bluuebunny/crossref_metadata_2025 huggingface dataset:
Probation migration(s): Examining occupational culture in a turbulent field
Authors: Burke Lol , Millings Matthew , Robinson Gwen
Published: July 2016

In June 2014 approximately 54 per cent of the total probation service workforce in England and Wales were transferred to the newly created Community Rehabilitation Companies (CRCs) as part of the government’s plans to establish a market for offender management services. This marked the beginning of one of the largest and most significant migrations of criminal justice staff from the public to the private sector in England and Wales. This article presents findings from an ethnographic study of the formation of one of these CRCs through to the period immediately following the transfer into private ownership. The authors discuss the key features of this migration which are identified as ‘splitting and fracturing’, ‘adapting and forming’ and ‘exiting or accommodation’. It is contended that this development not only has significant implications for the future of probation services but also provides a unique example of the impact on an occupational culture of migration from the public to the private sector.
Nivolumab in the treatment of advanced renal cell carcinoma: clinical trial evidence and experience
Authors: Mennitto Alessia , Grassi Paolo , Ratta Raffaele , Verzoni Elena , Prisciandaro Michele , Procopio Giuseppe
Published: July 2016

Renal cell carcinoma (RCC) is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Cytokine-based immunotherapies, including interferon-α and interleukin-2, have been used for the treatment of metastatic RCC (mRCC). Long-term responses and complete remissions were observed, but durable clinical benefit efficacy in the overall population was limited and associated with significant toxicity. As a consequence, new generation agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways replaced interferon alpha (IFN-α). Strategies of tumor immune evasion include T-cell suppression by negative signals deriving from the interaction between programmed death-1 (PD-1) on the T cell and its ligand (PDL-1) on the tumor cells. Nivolumab, a programmed death 1 checkpoint inhibitor, blocks this pathway, thus reversing T-cell suppression and activating antitumor responses.

The aim of this review is to summarize the safety and efficacy data of nivolumab in mRCC. Objective responses and safety profile of single-agent nivolumab are favorable in both previously treated and treatment-naïve mRCC patients. Despite toxic effects, combination therapies with nivolumab have shown promising results, indicating a potential role in the treatment of mRCC. Tailoring immunotherapy on a patient-to-patient basis represents a major challenge for the future.
Usability Evaluation of a Blood Glucose Monitoring System With a Spill-Resistant Vial, Easier Strip Handling, and Connectivity to a Mobile App
Authors: Harvey Craig , Koubek Richard , Bégat Vanessa , Jacob Stephan
Published: July 2016

Background:

Proper management of diabetes mellitus requires regular self-monitoring of blood glucose (SMBG). This research evaluated the usability of the Accu-Chek® Guide Meter that includes a spill-resistant vial, easier strip handling, and wireless connectivity to a mobile app.

Methods:

A total of 197 participants were allowed to experience typical blood glucose testing tasks on the Accu-Chek Guide Meter, review data such as last result, patterns, and target percentage on the meter and on the mobile app, and then evaluate their experience through a human factors usability survey. Participants used a 6-point agree/disagree scale to rate 34 market statement questions.

Results:

The results of a Pearson chi-square proportions test for each of the 34 market statement questions showed a significant difference ( P < .0001) between the disagree responses (1-3) and agree responses (4-6). An overwhelming majority of participants found all aspects of the system, including the test strips, strip vial, and data analysis on the meter and the mobile app, to be a good fit for their lifestyle and to provide a better testing experience.

Conclusions:

This study found superior usability of the new meter system over the participants’ current meters in both the United States and France.
Revision Tibiotalocalcaneal Arthrodesis With a Pseudoelastic Intramedullary Nail
Authors: Latt L. Daniel , Smith Kathryn Elizabeth , Dupont Kenneth Michael
Published: July 2016

Hindfoot (tibiotalocalcaneal or TTC) arthrodesis is commonly used to treat concomitant arthritis of the ankle and subtalar joints. Simultaneous fusion of both joints can be difficult to achieve especially in patients with impaired healing due to smoking, diabetes mellitus, or Charcot neuroarthropathy. Conventional intramedullary fixation devices allow for compression to be applied at the time of surgery, but this compression can be lost due to bone resorption or settling, leading to impaired healing. In contrast, the novel pseudoelastic intramedullary nail is designed to maintain compression at the arthrodesis sites throughout the healing process by the use of an internal pseudoelastic element. We present 2 cases of revision TTC arthrodesis using the pseudoelastic intramedullary nail. In the first case, an 80-year-old diabetic man with previous ankle and failed subtalar fusion with screws underwent revision TTC arthrodesis. In the second case, a 66-year-old man with Charcot neuroarthropathy and a failed TTC arthrodesis with a static intramedullary nail underwent revision tibiotalar arthrodesis. In both cases, computed tomography scan demonstrated successful union and patients were allowed full weight bearing by 3 months after surgery. These cases provide early evidence that sustained compression via an intramedullary nail can lead to rapid successful hindfoot fusion when standard approaches have failed.

Levels of Evidence: Therapeutic, Level IV: Case study
Measurement of Nitinol Recovery Distance Using Pseudoelastic Intramedullary Nails for Tibiotalocalcaneal Arthrodesis
Authors: Kildow Beau J. , Gross Christopher E. , Adams Samuel D. , Parekh Selene G.
Published: July 2016

Background. Tibiotalocalcaneal arthrodesis is a salvage procedure for patients with complex disease of the ankle and subtalar joints. Despite the clinical efficacy and mechanical advantage of intramedullary nails, complications, such as nonunion, are common. It may be possible to sustain compression in the face of bone resorption and implant loosening over the course of healing using a novel pseudoelastic intramedullary nail with an internal nitinol element. Methods. We identified 15 patients with average age of 54.7 years (range, 28-75 years) who had undergone a tibiotalocalcaneal arthrodesis using a pseudoelastic intramedullary nail. Serial radiographs were used to determine the amount and rate of nitinol element migration over the first 3 postoperative months. Results. Postoperatively, there was at least 2.38 mm of nitinol element migration proximally with mean of 5.58 mm (± 1.38), (range, 2.38-8.11 mm). Average follow-up time was 195 days (± 106.3), (range, 89-490 days). On average, 86% of the total recovered distance took place within the first 39.7 days (±10.03). Conclusions. The nitinol element recovers distance when stretched intraoperatively and maintains moderate compression in response to bone resorption. Further studies are needed to assess if this increased compression lends itself to higher fusion rates than traditional intramedullary nails.

Levels of Evidence: Therapeutic, Level IV: Case series
Autologous Chondrocyte Implantation to Isolated Patella Cartilage Defects
Authors: von Keudell Arvind , Han Roger , Bryant Tim , Minas Tom
Published: July 2016

Background

Autologous chondrocyte implantation (ACI) is a durable treatment for patients with chondral defects. This study presents the comprehensive evaluation of patients with patella defects treated with ACI at medium- to long-term follow-up.

Methods

Thirty consecutive patients with isolated chondral lesions of the patella were enrolled prospectively. Primary outcome measures were validated patient reported outcome measures and objective magnetic resonance imaging.

Results

Nineteen of 30 patients underwent tibial tubercle osteotomy (TTO) to correct lateral maltracking in combination with soft tissue balancing. The defect sizes were large, averaging 4.7 ± 2.1 cm2 (range 2.2-30.0 cm2). Pidoriano/Fulkerson classification revealed that 3 defects were type II (lateral), 9 were type III (medial), and 18 were type IV (central/panpatella). Age at the time of surgery was 32 ± 10 years. At follow-up of 2 to 14 years, knee function was rated good to excellent in 25 (83%) patients, fair in 4 (13%) patients, and poor in 1 (3%) patient. Three patients failed treatment after a mean of 75 months (6.25 years). All 3 failures were Workers Compensation (WC) cases. They were older than the non-WC patients, 42 ± 6 years compared with the non-WC 28 ± 9 years ( P = 0.0019). Significant increases in all clinical and health utility outcome scores were seen. Magnetic resonance imaging demonstrated that the fill grade, surface and integrity of the repair tissue correlated with clinical scores.

Conclusion

ACI to isolated patella defects results in significant functional improvement at a minimum of 24 months, with the results remaining durable at latest follow-up of 15 years.

Level of evidence

Level 4.
Review of Soluble Biomarkers of Osteoarthritis: Lessons From Animal Models
Authors: Legrand Catherine B. , Lambert Cécile J. , Comblain Fanny V. , Sanchez Christelle , Henrotin Yves E.
Published: July 2016

Objective

Osteoarthritis (OA) is one of the leading causes of disability within the adult population. Currently, its diagnosis is mainly based on clinical examination and standard radiography. To date, there is no way to detect the disease at a molecular level, before the appearance of structural changes and symptoms. So an attractive alternative for monitoring OA is the measurement of biochemical markers in blood, urine, or synovial fluid, which could reflect metabolic changes in joint tissue and therefore disease onset and progression. Animal models are relevant to investigate the early stage of OA and metabolic changes occurring in joint tissues. The goal of this narrative review is to summarize the scientific data available in the literature on soluble biomarkers in animal models of OA.

Design

A literature search was conducted using the PubMed/Medline and Scopus databases between February 1995 and December 2015. All original articles, systematic and narrative reviews published in French or in English were considered.

Results

We summarized the data of 69 studies and proposed a classification scheme for OA biomarkers in animal studies, largely inspired by the BIPEDS classification.

Conclusions

Studies about biomarkers and animal models indicate that some markers could be valuable to monitor OA progression and assess therapeutic response in some animal models.
Fresh Osteochondral Allograft Transplantation for Fractures of the Knee
Authors: Gracitelli Guilherme C. , Tirico Luis Eduardo Passarelli , McCauley Julie C. , Pulido Pamela A. , Bugbee William D.
Published: July 2016

Objective

The purpose of this study was to evaluate functional outcomes and allograft survivorship among patients with knee fracture who underwent fresh osteochondral allograft (OCA) transplantation as a salvage treatment option.

Design

Retrospective analysis of prospectively collected data.

Setting

Department of Orthopaedic Surgery at one hospital.

Patients

Fresh OCAs were implanted for osteochondral lesions after knee fracture in 24 males and 15 females with an average age of 34 years. Twenty-nine lesions (74%) were tibial plateau fractures, 6 (15%) were femoral condyle fractures, and 4 (10%) were patella fractures.

Main Outcome Measurements

Clinical evaluation included modified Merle d’Aubigné-Postel (18-point), International Knee Documentation Committee, and Knee Society function scores, and patient satisfaction. Failure of OCA was defined as revision OCA or conversion to total knee arthroplasty (TKA).

Results

Nineteen of 39 knees (49%) had further surgery. Ten knees (26%) were considered OCA failures (3 OCA revisions, 6 TKA, and 1 patellectomy). Survivorship of the OCA was 82.6% at 5 years and 69.6% at 10 years. Among the 29 knees (74%) that had the OCA still in situ, median follow-up was 6.6 years. Pain and function improved from preoperative to latest follow-up; 83% of patients reported satisfaction with OCA results.

Conclusion

OCA transplantation is a useful salvage treatment option for osteochondral lesions caused by knee fracture. Although the reoperation rate was high, successful outcome was associated with significant clinical improvement.
Ideological Fit Enhances Interpersonal Orientations
Authors: Chopik William J. , Motyl Matt
Published: July 2016

Living among politically dissimilar others leads individuals to feel left out and ultimately predicts mobility away from an area. However, does living in politically incongruent environment affect how we relate to other people? In two national samples ( n = 12,846 and n = 6,316), the congruence between an individual’s ideological orientation and their community’s ideological orientation were examined. Lack of ideological fit with one’s environment was associated with a difficulty to form close relationships and lower perspective taking. Our findings illustrate the psychological effects of living among dissimilar others and possible explanations for how social environments modulate interpersonal relations.
High-sensitivity cardiac troponin assays and unstable angina
Authors: Sandoval Yader , Apple Fred S , Smith Stephen W
Published: July 2016

The term unstable angina has been conventionally applied to patients with myocardial ischemia without myocardial necrosis. However, while the clinical context has remained constant over time, the biomarkers of myocardial injury and acute myocardial infarction have evolved. High-sensitivity cardiac troponin assays have several key analytical differences from prior cardiac troponin assay generations, which may alter the diagnosis and frequency of unstable angina, as well as affect our understanding of previously developed risk stratification strategies. This document reviews the current challenges in regards to unstable angina when using high-sensitivity cardiac troponin I and T assays.
Prevalence and clinical features of opioid‐induced constipation in the general population: A French study of 15,000 individuals
Authors: Ducrotté P , Milce J , Soufflet C , Fabry C
Published: July 2016

Background

Constipation is common during opioid therapy and can compromise analgesia.

Aim

The aim of this article is to determine the prevalence and clinical characteristics of opioid‐induced constipation (OIC) in France.

Methods

A questionnaire study was conducted in a representative sample of the French general population. Participants completed a 31‐item questionnaire covering opioid use during the previous six months, and the occurrence of constipation (defined as <3 bowel movements per week, straining during defaecation, or both) during opioid treatment.

Results

Data were obtained from 15,213 participants, of whom 4753 (31.2%) reported opioid use. Most analgesics (96.5%) were classified as World Health Organization step II analgesics, and the remainder were step III. The most common indications for opioids were bone or joint pain, and soft tissue pain. Overall, 414/4753 (8.7%) opioid users reported OIC while the prevalence of OIC reached 21% in case of regular or prolonged (>1 month) opioid use. Other characteristics associated with OIC included female gender, age ≥50 years and use of step III opioids. Only 177/414 (42.8%) participants with OIC had used medications (most commonly osmotic laxatives) to treat constipation, and satisfaction with constipation medication was moderate (mean (SD) score 7.2 (1.3) on a scale of 0–10).

Conclusions

Approximately one‐third of a representative French population had used opioids within the previous six months, and 9% of users had experienced OIC, which is more frequent in case of regular use. OIC appears to be under‐treated, and participants’ satisfaction with their constipation medications was only moderate, suggesting that significant unmet need remains in OIC management.
Cognitive evolution in natalizumab-treated multiple sclerosis patients
Authors: Jacques Francois H , Harel Brian T , Schembri Adrian J , Paquette Chantal , Bilodeau Brigitte , Kalinowski Pawel , Roy Reshmi
Published: July 2016

Background

Cognitive dysfunction affects up to 65% of multiple sclerosis (MS) patients and progresses over time. Natalizumab has been shown to be superior to placebo in preserving cognition for the first two years of therapy.

Objectives

The objectives of this study are to understand the impact of natalizumab on cognition beyond two years of therapy and to investigate whether baseline characteristics are predictive of clinical response.

Methods

This is a single-center, 24-month, observational study. Sixty-three patients treated with natalizumab were assessed prior to monthly infusions using a Cogstate battery and the Symbol Digit Modalities Test (SDMT). Patient demographics were collected at baseline. A linear mixed model was conducted with duration of natalizumab therapy as a between-subjects factor (≤2 or >2 years), assessment as a within-subjects factor, and Multiple Sclerosis Severity Score (MSSS) as a covariate.

Results

Aside from the MSSS ( p = 0.0074), the two groups were identical. No patient showed evidence of sustained cognitive deterioration over the 24-month period. Baseline parameters including impaired cognition did not influence the trajectory of cognitive change over 24 months.

Conclusions

Our results suggest that natalizumab preserves cognition following four to seven years of continuous therapy. This occurs irrespective of baseline characteristics, including impaired cognition.
Adolescents’ Stigma Attitudes Toward Internalizing and Externalizing Disorders
Authors: Lau Anna S. , Guo Sisi , Tsai William , Nguyen D. Julie , Nguyen Hannah T. , Ngo Victoria , Weiss Bahr
Published: July 2016

This study examined predictors of stigma attitudes toward common youth emotional behavioral problems to test the hypothesis that interdependent cultural values would be associated with differential stigma toward externalizing versus internalizing disorders. Furthermore, we examined whether problem-specific stigma attitudes would predict adolescents’ own self-reported manifestations of distress. A total of 1,224 Vietnamese American and European American adolescents completed measures of social distance stigma attitudes in response to vignettes depicting youth with internalizing (depression, social anxiety, somatization) and externalizing (alcohol use, aggressive behaviors, delinquency) disorders. A subset of 676 youth also provided self-reports on their own adjustment prospectively over 6 months. Measurement models revealed clear separation of negatively correlated factors assessing stigma toward externalizing versus internalizing problems. Values related to family interdependence were significantly associated with greater tolerance of internalizing disorders and lower tolerance of externalizing disorders. Stigma toward internalizing disorders was associated with lower concurrent self-reported internalizing symptoms, whereas stigma toward externalizing symptoms was associated with lower concurrent externalizing symptoms and greater decreases in externalizing symptoms over time. The results of the study suggest that stigma attitudes are differentiated by problem type and may represent one cultural factor shaping distress manifestations
Mapping the Walk of Shame
Authors: Irvine Janice M.
Published: July 2016

This article expands the concept of sexual scripts and the cognitive mapping method by adding an emotional dimension to both. It is based on a case study of college students reporting their experiences of the walk of shame, the term for women walking home in the early morning from a “hookup,” or casual sex, the night before. The walk of shame is a productive site in which to address conceptual and methodological challenges posed by sociology’s affective turn. In this article, I discuss emotional scripts as a conceptual framework for exploring women students’ experiences with the walk of shame. And I propose affective mapping as a methodological approach for capturing emotional dimensions in social life. Using the method to map the emergence of feelings and their temporal changes in relation to normative features of the spatial environment, I suggest that although the walk of shame appears to be a vehicle for the social control of women’s sexuality, women report more complexity during their walks, producing scripts of shame, pride, and ambivalence.
Joshua Watson: High Church Lay Activism and the Development of Colonial Anglicanism, 1814–1855
Authors: Andrews Robert M.
Published: July 2016

Joshua Watson (1771–1855) was a wealthy merchant who used his business acumen and administrative skills to become a key player in numerous Anglican societies that had missionary concerns, working alongside high-ranking clergy in various capacities. One aspect of Watson’s achievements was his impact on the emerging colonial church structures in Canada, India, Australia, and New Zealand. He was heavily involved in the reform and administration of the two main High Church mission societies: the SPCK and the SPG. Watson was a figure of immense significance to the development of early nineteenth-century colonial Anglicanism. His example illustrates the importance of lay figures both to the High Church tradition and to the broader history of Anglicanism.
Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen
Authors: Zamolodchikov Daria , Berk-Rauch Hanna E. , Oren Deena A. , Stor Daniel S. , Singh Pradeep K. , Kawasaki Masanori , Aso Kazuyoshi , Strickland Sidney , Ahn Hyung Jin
Published: July 2016

The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with β-amyloid (Aβ), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the Aβ-fibrinogen interaction. We identified the central region of Aβ42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of Aβ and by naturally occurring p3 peptides, Aβ17-40 and Aβ17-42. X-ray crystallographic analysis revealed that Aβ42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen β-chain (β384-393). Furthermore, we identified an additional Aβ-binding site within the αC region of fibrinogen. Aβ binding to this αC region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the Aβ-fibrinogen interaction and clarifies the mechanism by which Aβ-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the Aβ-fibrinogen interaction to treat cerebrovascular abnormalities in AD.
Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency
Authors: Escribano Amparo , Pastor Sara , Reula Ana , Castillo Silvia , Vicente Silvia , Sanz Francisco , Casas Francisco , Torres María , Fernández-Fabrellas Estrella , Codoñer-Franch Pilar , Dasí Francisco
Published: July 2016

Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.

Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2–18 years) diagnosed with AATD and 18 controls (aged 3–16 years).

Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity,hTERTexpression and AATD phenotypes; high-risk patients showed shorter telomeres, lowerhTERTexpression and decreased telomerase activity than intermediate-risk and low-risk patients.

AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression.
Beta-blockers in COPD: time for reappraisal
Authors: Lipworth Brian , Wedzicha Jadwiga , Devereux Graham , Vestbo Jørgen , Dransfield Mark T.
Published: July 2016

The combined effects on the heart of smoking and hypoxaemia may contribute to an increased cardiovascular burden in chronic obstructive pulmonary disease (COPD). The use of beta-blockers in COPD has been proposed because of their known cardioprotective effects as well as reducing heart rate and improving systolic function. Despite the proven cardiac benefits of beta-blockers post-myocardial infarction and in heart failure they remain underused due to concerns regarding potential bronchoconstriction, even with cardioselective drugs. Initiating treatment with beta-blockers requires dose titration and monitoring over a period of weeks, and beta-blockers may be less well tolerated in older patients with COPD who have other comorbidities. Medium-term prospective placebo-controlled safety studies in COPD are warranted to reassure prescribers regarding the pulmonary and cardiac tolerability of beta-blockers as well as evaluating their potential interaction with concomitant inhaled long-acting bronchodilator therapy. Several retrospective observational studies have shown impressive reductions in mortality and exacerbations conferred by beta-blockers in COPD. However, this requires confirmation from long-term prospective placebo-controlled randomised controlled trials. The real challenge is to establish whether beta-blockers confer benefits on mortality and exacerbations in all patients with COPD, including those with silent cardiovascular disease where the situation is less clear.
An assessment of the diagnostic criteria for sessile serrated adenoma/polyps: SSA/Ps using image processing software analysis for Ki67 immunohistochemistry
Authors: Fujimori Yukari , Fujimori Takahiro , Imura Johji , Sugai Tamotsu , Yao Takashi , Wada Ryo , Ajioka Yoichi , Ohkura Yasuo
Published: July 2016

Background

Serrated polyps belong to a heterogeneous group of lesions that are generally characterized morphologically. This type of lesion is thought to be the precursor of sporadic carcinomas with microsatellite instability, and probably also the precursor for CpG island-methylated microsatellite-stable carcinomas. For practical purposes, according to the 2010 WHO classification, the diagnostic criteria for sessile serrated adenomas/polyps (SSA/Ps) was established by the research project “Potential of Cancerization of Colorectal Serrated Lesions” led by the Japanese Society for Cancer of the Colon and Rectum. The aim of this study was to evaluate the validity of the morphologic characteristics established in Japan by using immunohistochemical staining for Ki-67.

Methods

To calculate the target cells, 2 contiguous crypts which could be detected from the bottom of the crypt to the surface of the colorectal epithelium were selected. To validate the proliferative activity, we evaluated the percentage and the asymmetrical staining pattern of Ki67 positive cells in each individual crypt. To examine the immunoreactivity of Ki67, computer-assisted cytometrical analysis was performed.

Results

SSA/Ps had a higher proliferative activity as compared to hyperplastic polyps (HPs) based on the difference in incidence of Ki67 positive cells, and the former also exhibited a significantly higher asymmetric distribution of these cells as compared to HPs, even in lesions with a diameter <10 mm.

Conclusion

We conclude that assessment of the pathological findings of SSA/Ps, including crypt dilation, irregularly branching crypts, and horizontally arranged basal crypts (inverted T- and/or L-shaped crypts) is appropriate to show a significantly higher proliferative activity as compared to HPs. Further, the use of two-dimensional image analysis software is an objective and reproducible method for this type of histological examination.

Virtual slides

The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6718091416698112
The Glasgow‐Maastricht foot model, evaluation of a 26 segment kinematic model of the foot
Authors: Oosterwaal Michiel , Carbes Sylvain , Telfer Scott , Woodburn James , Tørholm Søren , Al‐Munajjed Amir A. , van Rhijn Lodewijk , Meijer Kenneth
Published: July 2016

Background

Accurately measuring of intrinsic foot kinematics using skin mounted markers is difficult, limited in part by the physical dimensions of the foot. Existing kinematic foot models solve this problem by combining multiple bones into idealized rigid segments. This study presents a novel foot model that allows the motion of the 26 bones to be individually estimated via a combination of partial joint constraints and coupling the motion of separate joints using kinematic rhythms.

Methods

Segmented CT data from one healthy subject was used to create a template Glasgow‐Maastricht foot model (GM‐model). Following this, the template was scaled to produce subject‐specific models for five additional healthy participants using a surface scan of the foot and ankle. Forty‐three skin mounted markers, mainly positioned around the foot and ankle, were used to capture the stance phase of the right foot of the six healthy participants during walking. The GM‐model was then applied to calculate the intrinsic foot kinematics.

Results

Distinct motion patterns where found for all joints. The variability in outcome depended on the location of the joint, with reasonable results for sagittal plane motions and poor results for transverse plane motions.

Conclusions

The results of the GM‐model were comparable with existing literature, including bone pin studies, with respect to the range of motion, motion pattern and timing of the motion in the studied joints. This novel model is the most complete kinematic model to date. Further evaluation of the model is warranted.
Clozapinev. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis
Authors: Siskind Dan , McCartney Lara , Goldschlager Romi , Kisely Steve
Published: July 2016

Background

Although clozapine is the ‘gold standard’ for treatment-refractory schizophrenia, meta-analyses of clozapine for this condition are lacking.

Aims

We conducted a systematic review and meta-analysis of clozapine treatment for people with treatment-refractory schizophrenia.

Method

We searched the Cochrane Schizophrenia Group's trial register, PubMed and EMBASE and hand-searched key papers for randomised controlled trials of clozapine for treatment-refractory schizophrenia.

Results

Twenty-one papers with 25 comparisons were included. The number needed to treat was 9. Clozapine was superior for positive symptoms in both the short and long term. In the short term only clozapine was superior for total and negative symptoms, with higher response rates. Both funding source and dosage affected results. Higher baseline psychosis scores predicted better outcomes for clozapine in a meta-regression.

Conclusions

Clozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered.
Use of lithium and cancer risk in patients with bipolar disorder: population-based cohort study
Authors: Huang Ru-Yu , Hsieh Kun-Pin , Huang Wan-Wen , Yang Yi-Hsin
Published: July 2016

Background

Lithium inhibits glycogen synthase kinase-3, which is an enzyme involved in the pathogenesis of cancer.

Aims

To investigate the association between lithium and cancer risk in patients with bipolar disorder.

Method

A retrospective cohort study was designed using the National Health Insurance Research Database (NHIRD) in Taiwan. Patients using lithium comprised the index drug group and patients using anticonvulsants only comprised the control group. Time-dependent Cox regression was used to evaluate the hazard ratios (HRs) for risk of cancer.

Results

Compared with anticonvulsant-only exposure, lithium exposure was associated with significantly lower cancer risk (HR = 0.735, 95% CI 0.554–0.974). The hazard ratios for the first, second and third tertiles of the cumulative defined daily dose were 0.762 (95% CI 0.516–1.125), 0.919 (95% CI 0.640–1.318) and 0.552 (95% CI 0.367–0.831), respectively.

Conclusions

Lithium is associated with reduced overall cancer risk in patients with bipolar disorder. A dose–response relationship for cancer risk reduction was observed.
Plasmodium AdoMetDC/ODC bifunctional enzyme is essential for male sexual stage development and mosquito transmission
Authors: Hart Robert J. , Ghaffar Atif , Abdalal Shaymaa , Perrin Benjamin , Aly Ahmed S. I.
Published: July 2016

Polyamines are positively-charged organic molecules that are important for cellular growth and division. Polyamines and their synthesizing enzymes are particularly abundant in rapidly proliferating eukaryotic cells such as parasitic protozoa and cancer cells. Polyamine biosynthesis inhibitors, such as Elfornithine, are now being considered for cancer prevention and have been used effectively against Trypanosoma brucei. Inhibitors of polyamine biosynthesis have caused growth arrest of Plasmodium falciparum blood stages in vitro, but in P. berghei only partial inhibition has been observed. While polyamine biosynthesis enzymes are characterized and conserved in Plasmodium spp., little is known on the biological roles of these enzymes inside malaria parasite hosts. The bifunctional polyamine biosynthesis enzyme S-adenosyl methionine decarboxylase/ornithine decarboxylase (AdoMetDC/ODC) was targeted for deletion in P. yoelii. Deletion of AdoMetDC/ODC significantly reduced blood stage parasitemia but Anopheles transmission was completely blocked. We showed that male gametocytogenesis and male gamete exflagellation were abolished and consequently no ookinetes or oocyst sporozoites could be generated from adometdc/odc(–) parasites. Supplementation of putrescine and spermidine did not rescue the defective phenotypes of male gametocytes and gametes of the knockout parasites. These results highlight the crucial role of polyamine homeostasis in the development and functions of Plasmodium erythrocytic stages in the blood and in the mosquito vector and validate polyamine biosynthesis pathway enzymes as drug targeting candidates for malaria parasite transmission blocking.
Ultra-superovulation for the CRISPR-Cas9-mediated production of gene-knockout, single-amino-acid-substituted, and floxed mice
Authors: Nakagawa Yoshiko , Sakuma Tetsushi , Nishimichi Norihisa , Yokosaki Yasuyuki , Yanaka Noriyuki , Takeo Toru , Nakagata Naomi , Yamamoto Takashi
Published: July 2016

Current advances in producing genetically modified mice using genome-editing technologies have indicated the need for improvement of limiting factors including zygote collection for microinjection and their cryopreservation. Recently, we developed a novel superovulation technique using inhibin antiserum and equine chorionic gonadotropin to promote follicle growth. This method enabled the increased production of fertilized oocytes via in vitro fertilization compared with the conventional superovulation method. Here, we verify that the ultra-superovulation technique can be used for the efficient generation of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated knockout mice by microinjection of plasmid vector or ribonucleoprotein into zygotes. We also investigated whether single-amino-acid-substituted mice and conditional knockout mice could be generated. Founder mice bearing base substitutions were generated more efficiently by co-microinjection of Cas9 protein, a guide RNA and single-stranded oligodeoxynucleotide (ssODN) than by plasmid microinjection with ssODN. The conditional allele was successfully introduced by the one-step insertion of an ssODN designed to carry an exon flanked by two loxP sequences and homology arms using a double-cut CRISPR-Cas9 strategy. Our study presents a useful method for the CRISPR-Cas9-based generation of genetically modified mice from the viewpoints of animal welfare and work efficiency.
Lizard tail skeletal regeneration combines aspects of fracture healing and blastema-based regeneration
Authors: Lozito Thomas P. , Tuan Rocky S.
Published: July 2016

Lizards are amniotes with the remarkable ability to regenerate amputated tails. The early regenerated lizard tail forms a blastema, and the regenerated skeleton consists of a cartilage tube (CT) surrounding the regenerated spinal cord. The proximal, but not distal, CT undergoes hypertrophy and ossifies. We hypothesized that differences in cell sources and signaling account for divergent cartilage development between proximal and distal CT regions. Exogenous spinal cord implants induced ectopic CT formation in lizard (Anolis carolinensis) blastemas. Regenerated spinal cords expressed Shh, and cyclopamine inhibited CT induction. Blastemas containing vertebrae with intact spinal cords formed CTs with proximal hypertrophic regions and distal non-hypertrophic regions, whereas removal of spinal cords resulted in formation of proximal CT areas only. In fate-mapping studies, FITC-labeled vertebra periosteal cells were detected in proximal, but not distal, CT areas. Conversely, FITC-labeled blastema cells were restricted to distal CT regions. Proximal cartilage formation was inhibited by removal of periosteum and could be recapitulated in vitro by periosteal cells treated with Ihh and BMP-2. These findings suggest that proximal CTs are directly derived from vertebra periosteal cells in response to BMP and Ihh signaling, whereas distal CTs form from blastema cells in response to Shh signals from regenerated spinal cords.
Multiscale quantification of morphodynamics: MorphoLeaf, software for 2-D shape analysis
Authors: Biot Eric , Cortizo Millán , Burguet Jasmine , Kiss Annamaria , Oughou Mohammed , Maugarny-Calès Aude , Gonçalves Beatriz , Adroher Bernard , Andrey Philippe , Boudaoud Arezki , Laufs Patrick
Published: July 2016

A major challenge in morphometrics is to analyse complex biological shapes formed by structures at different scales. Leaves exemplify this challenge as they combine differences in their overall shape with smaller shape variations at their margin leading to lobes or teeth. Current methods based on contour or on landmarks analysis are successful in quantifying either overall leaf shape or leaf margin dissection, but fail in combining the two. Here, we present a comprehensive strategy and its associated freely available platform for the quantitative, multiscale analysis of the morphology of leaves with different architectures. For this, biologically relevant landmarks are automatically extracted and hierarchized, and used to guide the reconstruction of accurate average contours that properly represent both global and local features. Using this method we established a quantitative framework of the developmental trajectory of Arabidopsis leaves of different ranks and retraced the origin of leaf heteroblasty. When applied to different mutant forms our method can contribute to a better comprehension of gene function as we show here for the role of CUC2 during Arabidopsis leaf serration. Finally, we illustrated the wider applicability of our tool by analysing hand morphometrics.
The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN
Authors: Guan J. , Tucker E. R. , Wan H. , Chand D. , Danielson L. S. , Ruuth K. , El Wakil A. , Witek B. , Jamin Y. , Umapathy G. , Robinson S. P. , Johnson T. W. , Smeal T. , Martinsson T. , Chesler L. , Palmer R. H. , Hallberg B.
Published: July 2016

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALKF1174L/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.
Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration
Authors: Kawasaki Fumiko , Koonce Noelle L. , Guo Linda , Fatima Shahroz , Qiu Catherine , Moon Mackenzie T. , Zheng Yunzhen , Ordway Richard W.
Published: July 2016

Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila. This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the microtubule cytoskeleton after HS stress. These findings establish a model for genetic analysis of degeneration and protection mechanisms involving contributions of environmental factors, and advance our understanding of the protective functions and therapeutic potential of small HSPs.
Two novel competing pathways establish the threshold for cyclin B-Cdk1 activation at the meiotic G2/M transition
Authors: Hiraoka Daisaku , Aono Ryota , Hanada Shin-ichiro , Okumura Eiichi , Kishimoto Takeo
Published: July 2016

Extracellular ligand stimuli control biological phenomena. Cells distinguish physiological stimuli from weak noise stimuli by establishing a ligand-concentration threshold. Hormonal control of the meiotic G2/M transition in oocytes is essential for reproduction. However, the mechanism for threshold establishment is unclear. In starfish oocytes, maturation-inducing hormones activate the PI3K-Akt pathway via Gβγ. Akt directly phosphorylates both Cdc25 and Myt1, resulting in activation of cyclin B-Cdk1, which then induces meiotic G2/M transition. Here, we show that cyclin B-Cdk1 is partially activated after subthreshold hormonal stimuli, but this triggers negative feedback (Cdk-NF), resulting in dephosphorylation of Akt sites on Cdc25 and Myt1, thereby canceling the signal. We also identified phosphatase activity for Akt substrates that exists independent of stimuli. In contrast to these negative regulatory activities, an atypical Gβγ-dependent pathway enhances PI3K-Akt-dependent phosphorylation. Based on these findings, we propose a model for threshold establishment in which hormonal dose-dependent competition between these novel pathways establishes a threshold; the atypical Gβγ-pathway becomes predominant over Cdk-NF when the stimulus exceeds this threshold. Our findings provide a regulatory connection between cell cycle and signal transduction machineries.
The N-terminal extension of yeast ribosomal protein L8 is involved in two major remodeling events during late nuclear stages of 60S ribosomal subunit assembly
Authors: Tutuncuoglu Beril , Jakovljevic Jelena , Wu Shan , Gao Ning , Woolford John L.
Published: July 2016

Assaying effects on pre-rRNA processing and ribosome assembly upon depleting individual ribosomal proteins (r-proteins) provided an initial paradigm for assembly of eukaryotic ribosomes in vivo—that each structural domain of ribosomal subunits assembles in a hierarchical fashion. However, two features suggest that a more complex pathway may exist: (i) Some r-proteins contain extensions that reach long distances across ribosomes to interact with multiple rRNA domains as well as with other r-proteins. (ii) Individual r-proteins may assemble in a stepwise fashion. For example, the globular domain of an r-protein might assemble separately from its extensions. Thus, these extensions might play roles in assembly that could not be revealed by depleting the entire protein. Here, we show that deleting or mutating extensions of r-proteins L7 (uL30) and L35 (uL29) from yeast reveal important roles in early and middle steps during 60S ribosomal subunit biogenesis. Detailed analysis of the N-terminal terminal extension of L8 (eL8) showed that it is necessary for late nuclear stages of 60S subunit assembly involving two major remodeling events: removal of the ITS2 spacer; and reorganization of the central protuberance (CP) containing 5S rRNA and r-proteins L5 (uL18) and L11 (uL5). Mutations in the L8 extension block processing of 7S pre-rRNA, prevent release of assembly factors Rpf2 and Rrs1 from pre-ribosomes, which is required for rotation of the CP, and block association of Sda1, the Rix1 complex, and the Rea1 ATPase involved in late steps of remodeling.