with more study data and smaller CrIs. Pregabalin (≥ 300 mg/day) was the most effective on the 100‐point visual analog scale (−21.88; [−27.06, −16.68]); topiramate was the least (−3.09; [−3.99, −2.18]). Relative risks (RRs) of 30% pain reduction ranged from 0.78 (Sativex) to 1.84 (lidocaine 5% plaster). Analysis of the RR ratio of these 2 treatments reveals marginal significance for Sativex (3.27; [1.07, 9.81]), indicating the best treatment is only slightly better than the worst. Relative risks of 50% pain reduction ranged from 0.98 (0.56, 1.52) (amitriptyline) to 2.25 (1.51, 3.00) (alpha‐lipoic acid). RR ratio for these treatments was not statistically different (3.39; [0.88, 3.34]). Fluoxetine had the lowest risk of adverse events (0.94; [0.62, 1.23]); oxycodone had the highest (1.55; [1.45, 1.64]). Discontinuation RRs were clustered around 0.8 to 1.5, with those on the extreme having greater uncertainty.

Conclusions

Selecting an appropriate pDPN therapy is key given the large number of available treatments. Comparative results revealed relative equivalence among many of the studied interventions having the largest overall sample sizes and highlight the importance of standardization of methods to effectively assess pain.
Acral Peeling Skin Syndrome Resulting from a Homozygous Nonsense Mutation in the CSTA Gene Encoding Cystatin A
Authors: Krunic Aleksandar L. , Stone Kristina L. , Simpson Michael A. , McGrath John A.
Published: March 2013

Acral peeling skin syndrome (APSS) is a clinically and genetically heterogeneous disorder. We used whole‐exome sequencing to identify the molecular basis of APSS in a consanguineous Jordanian‐American pedigree. We identified a homozygous nonsense mutation (p.Lys22X) in the CSTA gene, encoding cystatin A, that was confirmed using Sanger sequencing. Cystatin A is a protease inhibitor found in the cornified cell envelope, and loss‐of‐function mutations have previously been reported in two cases of exfoliative ichthyosis. Our study expands the molecular pathology of APSS and demonstrates the value of next‐generation sequencing in the genetic characterization of inherited skin diseases.
Periocular Granuloma Annulare: A Case Report and Review of Literature
Authors: Chiang Katherine , Bhalla Rohan , Mesinkovska Natasha A. , Piliang Melissa P. , Tamburro Joan E.
Published: March 2013

Granuloma annulare (GA) is a granulomatous dermatosis that rarely presents on the face and is extremely uncommon in the periocular region. We report our experience with the presentation and management of GA lesions on the eyelids of a 17‐year‐old girl. We performed a review of published literature and identified 13 cases of pediatric periocular GA. One additional case was identified upon review of all pediatric GA cases at the Cleveland Clinic Foundation. Review of these cases suggests that periocular GA is a benign condition that spontaneously regresses within a few months. GA nodules have a predilection for the upper eyelids. A greater incidence is noted in African American children. Awareness of the self‐resolving nature of this condition can prevent unnecessary surgical excisions in affected children.
Epidermodysplasia Verruciformis in Lipoid Proteinosis: Case Report and Discussion of Pathophysiology
Authors: O'Blenes Catherine , Pasternak Sylvia , Issekutz Andrew , Gillis Jane , Chowdhury Dhiman , Finlayson Laura
Published: March 2013

Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis caused by mutations in extracellular matrix protein 1 (ECM1) that involves deposition of basement membrane–like material in the skin and other organs. Epidermodysplasia verruciformis (EV) is also a rare autosomal recessive genodermatosis involving susceptibility to human papillomavirus (HPV) infections and squamous cell carcinoma, caused in most cases by homozygous mutations in EVER1 or EVER2. We describe a case of EV in a patient with LP and discuss the pathophysiology. A 3‐year‐old Lebanese girl presented with hoarseness, beaded papules along the eyelid margins, waxy papules and plaques on her head and neck, and lichenoid verrucous papules on the forearms and hands. Histopathology of the waxy papules exhibited deposition of periodic acid Schiff–positive basement membrane–like material in the superficial dermis, characteristic of LP. The verruca plana–like lesions exhibited acanthosis and enlarged keratinocytes with pale blue‐grey cytoplasm and a perinuclear halo, consistent with verrucae and EV. Polymerase chain reaction amplification and sequencing of ECM1, EVER1, and EVER2 demonstrated a homozygous point mutation, c.389C>T (p.Thr130Met), in exon 6 of ECM1 and a heterozygous point mutation, c.917 A>T (p.Asn306Ile), in exon 8 in EVER2, known to cause EV in homozygous patients. The homozygous point mutation c.389C>T in ECM1 may be a novel mutation causing LP. Verruca plana–like lesions seen in LP appear to represent a form of acquired EV. In this patient, a heterozygous mutation in EVER2 at c.917 A>T may also have conferred susceptibility to HPV infection.
Eccrine Nevus Affecting the Forearm of an 11‐Year‐Old Girl Successfully Controlled with Topical Glycopyrrolate
Authors: Dua Janet , Grabczynska Sophie
Published: March 2013

Eccrine nevi are rare lesions characterized by a sharply demarcated area of localized hyperhidrosis. We present an 11‐year‐old girl with an eccrine nevus on her right lower forearm. To the best of our knowledge, this is the first case successfully controlled with topical glycopyrrolate wipes.
Expecting the Unexpected: Predicting Physiological and Psychological Wildfire Preparedness from Perceived Risk, Responsibility, and Obstacles
Authors: McNeill Ilona M. , Dunlop Patrick D. , Heath Jonathan B. , Skinner Timothy C. , Morrison David L.
Published: March 2013

People who live in wildfire‐prone communities tend to form their own hazard‐related expectations, which may influence their willingness to prepare for a fire. Past research has already identified two important expectancy‐based factors associated with people's intentions to prepare for a natural hazard: Perceived risk (i.e., perceived threat likelihood and severity) and perceived protection responsibility. We expanded this research by differentiating the influence of these factors on different types of wildfire preparedness (e.g., preparations for evacuation vs. for defending the house) and measured actual rather than intended preparedness. In addition, we tested the relation between preparedness and two additional threat‐related expectations: the expectation that one can rely on an official warning and the expectation of encountering obstacles (e.g., the loss of utilities) during a fire. A survey completed by 1,003 residents of wildfire‐prone areas in Perth, Australia, revealed that perceived risk (especially risk severity) and perceived protection responsibility were both positively associated with all types of preparedness, but the latter did not significantly predict preparedness after controlling for other predictors and demographics. Also, the two new expectancy‐based factors were significantly associated with all types of preparedness, and remained significant predictors of some types of preparedness after controlling for other predictors and demographics: the expectation of being able to rely on an official fire warning and expecting to lose electricity both still predicted less preparedness around house resilience, and expecting to lose water still predicted increased planning preparedness. We discuss public policy implications that follow from this research.
When Opportunity Matters: Comparing the Risk‐Taking Attitudes of Prisoners and Recently Released Ex‐Prisoners
Authors: Rolison Jonathan J. , Hanoch Yaniv , Gummerum Michaela
Published: March 2013

Risk‐taking tendencies and environmental opportunities to commit crime are two key features in understanding criminal behavior. Upon release from prison, ex‐prisoners have a much greater opportunity to engage in risky activity and to commit criminal acts. We hypothesized that ex‐prisoners would exhibit greater risk‐taking tendencies compared to prisoners who have fewer opportunities to engage in risky activity and who are monitored constantly by prison authorities. Using cumulative prospect theory to compare the risky choices of prisoners and ex‐prisoners our study revealed that ex‐prisoners who were within 16 weeks of their prison release made riskier choices than prisoners. Our data indicate that previous studies comparing prisoners behind bars with nonoffenders may have underestimated the risk‐taking tendencies of offenders. The present findings emphasize the central role played by risk‐taking attitudes in criminal offending and highlight a need to examine offenders after release from prison.
Silent, invisible and unacknowledged: experiences of young caregivers of single parents diagnosed with multiple sclerosis
Authors: Bjorgvinsdottir Katrin , Halldorsdottir Sigridur
Published: March 2013

The study's rationale

Most people diagnosed with multiple sclerosis (MS) choose to live at home without known consequences for their children.

Aims and objectives

To study the personal experience of being a young caregiver of a chronically ill parent diagnosed with MS.

Methodological design and justification

Phenomenology was the methodological approach of the study since it gives an inside information of the lived experience.

Ethical issues and approval

The study was approved by the National Bioethics Committee and reported to the Data Protection Authority.

Research methods

We explored in 21 interviews the lived experience of 11 young caregivers who had cared for single chronically ill parents, diagnosed with MS.

Results

The participants felt silent, invisible and unacknowledged as caregivers and received limited professional assistance. They were left to provide their parents with intimate physical and emotional care and support that was demanding, embarrassing and quite difficult while feeling unsupported, excluded and abandoned. Their caring responsibilities lead to severe restrictions in life as their parents' disease progressed and they lived without a true childhood; left to manage far too many responsibilities completely on their own and at a young age. At the time of the interviews, most of the participants had left their post as primary caregivers. They were learning to let go of the emotional pain, some of them with a welcomed partner. Most of them were experiencing a healthy transition and personal growth, existentially moving from feeling abandoned towards feeling independent. However, some of them were still hurting.

Study limitations

In choosing participants for the study a sampling bias may have occurred.

Conclusions

Health professionals are urged to provide information, support and guidance for young carers in a culturally sensitive way and to take on the leading role of helping and empowering children and adolescents in similar situations.
Revised status ofChlorideaDuncan and (Westwood), 1841, for theHeliothis virescensspecies group (Lepidoptera: Noctuidae: Heliothinae) based on morphology and three genes
Authors: POGUE MICHAEL G.
Published: March 2013

The Heliothinae comprise some of the world's most injurious agricultural pests. This study reanalyses a subsample of theHeliothisgroup to determine the monophyly ofChloridea(Heliothis virescensandH. subflexa). Two nuclear gene regions,elongation factor‐1α(EF‐1α; 1240 bp) anddopa decarboylase(DDC; 687 bp), and the barcoding region of mitochondrialcytochrome oxidase I(COI; 708 bp) were used in this analysis for a total of 2635 bp and a morphological dataset of 20 characters and 62 character states. Sixteen species representing five genera plus two outgroup species were used in the analysis. Analyses used were Maximum Parsimony (MP), Maximum Likelihood (ML) and Bayesian Inference (BI). The revised status for the monophyletic genusChlorideaDuncan and (Westwood) was supported by a very strong bootstrap support (BP = 98–100). Larval host‐plant usage is discussed within theHeliothisclade. Polyphagy is most likely the ancestral condition with a host shift to monophagy and oligophagy. Based on known larval hosts,Heliocheilusis oligophagous on Poaceae. Traits of host plant use inHelicoverpaandChlorideawhere both polyphagy and oligophagy occur in closely related species are discussed.
Visualizing metabolite distribution and enzymatic conversion in plant tissues by desorption electrospray ionization mass spectrometry imaging
Authors: Li Bin , Knudsen Camilla , Hansen Natascha Krahl , Jørgensen Kirsten , Kannangara Rubini , Bak Søren , Takos Adam , Rook Fred , Hansen Steen H. , Møller Birger Lindberg , Janfelt Christian , Bjarnholt Nanna
Published: March 2013

In comparison with the technology platforms developed to localize transcripts and proteins, imaging tools for visualization of metabolite distributions in plant tissues are less well developed and lack versatility. This hampers our understanding of plant metabolism and dynamics. In this study, we demonstrate that desorption electrospray ionization mass spectrometry imaging (DESI‐MSI) of tissue imprints on porous Teflon may be used to accurately image the distribution of even labile plant metabolites such as hydroxynitrile glucosides, which normally undergo enzymatic hydrolysis by specific β‐glucosidases upon cell disruption. This fast and simple sample preparation resulted in no substantial differences in the distribution and ratios of all hydroxynitrile glucosides between leaves from wild‐type Lotus japonicus and a β‐glucosidase mutant plant that lacks the ability to hydrolyze certain hydroxynitrile glucosides. In wild‐type, the enzymatic conversion of hydroxynitrile glucosides and the concomitant release of glucose were easily visualized when a restricted area of the leaf tissue was damaged prior to sample preparation. The gene encoding the first enzyme in hydroxynitrile glucoside biosynthesis in L. japonicus leaves, CYP79D3, was found to be highly expressed during the early stages of leaf development, and the hydroxynitrile glucoside distribution in mature leaves reflected this early expression pattern. The utility of direct DESI‐MSI of plant tissue was demonstrated using cryo‐sections of cassava (Manihot esculenta) tubers. The hydroxynitrile glucoside levels were highest in the outer cell layers, as verified by LC–MS analyses. The unexpected discovery of a hydroxynitrile‐derived di‐glycoside shows the potential of DESI‐MSI to discover and guide investigations into new metabolic routes.
PIN6 is required for nectary auxin response and short stamen development
Authors: Bender Ricci L. , Fekete Megan L. , Klinkenberg Peter M. , Hampton Marshall , Bauer Brittany , Malecha Matthew , Lindgren Khrystyne , A. Maki Jennifer , Perera M. Ann D. N. , Nikolau Basil J. , Carter Clay J.
Published: March 2013

The PIN family of proteins is best known for its involvement in polar auxin transport and tropic responses. PIN6 (At1g77110) is one of the remaining PIN family members in Arabidopsis thaliana to which a biological function has not yet been ascribed. Here we report that PIN6 is a nectary‐enriched gene whose expression level is positively correlated with total nectar production in Arabidopsis, and whose function is required for the proper development of short stamens. PIN6 accumulates in internal membranes consistent with the ER, and multiple lines of evidence demonstrate that PIN6 is required for auxin‐dependent responses in nectaries. Wild‐type plants expressing auxin‐responsive DR5:GFP or DR5:GUS reporters displayed intense signal in lateral nectaries, but pin6 lateral nectaries showed little or no signal for these reporters. Further, exogenous auxin treatment increased nectar production more than tenfold in wild‐type plants, but nectar production was not increased in pin6 mutants when treated with auxin. Conversely, the auxin transport inhibitor N–1–naphthylphthalamic acid (NPA) reduced nectar production in wild‐type plants by more than twofold, but had no significant effect on pin6 lines. Interestingly, a MYB57 transcription factor mutant, myb57–2, closely phenocopied the loss‐of‐function mutant pin6–2. However, PIN6 expression was not dependent on MYB57, and RNA‐seq analyses of pin6–2 and myb57–2 mutant nectaries showed little overlap in terms of differentially expressed genes. Cumulatively, these results demonstrate that PIN6 is required for proper auxin response and nectary function in Arabidopsis. These results also identify auxin as an important factor in the regulation of nectar production, and implicate short stamens in the maturation of lateral nectaries.
Cold shock protein 1 chaperones mRNAs during translation in Arabidopsis thaliana
Authors: Juntawong Piyada , Sorenson Reed , Bailey‐Serres Julia
Published: March 2013

RNA binding proteins (RBPs) function post‐transcriptionally to fine‐tune gene regulation. Arabidopsis thaliana has four Gly‐rich, zinc finger‐containing RBPs called cold shock proteins 1–4 (CSP1–CSP4), that possess an evolutionary conserved cold shock domain. Here, we determined that CSP1 associates with polyribosomes (polysomes) via an RNA‐mediated interaction. Both the abundance and polysomal co‐fractionation of CSP1 was enhanced in the cold (4°C), but did not influence global levels of polysomes, which were minimally perturbed by above freezing cold temperatures. Using a polyclonal antiserum, CSP1 was co‐immunopurified with several hundred transcripts from rosettes of plants cultivated at 23°C or transferred to 4°C for 12 h. CSP1‐associated mRNAs were characterized by G+C‐rich 5′ untranslated regions and gene ontologies related to cellular respiration, mRNA binding and translation. The majority of the CSP1‐associated mRNAs were constitutively expressed and stable in the cold. CSP1 abundance was correlated with improved translation of ribosomal protein mRNAs during cold stress and improved maintenance of homeostasis and translation of mRNAs under water‐deficit stress. In summary, CSP1 selectively chaperones mRNAs, providing translational enhancement during stress.