bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term observational studies of chronic granulomatous disease
Authors: Kanariou Maria , Spanou Kleopatra , Tantou Sofia
Published: November 2017

Purpose of review

Chronic granulomatous disease (CGD) is a primary immunodeficiency, with a defect of phagocytes in killing specific pathogens. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory response. Since its first description as fatal disease about 60 years ago, a significant improvement in outcome has been achieved in the last 20 years. The purpose of this review is to framework recent advances in CGD immunopathogenesis, management of disease manifestation and cure of CGD patients.

Recent findings

For years, CGD is a known cause of life-threatening infections and excessive inflammation. The cause and the management of inflammatory reactions, however, have not been clarified, and the range of clinical presentation is growing with corresponding novel therapeutic interventions. Recent work focuses on the best outcome of hematopoietic stem cell transplantation (HSCT) and gene therapy for the cure of CGD patients, more specifically, those with X-linked and p47phox mutations.

The genetics and phenotype of CGD is well characterized; however, the underlying mechanisms, the treatment of its inflammatory manifestations and the cure of CGD is under further investigation.
The Changing Face of Pediatric Ulcerative Colitis
Authors: Martinelli Massimo , Giugliano Francesca P. , Russo Marina , Giannetti Eleonora , Andreozzi Marialuisa , Bruzzese Dario , Perrone Laura , Staiano Annamaria , Miraglia Del Giudice Emanuele , Miele Erasmo , Marzuillo Pierluigi , Strisciuglio Caterina
Published: November 2017

Objectives:

The aims of this retrospective study were to describe ulcerative colitis (UC) phenotype at diagnosis and follow‐up and to identify possible predictors of severe disease course.

Methods:

This was a retrospective, single‐center study. We reviewed the charts of patients with UC diagnosed between 2 and 18 years at our referral center from January 2007 to January 2016. Laboratory and clinical features at diagnosis, such as disease extent, atypical phenotypes, extraintestinal manifestations, and therapies, and pattern changes during the follow‐up, including relapse rate, disease extension, and the cumulative risk for colectomy were collected.

Results:

One hundred eleven patients were enrolled. Atypical phenotypes were identified at diagnosis in 55 out of 111 patients (49.5%). Extraintestinal manifestations were detected in 16 out of 111 (14.4%) at the diagnosis. During the follow‐up 60 out of 111 (54%) patients needed to start azathioprine, 9 out of 111 (8.1%) patients started biologic therapy and 10 out of 111 (patients underwent surgery, resulting in a cumulative risk of 8% at 5 years and 16% at 10 years. Steroid refractoriness (hazard ratio: 13.9) and starting of biologic therapy (hazard ratio: 25.3) represented the best predictors for surgery. The cumulative probability of first relapse was 47% at 6 months and 63% at 1 year. Disease extension was reported in 21 out of 70 patients (30%).

Conclusion:

Pediatric UC is associated with a severe phenotype and a high percentage of atypical features. Surgery rate seems to be decreased from early reports.
Compliance With Fecal Calprotectin Testing in Pediatric Patients With Inflammatory Bowel Disease
Authors: Queliza Karen , Wang Michael K. , Kellermayer Richard
Published: November 2017

Fecal calprotectin (FC) is a highly sensitive biomarker for inflammatory bowel diseases (IBDs). Utilization of this assay has been steadily increasing. Adherence levels for FC have, however, yet to be examined in the pediatric IBD setting. We analyzed 100 consecutive patients diagnosed with IBD between 2014 and 2015 at Texas Children's Hospital. Fifty‐six percent of patients were men and median age at diagnosis was 13.7 years. Following diagnosis of IBD, 84 patients had a minimum of 1 FC requested, and 95.2% of these patients completed the test at least once. An average of 2 FCs per patient was ordered each year, and the overall compliance was 76.6%. Patients who completed the initial testing with a minimum of 3 consecutive tests were more likely to remain compliant than those who failed to perform the first lab (P < 0.001). Our findings indicate good compliance with FC testing in pediatric patients with IBD.
Shortened 8 Weeks Course of Dual Sofosbuvir/Daclatasvir Therapy in Adolescent Patients, With Chronic Hepatitis C Infection
Authors: El‐Shabrawi Mortada H. , Abdo Alaa M. , El‐Khayat Hisham R. , Yakoot Mostafa
Published: November 2017

Recently, sofosbuvir and the fixed‐dose combination of sofosbuvir/ledipasvir were approved for the treatment of chronic hepatitis C virus infection in adolescents, criteria being 12 years old and above or weighing at least 35 kg. Here we present the results of a pilot single cohort of 10 consecutive adolescent patients with chronic hepatitis C virus and treated with dual sofosbuvir/daclatasvir therapy for a response‐tailored duration of 8 weeks for those who achieved very rapid virologic response (vRVR) and 12 weeks for those who did not. All patients achieved vRVR at week 2 and completed the shortened 8 weeks course. All patients (10/10) (100% [confidence interval 72.25–100%]) achieved sustained vRVR at week 12 post‐treatment with good tolerability and no serious adverse events. These data could provide support to our suggested response‐tailored protocol of dual therapy with sofosbuvir/daclatasvir in adolescents particularly for shortened duration in those who achieved vRVR. Further larger randomized controlled studies are recommended.
Cost-Effectiveness of Peer- Versus Venue-Based Approaches for Detecting Undiagnosed HIV Among Heterosexuals in High-Risk New York City Neighborhoods
Authors: Stevens Elizabeth R. , Nucifora Kimberly A. , Zhou Qinlian , Braithwaite Ronald Scott , Cleland Charles M. , Ritchie Amanda S. , Kutnick Alexandra H. , Gwadz Marya V.
Published: November 2017

Introduction:

We used a computer simulation of HIV progression and transmission to evaluate the cost-effectiveness of a scale-up of 3 strategies to seek out and test individuals with undiagnosed HIV in New York City (NYC).

Setting:

Hypothetical NYC population.

Methods:

We incorporated the observed effects and costs of the 3 “seek and test” strategies in a computer simulation of HIV in NYC, comparing a scenario in which the strategies were scaled up with a 1-year implementation or a long-term implementation with a counterfactual scenario with no scale-up. The simulation combined a deterministic compartmental model of HIV transmission with a stochastic microsimulation of HIV progression, calibrated to NYC epidemiological data from 2003 to 2015. The 3 approaches were respondent-driven sampling (RDS) with anonymous HIV testing (“RDS-A”), RDS with a 2-session confidential HIV testing approach (“RDS-C”), and venue-based sampling (“VBS”).

Results:

RDS-A was the most cost-effective strategy tested. When implemented for only 1 year and then stopped thereafter, using a societal perspective, the cost per quality-adjusted life-year (QALY) gained versus no intervention was $812/QALY, $18,110/QALY, and $20,362/QALY for RDS-A, RDS-C, and VBS, respectively. When interventions were implemented long term, the cost per QALY gained versus no intervention was cost-saving, $31,773/QALY, and $35,148/QALY for RDS-A, RDS-C, and VBS, respectively. When compared with RDS-A, the incremental cost-effectiveness ratios for both VBS and RDS-C were dominated.

Conclusions:

The expansion of the RDS-A strategy would substantially reduce HIV-related deaths and new HIV infections in NYC, and would be either cost-saving or have favorable cost-effectiveness.
Comparison of the Pharmacokinetics and Pharmacodynamics of Single-Dose Tenofovir Vaginal Film and Gel Formulation (FAME 05)
Authors: Robinson Jennifer A. , Marzinke Mark A. , Fuchs Edward J. , Bakshi Rahul P. , Spiegel Hans M. L. , Coleman Jenell S. , Rohan Lisa C. , Hendrix Craig W.
Published: November 2017

Objective:

Although preexposure prophylaxis with oral tenofovir (TFV) disoproxil fumarate/emtricitabine reduces HIV acquisition rates, poor adherence to and acceptability of daily vaginal gels have led to development of vaginal film formulations to improve adherence and, potentially, to enable episodic use.

Study Design:

In this 2-arm, cross-over study of a fast-dissolving tenofovir film (40 mg) compared with a previously studied semisolid tenofovir 1% gel (40 mg), 10 healthy women received a single vaginal dose of each study product. Clinical, pharmacokinetic, and antiviral assessments were performed over 1 week after dose.

Results:

Nine of 10 participants experienced mild to moderate adverse effects, similar between products, with no severe adverse events or events attributed to study products. TFV concentrations after film dosing exceeded concentrations after gel dosing in plasma between 8 and 24 hours (P ≤ 0.02). TFV concentrations in cervicovaginal fluid and both TFV and TFV diphosphate concentrations in cervical tissue homogenates were higher after film dosing (all P values < 0.04). The differences ranged from median (interquartile range) 2.9-fold (1.1, 9.0; midvaginal cervicovaginal fluid) to 4.4-fold (2.9, 7.7; plasma). Neither film nor gel demonstrated reduced cervical tissue biopsy infectivity after ex vivo HIV challenge.

Conclusion:

Single-dose tenofovir film demonstrated consistently higher concentrations in plasma and cervicovaginal samples when compared with gel during the first day after dosing. Single-dose cervical tissue TFV-diphosphate concentrations at 5 hours exceeded steady-state concentrations previously reported with daily oral Truvada dosing. Tenofovir film may provide an alternative to tenofovir oral and gel formulations. Clinical efficacy remains to be tested.
Pathways From HIV-Related Stigma to Antiretroviral Therapy Measures in the HIV Care Cascade for Women Living With HIV in Canada
Authors: Logie Carmen H. , Lacombe-Duncan Ashley , Wang Ying , Kaida Angela , Conway Tracey , Webster Kath , de Pokomandy Alexandra , Loutfy Mona R.
Published: November 2017

Background:

Associations between HIV-related stigma and reduced antiretroviral therapy (ART) adherence are widely established, yet the mechanisms accounting for this relationship are underexplored. There has been less attention to HIV-related stigma and its associations with ART initiation and current ART use. We examined pathways from HIV-related stigma to ART initiation, current ART use, and ART adherence among women living with HIV in Canada.

Methods:

We used baseline survey data from a national cohort of women living with HIV in Canada (n = 1425). Structural equation modeling using weighted least squares estimation methods was conducted to test the direct effects of HIV-related stigma dimensions (personalized, negative self-image, and public attitudes) on ART initiation, current ART use, and 90% ART adherence, and indirect effects through depression and HIV disclosure concerns, adjusting for sociodemographic factors.

Results:

In the final model, the direct paths from personalized stigma to ART initiation (β = −0.104, P < 0.05) and current ART use (β = −0.142, P < 0.01), and negative self-image to ART initiation (β = −0.113, P < 0.01) were significant, accounting for the mediation effects of depression and HIV disclosure concerns. Depression mediated the pathways from personalized stigma to ART adherence, and negative self-image to current ART use and ART adherence. Final model fit indices suggest that the model fit the data well [χ2(25) = 90.251, P < 0.001; comparative fit index = 0.945; root-mean-square error of approximation = 0.044].

Conclusions:

HIV-related stigma is associated with reduced likelihood of ART initiation and current ART use, and suboptimal ART adherence. To optimize the benefit of ART among women living with HIV, interventions should reduce HIV-related stigma and address depression.
Magnetic Resonance Imaging of a Urethral Caruncle and the Pathologic Correlation: A Report of 3 Cases
Authors: Tomita Hayato , Takeyama Nobuyuki , Hayashi Takaki , Tanihuji Satoru , Yamamoto Kenro , Sasaki Haruaki , Ohike Nobuyuki , Nakajima Yasuo , Hashimoto Toshi
Published: November 2017

A urethral caruncle is the most common disease of the urethra in postmenopausal women. A definitive diagnosis can usually be reached based on physical examination. Cross-sectional imaging is performed when malignant urethral tumor is suspected, such as a urethral carcinoma. No articles have discussed the detailed imaging of urethral caruncles. We present 3 patients with symptomatic urethral caruncles who underwent magnetic resonance imaging preoperatively.
Pendular Seesaw Nystagmus in a Patient With a Giant Pituitary Macroadenoma: Pathophysiology and the Role of the Accessory Optic System
Authors: Yat-Ming Woo Peter , Takemura Saori , Ming-Yan Cheong Allen , Chi-Ho Chu Alberto , Chan Yung , Wong Hoi-Tung , Chan Kwong-Yau
Published: November 2017

Seesaw nystagmus is characterized by cyclic eye movements with a conjugate torsional component and a dissociated vertical component. In the first half of the cycle, one eye elevates and intorts, whereas the other eye depresses and extorts. The pattern is reversed in the remaining half of the cycle. We describe a patient with a giant pituitary adenoma who developed pendular seesaw nystagmus. Disturbance in the visuovestibular system is postulated to contribute to this form of seesaw nystagmus. Lesions compressing the optic chiasm and the accessory optic system could interrupt the transmission of retinal error signals to the inferior olivary nucleus and the interstitial nucleus of Cajal, thus interfering with the adaptive mechanism of the vestibulo-ocular reflex and leading to pendular seesaw nystagmus.
Using Facebook differently in two education policy protests
Authors: Avigur-Eshel Amit , Berkovich Izhak
Published: November 2017

Purpose

Scholars have identified various uses of Facebook by activists and social movements in political activism and beyond. They overlooked, however, the possibility that social movements may take advantage of certain capabilities provided by social media platforms, while neglecting others, thereby creating differences in patterns of use between movements. The purpose of this paper is to investigate these differences and to assess the role of the lived experience of activists and supporters in shaping them.

Design/methodology/approach

This study compared two protests in Israel with respect to activists’ use of social media, the class profile of participants and the leadership’s demands and their resonance among various social groups. Each case was analyzed by combining thematic and quantitative analysis of online data from Facebook pages and of offline data from various sources.

Findings

The two protests exhibited distinctively different patterns of use of the capabilities provided by Facebook. These differences are associated with the lived experience of protest participants and of the individuals the movement leadership sought to mobilize.

Originality/value

This study is the first to show that successful public policy protests can exhibit distinctive use patterns of social media for political activism. It also identifies lived experience as an important factor in shaping these patterns.
Transparency and effective e-Governance: a case of telecentres in the Indian State of Karnataka
Authors: Iyer Lakshmi Shankar , R.N. Subba Rao
Published: November 2017

Purpose

It is the responsibility of any government to ensure efficient, transparent and reliable services to the common man through telecentres. The purpose of this study is to take into account the influence of people and process on transparency that leads to effective e-governance.

Design/methodology/approach

This study involved collecting data through questionnaire method from 400 citizens who visited the telecentres. Data were analysed by conducting chi-square test and independent sample t-test, and it was found that there exists significant influence of location on transparency.

Findings

The current study reiterates the fact from literature that transparency in transactions enables effective e-governance. Beneficiaries perceive that people and processes have influence on transparency.

Research limitations/implications

The research adds up to the literature in establishing that there exist differentials among the rural and urban population with respect to transparency. Results could be skewed, as there could be an impact of population density across urban and rural areas.

Practical implications

This study brings out a framework and an action plan for the government to implement and ensure transparency in processes leading to effective e-governance.

Social implications

The action plan ensures transparency in service delivery leading to effective e-governance. Increased transparency empowers citizens with increased trustworthiness towards services delivered through telecentres.

Originality/value

This paper fulfils the need for an action plan to assure citizens to use deliveries through telecentres with better transparency. The aspect of transparency is not being studied in the present context of service delivery by the government authorities in India. Moreover, the influence of transparency on e-governance is also under-explored.
Genomic data reveal high conservation but divergent evolutionary pattern of Polycomb/Trithorax group genes in arthropods
Authors: Jiang Feng , Liu Qing , Liu Xiang , Wang Xian‐Hui , Kang Le
Published: November 2017

Epigenetic gene control is maintained by chromatin‐associated Polycomb group (PcG) and Trithorax group (TrxG) genes, which act antagonistically via the interplay between PcG and TrxG regulation to generate silenced or permissive transcriptional states. In this study, we searched for PcG/TrxG genes in 180 arthropod genomes, covering all the sequenced arthropod genomes at the time of conducting this study, to perform a global investigation of PcG/TrxG genes in a phylogenetic frame. Results of ancestral state reconstruction analysis revealed that the ancestor of arthropod species has an almost complete repertoire of PcG/TrxG genes, and most of these genes were seldom lost above order level. The domain diversity analysis indicated that the PcG/TrxG genes show variable extent of domain structure changes; some of these changes could be associated with lineage‐specific events. The likelihood ratio tests for selection pressure detected a number of PcG/TrxG genes which underwent episodic positive selection on the branch leading to the insects with holometabolous development. These results suggest that, despite their high conservation across arthropod species, different members of PcG/TrxG genes showed considerable differences in domain structure and sequence divergence in arthropod evolution. Our cross species comparisons using large‐scale genomic data provide insights into divergent evolutionary pattern on highly conserved genes in arthropods.
Comparison of anthropometrical parameters and dietary habits of young women with and without menstrual disorders
Authors: Łagowska Karolina , Kazmierczak Daria , Szymczak Katarzyna
Published: November 2017

Aim

The aim of this study was to assess the nutritional status and dietary habits of young women, in order to explore their relationship with the menstrual cycle and to determine the proportion of women with menstrual cycle irregularities.

Methods

A total of 348 young women aged 15–25 years (19.7 ± 3.7 years) participated in the study and were assigned to a younger group (15–18 years; YG) or an older group (19–25 years; OG). Two subgroups were also distinguished: women with menstrual disorders (MD) and women with regular cycles (RC). Body mass, waist circumference, fat mass (FM), energy and nutrient intakes, and eating behaviour of the subjects were evaluated.

Results

In both age groups, women with menstrual cycle disorders were more likely to have higher body weight, higher body mass index, larger waist circumference and higher body FM. The daily diets of these women contained larger quantities of animal protein and fat, including saturated fat (in OG), but were poorer in vitamins B1 and B6 (in YG) and in iron. Disinhibition was significantly more common in the MD group.

Conclusions

The results of this study suggest that nutritional habits and status can interfere with the course of the menstrual cycle in young women.
UNBS5162 inhibits the proliferation of human A549 non‐small‐cell lung cancer cells by promoting apoptosis
Authors: Liu Cuicui , Xing Jiaqiang , Gao Yujun
Published: November 2017

Background

Lung cancer is one of the most frequently diagnosed malignancies in the world, thus developing novel anticancer reagents for lung cancer treatment is critical.

Methods

We performed cell counting kit‐8 and cell colony formation assays to investigate the role of UNBS5162 in the proliferation of A549 cells. Invasion and migration assays were applied to study the inhibitory effect of UNBS5162 on non‐small cell lung cancer cells. To detect the effect of UNBS5162 on A549 cell apoptosis, Annexin‐V fluorescein isothiocyanate and propidium iodide staining methods were used. Protein expression was analyzed using Western blot assay.

Results

UNBS5162 not only inhibited proliferation but also decreased invasion and migration in A549 cells. Most cells were intact (96.93%) under control conditions, but the number of intact cells decreased (84.8%) after 24 hours of treatment with UNBS5162, and the number of early and late apoptotic cells significantly increased (P < 0.05). Anti‐apoptotic protein Bcl‐2 expression in the UNBS5162 group was significantly decreased (P < 0.05), and expression of proapoptotic proteins Bim, Bax, and active caspase‐3 were significantly increased (P < 0.05) compared to the control. In the PI3K signaling pathway, phospo‐AKT and phospo‐mTOR levels were significantly decreased (P < 0.05), while S6K and Cyclin D1 protein levels were significantly decreased in UNBS5162 treated A549 cells (P < 0.05).

Conclusion

These findings suggest that UNBS5162 could inhibit A549 cell proliferation and metastasis by inhibiting PI3K pathway mediated apoptosis.
Self‐reported marijuana use over 25 years and abdominal adiposity: the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Bancks Michael P. , Auer Reto , Carr J. Jeffrey , Goff David C. , Kiefe Catarina , Rana Jamal S. , Reis Jared , Sidney Stephen , Terry James G. , Schreiner Pamela J.
Published: November 2017

Aims

We investigated the association between cumulative lifetime and current marijuana use with total abdominal adipose tissue (AT), visceral AT, subcutaneous AT, intermuscular AT, and mean liver attenuation (LA) at mid‐life.

Design

Longitudinal and cross‐sectional secondary data analysis of participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Setting

CARDIA field centers in Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA, USA.

Participants

CARDIA participants, aged 18–30 years in 1985–1986, who were present at the clinic examination in 2010–2011 (n = 2902).

Measurements

Marijuana use was assessed from responses to self‐administered questionnaires at 8 CARDIA examinations over 25 years, determined as cumulative marijuana‐years and current use status. Non‐contrast computed tomography imaging of the abdomen was obtained in 2010–2011.

Findings

In 2010–2011, 84% of participants reported a history of marijuana use with 11% reporting use within the past 30 days. Before adjustment, we observed greater cumulative marijuana use was associated with lower total abdominal and subcutaneous AT volume and lower LA and current marijuana use was associated with lower subcutaneous AT. However, after adjustment for age, sex, race, field center, cigarette pack‐years and current use, regular alcohol consumption, cumulative drink‐years, and physical activity, neither cumulative marijuana use nor current use showed an association with any abdominal adipose depot. Our estimates did not differ by age, sex, or race nor after accounting for cohort attrition.

Conclusion

Neither cumulative marijuana use nor current marijuana use is associated with total abdominal, visceral, subcutaneous, or intermuscular adipose tissue, or liver attenuation in mid‐life.
CBX3/heterochromatin protein 1 gamma is significantly upregulated in patients with non–small cell lung cancer
Authors: Chang Shih‐Chieh , Lai Yi‐Chun , Chen Yen‐Chung , Wang Nai‐Kuan , Wang Wei‐Shu , Lai Jiun‐I
Published: November 2017

Aim

Lung cancer is typically categorized into small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). NSCLC comprises of the majority of lung cancer with a poor prognosis in advanced cases. Transcriptional profiling studies, including microarrays and RNA‐sequencing studies, have significantly enriched our knowledge of gene expression patterns in NSCLC. A recent transcriptional profiling study identified high prevalence ofCBX3/HP1‐gamma upregulation in human NSCLC samples.CBX3/HP1‐gamma is an isoform of the heterochromatin protein 1 family, which plays a role in heterochromatin formation and is linked to cancer.

Methods

We examined lung cancer samples from our hospital using immunohistochemistry forCBX3/HP1‐gamma staining. We also analyzed publicly available databases of NSCLC transcriptional profiling to validate our results.

Results

We identified a high prevalence (77.2%) of samples with positive CBX3/HP1‐gamma staining by immunohistochemistry in NSCLC patient samples. Independently, we queried a publicly available dataset (GSE40419) containing RNA‐seq data from 77 patients. Upregulation ofCBX3/HP1‐gamma in tumor samples was present in 60.2% of the patients. A similar correlation was also observed in the The Cancer Genome Atlas (TCGA) database. Interestingly, we discovered a highly significant association between positiveCBX3/HP1‐gamma staining andEGFRmutation in our patient samples (40 of 42 patients,P < 0.001). Treatment ofEGFRmutant NSCLC cell lines with theEGFRinhibitor gefitinib failed to yield a change inCBX/HP1‐gamma expression, suggesting thatCBX/HP1‐gamma expression may be independent of EGFR downstream signaling.

Conclusion

We report a significant upregulation ofCBX3/HP1‐gamma in NSCLC patients, and also a possible relationship betweenCBX3/HP1‐gamma expression andEGFRmutation.
Calcimimetic and calcilytic therapies for inherited disorders of the calcium‐sensing receptor signalling pathway
Authors: Hannan Fadil M , Olesen Mie K , Thakker Rajesh V
Published: November 2017

The calcium‐sensing receptor (CaS receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss‐of‐function and gain‐of‐function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS receptor signal transduction in the parathyroid glands is probably regulated by G‐protein subunit α11 (Gα11) and adaptor‐related protein complex‐2 σ‐subunit (AP2σ), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS receptor, Gα11 or AP2σ proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient‐based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS receptor signalling pathway.

Linked Articles

This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc
PRN473, an inhibitor of Bruton's tyrosine kinase, inhibits neutrophil recruitment via inhibition of macrophage antigen‐1 signalling
Authors: Herter Jan M , Margraf Andreas , Volmering Stephanie , Correia Benedito Eduardo , Bradshaw J Michael , Bisconte Angelina , Hill Ronald J , Langrish Claire L , Lowell Clifford A , Zarbock Alexander
Published: November 2017

Background and Purpose

Following inflammatory stimuli, neutrophils are recruited to sites of inflammation and exert effector functions that often have deleterious effects on tissue integrity, which can lead to organ failure. Bruton's tyrosine kinase (Btk) is expressed in neutrophils and constitutes a promising pharmacological target for neutrophil‐mediated tissue damage. Here, we evaluate a selective reversible inhibitor of Btk, PRN473, for its ability to dampen neutrophil influx via inhibition of adhesion receptor signalling pathways.

Experimental Approach

In vitro assays were used to assess fMLP receptor 1 (Fpr‐1)‐mediated binding of ligands to the adhesion receptors macrophage antigen‐1 (Mac‐1) and lymphocyte function antigen‐1. Intravital microscopy of the murine cremaster was used to evaluate post‐adhesion strengthening and endoluminal crawling. Finally, neutrophil influx was visualized in a clinically relevant model of sterile liver injury in vivo. Btk knockout animals were used as points of reference for Btk functions.

Key Results

Pharmacological inhibition of Btk by PRN473 reduced fMLP‐induced phosphorylation of Btk and Mac‐1 activation. Biochemical experiments demonstrated the specificity of the inhibitor. PRN473 (20 mg·kg−1) significantly reduced intravascular crawling and neutrophil recruitment into inflamed tissue in a model of sterile liver injury, down to levels seen in Btk‐deficient animals. A higher dose did not provide additional reduction of intravascular crawling and neutrophil recruitment.

Conclusions and Implications

PRN473, a highly selective inhibitor of Btk, potently attenuates sterile liver injury by inhibiting the activation of the β2‐integrin Mac‐1 and subsequently neutrophil recruitment into inflamed tissue.
Sophocarpine attenuates wear particle‐induced implant loosening by inhibiting osteoclastogenesis and bone resorptionviasuppression of the NF‐κB signalling pathway in a rat model
Authors: Zhou Chen‐he , Shi Zhong‐li , Meng Jia‐hong , Hu Bin , Zhao Chen‐chen , Yang Yu‐te , Yu Wei , Chen Ze‐xin , Heng Boon Chin , Parkman Virginia‐Jeni Akila , Jiang Shuai , Zhu Han‐xiao , Wu Hao‐bo , Shen Wei‐liang , Yan Shi‐gui
Published: November 2017

Background and Purpose

Aseptic prosthesis loosening, caused by wear particles, is one of the most common causes of arthroplasty failure. Extensive and over‐activated osteoclast formation and physiological functioning are regarded as the mechanism of prosthesis loosening. Therapeutic modalities based on inhibiting osteoclast formation and bone resorption have been confirmed to be an effective way of preventing aseptic prosthesis loosening. In this study, we have investigated the effects of sophocarpine (SPC, derived fromSophora flavescens) on preventing implant loosening and further explored the underlying mechanisms.

Experimental Approach

The effects of SPC in inhibiting osteoclastogenesis and bone resorption were evaluated in osteoclast formation, inducedin vitroby the receptor activator of NF‐κB ligand (RANKL). A rat femoral particle‐induced peri‐implant osteolysis model was established. Subsequently, micro‐CT, histology, mechanical testing and bone turnover were used to assess the effects of SPC in preventing implant loosening.

Key Results

In vitro, we found that SPC suppressed osteoclast formation, bone resorption, F‐actin ring formation and osteoclast‐associated gene expression by inhibiting NF‐κB signalling, specifically by targeting IκB kinases. Ourin vivostudy showed that SPC prevented particle‐induced prosthesis loosening by inhibiting osteoclast formation, resulting in reduced periprosthetic bone loss, diminished pseudomembrane formation, improved bone‐implant contact, reduced bone resorption‐related turnover and enhanced stability of implants. Inhibition of NF‐κB signalling by SPC was confirmedin vivo.

Conclusion and Implications

SPC can prevent implant loosening through inhibiting osteoclast formation and bone resorption. Thus, SPC might be a novel therapeutic agent to prevent prosthesis loosening and for osteolytic diseases.
Dimensionality of oppositional defiant disorder
Authors: Hukkelberg Silje S. , Ogden Terje
Published: November 2017

Background

The present study examined dimensionality of oppositional defiant disorder (ODD) using 10 alternative items using network analysis and confirmatory factor analysis.

Methods

The sample constituted 551 Norwegian children aged 2–12 and their parents. We used network analysis to investigate the connections between different symptoms. Next, we analysed data using traditional confirmatory factor methods, including the more recently proposed bifactor approach.

Results

The bifactor model, with a strong general factor and three specific factors, provided the best model fit. Omega values did, however, reveal that only the general and the specific hurtful factor had satisfactory reliability. Network analysis showed that symptoms in general were positively connected within the ODD network. Strong connections between several symptoms within the irritable and hurtful cluster emerged, whereas some symptoms of the headstrong cluster seem to function as bridge nodes between the irritable and hurtful symptom clusters.

Conclusions

The findings support a bifactor model of ODD indicators, but omegas only gave support to the use of a general latent factor, and one specific factor. Network analysis did, however, provide some additional and interesting findings, revealing clusters of strongly connected symptoms and central bridge node symptoms. Implications of the results are discussed.
Synthetic piperine amide analogs with antimycobacterial activity
Authors: Philipova Irena , Valcheva Violeta , Mihaylova Rositsa , Mateeva Mina , Doytchinova Irini , Stavrakov Georgi
Published: November 2017

Piperine amide analogs are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene‐derived fragments. The compounds are screened for activity against Mycobacterium tuberculosis H37Rv. The most potent compounds are the 1‐adamantyl and the monoterpene‐derived hybrids, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells. The presence of quaternary carbon atom as main structural requirement for anti‐TB activity is pointed out by a QSAR study. The most promising compound is the (+)‐isopinocampheylamine‐derived amide which is characterized with selectivity index of 1387.8.
Dendritic cell phenotype in severe asthma reflects clinical responsiveness to glucocorticoids
Authors: Chambers E. S. , Nanzer A. M. , Pfeffer P. E. , Richards D. F. , Martineau A. R. , Griffiths C. J. , Corrigan C. J. , Hawrylowicz C. M.
Published: November 2017

Background

Subsets of patients with severe asthma remain symptomatic despite prolonged, high‐dose glucocorticoid therapy. We hypothesized that the clinical glucocorticoid sensitivity of these asthmatics is reflected in differences in peripheral blood dendritic cell subsets.

Objective

To compare peripheral blood leucocyte populations using flow cytometry at baseline and after 2 weeks of systemic glucocorticoid (steroid) treatment to identify immunological differences between steroid‐sensitive (SS) and steroid‐resistant (SR) asthmatics.

Methods

Adult severe asthmatics (SS n = 12; SR n = 23) were assessed for their response to 2 weeks of therapy with oral prednisolone. Peripheral blood was obtained before and after therapy and stained for lymphocyte (CD3, CD19, CD4, CD8 and Foxp3) and dendritic cell markers (Lineage negative [CD3, CD14, CD16, CD19, CD20, CD56], HLA‐DR+, CD304, CD11c, ILT3 and CD86).

Results

A higher median frequency of myeloid DCs (mDCs) but not plasmacytoid DCs (pDCs) was observed in the blood of SR as compared to SS asthmatics (P = .03). Glucocorticoid therapy significantly increased median B cell, but not T cell numbers in both cohorts, with a trend for increased numbers of Foxp3+ Tregs in SS (P = .07), but not SR subjects. Oral prednisolone therapy significantly reduced the median numbers and frequencies of total DCs and pDCs in both SS and SR asthmatics. Interestingly, the expression of HLA‐DR and ILT3 was also reduced on pDCs in all patients. In contrast, therapy increased the median frequency of mDCs in SS, but reduced it in SR asthmatics.

Conclusions

Myeloid DC frequency is elevated in SR compared with SS asthmatics, and mDC shows a differential response to oral prednisolone therapy.
Magnesium boosts the memory restorative effect of environmental enrichment in Alzheimer's disease mice
Authors: Huang Ying , Huang Xian , Zhang Ling , Han Fang , Pang Ke‐Liang , Li Xue , Shen Jian‐Ying
Published: November 2017

Background

Environmental enrichment (EE) has been shown to enhance cognitive function in mouse models of Alzheimer's disease (AD). Magnesium‐L‐threonate (MgT) is a compound with a newly discovered effect to rescue learning and memory function in aging and AD mice.

Aim

To study the additive therapeutic effect of EE combined with MgT (EM) and the potential mechanism underlying the effects.

Materials and Methods

APP/PS1 mice were treated with EE, MgT, or combination of EE and MgT (EM) and compared for restored memory function.

Results

EM was more effective in improving cognition and spatial memory than either treatment alone in either long‐term (12 months, started at 3 months old, which was before disease manifestation) or short‐term (3 months, started at 6 months old, which was after disease manifestation) treatment. The behavioral improvement has coincided with rescue of synaptic contacts in the hippocampal region of the AD mouse brain. Immunoblots also showed that EM but neither single treatment rescued the activity reduction in CaMKII and CREB, two important downstream molecules in the N‐methyl‐D‐aspartate receptor (NMDAR) pathway.

Conclusion

Environmental enrichment and MgT may synergistically improve recognition and spatial memory by reducing synaptic loss and restoring the NMDAR signaling pathway in AD mice, which suggests that combination of EE and MgT may be a novel therapeutic strategy for AD.
Endoscopic submucosal dissection of early gastric neoplasms in the fornix using the newly developed scissor‐type SB knife GX
Authors: Sumida Yuki , Kuwai Toshio , Ishaq Sauid
Published: November 2017

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The Akkermansia muciniphila is a gut microbiota signature in psoriasis
Authors: Tan LiRong , Zhao Shuang , Zhu Wu , Wu Lisha , Li Jie , Shen MinXue , Lei Li , Chen Xiang , Peng Cong
Published: November 2017

Psoriasis is an immune‐mediated chronic inflammatory skin disease. Although its pathogenesis is not fully understood, Th17 cells and the cytokines they produce, such as IL‐17, IL‐22 and IL‐23, play critical roles in the pathogenesis of psoriasis. Evidence has demonstrated that psoriasis has some common features, including immune responses (due to Th17 cells) and inflammatory cytokine profiles, with systematic diseases including inflammatory bowel diseases (IBDs) and obesity. Recently, studies have demonstrated that the gut microbiota plays a crucial role in host homoeostasis and immune response, particular in Th17 cells, but the role of the gut microbiota in psoriasis remains unclear. To study the relationship between gut microbiota and psoriasis, we analysed microbiota profiles in psoriasis using a 16S rDNA sequencing platform, and we found that the abundance of Akkermansia muciniphila was significantly reduced in patients with psoriasis. A. muciniphila is believed to have an important function in the pathogenesis of IBD and obesity; therefore, A. muciniphila, which is an indicator of health status, may be a key node for psoriasis as well as IBD and obesity. Taken together, our study identified that gut microbiota signature and function are significantly altered in the gut of patients with psoriasis, which provides a novel angle to understanding the pathogenesis of psoriasis.
Longitudinal observational study of hidradenitis suppurativa: impact of surgical intervention with adjunctive biologic therapy
Authors: Shanmugam Victoria K. , Mulani Shaunak , McNish Sean , Harris Sarah , Buescher Teresa , Amdur Richard
Published: November 2017

Background

Hidradenitis supppurativa (HS) is a chronic inflammatory disease of the apocrine sweat glands affecting 1–4% of the population. While surgical excision is a mainstay of therapy, lesions often recur. Biologic therapies, including tumor necrosis factor‐α and IL‐12/23 inhibitors, are effective for mild to moderate HS. However, longitudinal studies investigating biologic therapy in conjunction with surgery are limited. The purpose of this analysis was to investigate impact of surgery and biologic therapy on HS disease activity.

Methods

Data from 68 HS patients were analyzed. Outcome measures included hidradenitis suppurativa Sartorius Score (HSS), active nodule (AN) count, Hurley stage, and probability of achieving 75% reduction in active nodule count (AN75).

Results

Mean age was 40 ± 14 years; 66% were female and 72% were African American. Mean disease duration was 10 years, and Hurley stage III disease was seen in 63% of patients. Patients who received biologics had a larger drop in HSS and AN count than those who never received biologics (P = 0.002). Biologic treatment was associated with average reduction in 22 (15–29) HSS points (P < 0.0001). The effect of biologics was greater in patients who also underwent surgery (P = 0.013). Timing of biologics relative to surgery did not impact efficacy. Patients who received HS surgery with biologic therapy were most likely to achieve the AN75 (P = 0.017).

Conclusions

In this diverse cohort of patients with severe HS, biologic therapy was associated with a more rapid decline in disease activity, with the greatest effect in patients who also underwent HS surgery.
Pellicle formation, microbial succession and lactic acid utilisation during the aerobic deteriorating process of Sichuan pickle
Authors: Rao Yu , Qian Yang , She Xiao , Yang Jiantao , He Penghui , Jiang Yunlu , Wang Meng , Xiang Wenliang
Published: November 2017

The pellicles formation, microbial changes and lactic acid utilisation during the aerobic deterioration of Sichuan pickle were discussed in this study. By plate counting, chemical detection and HPLC analysis, the aerobic deterioration of Sichuan pickle was featured by microbial growth, pellicle formation, lactic acid decrease and pH elevation. Bacteria dominated in pellicles and the pellicles present morphological change from smooth to wrinkly along with the aerobic deteriorating process. Nine species of bacteria were identified and responsible for the pellicle formation. Combined with Lactobacillus plantarum, eight pellicle‐forming bacteria were the dominant lactic acid consuming organisms in deteriorating Sichuan pickle. Especially under the harsh acid condition of the early deteriorating period, Lb. plantarum, pellicle‐forming bacteria Bacillus amyloliquefaciens, B. subtilis and Citrobacter freundii participated in the pellicles, utilised lactic acid and increased the brine pH effectively. Sequence analysis of 16S rDNA libraries suggested that the resulting pH of 4.8–5.0 initiated the growth of more undesirable organisms, and the pellicle bacterial diversity changed greatly compared with that in the early deteriorating period. The study indicated the important role of pellicles in the initiation of Sichuan pickle's aerobic deterioration and enhanced our ability to understand and potentially control the aerobic deterioration.
Changes in degradation and phosphorylation level of titin in three ovine muscles during postmortem
Authors: Wang Ying , Li Xin , Li Zheng , Li Meng , Zhu Jie , Zhang Dequan
Published: November 2017

The objective of this study was to investigate the degradation of titin and its phosphorylation level in three muscles from sheep. The MFI and pH from the longissimus lumborum (LL), semimembranosus (SM) and psoas major (PM) muscles were measured at 30 min, 1, 2, 7, 14, 21 and 28 days postmortem. Myofibrillar proteins were extracted, separated by SDS‐PAGE and quantified by phosphor‐specific staining. Phosphorylation of titin was predicted by Pro‐Q Diamond‐SYPRO Ruby staining. Two days after exsanguination, the pH and MFI of the PM were higher than those of the LL and SM muscles (P < 0.05). The sarcomere length of the PM muscle was also longer than that of the LL and SM muscle (P < 0.05). PM muscles had a highest phosphorylation level (P < 0.05) at 0.5 h postmortem and showed the greatest degree of titin degradation over 28 days. This suggests that phosphorylation of titin might accelerate its degradation.
Influence of composition on degradation during repeated deep‐fat frying of binary and ternary blends of palm, sunflower and soybean oils with health‐optimised saturated‐to‐unsaturated fatty acid ratios
Authors: Rudzińska Magdalena , Hassanein Minar M. M. , Abdel‐Razek Adel G. , Kmiecik Dominik , Siger Aleksander , Ratusz Katarzyna
Published: November 2017

The American Heart Association recommended the fatty acid balance contributed by all the fats in our diet, suggesting it would be best at approximately 1:1:1 for saturated (SFA), monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA), respectively. Three individual oils: palm oil (PO), soybean oil (SBO) and sunflower oil (SNF) and their binary and ternary blends were prepared and used for repeated deep‐fat frying of French fries. The acid value, peroxide value, p‐anisidine value and Totox values, as well as oxidative stability, contents of total polar compounds, tocochromanols, triacylglycerol dimers and oligomers, were determined in individual and blended oils. The lowest Totox value and highest stability were found for PO, and the opposite data were obtained for SNF and SBO. The degradation of tocochromanols in blends ranged from 91% to 95% after 4 days of frying, while in individual oils, it was 63% in SBO, 71% in SNF and 100% in PO. The lowest formation of dimers and oligomers was observed for the PO: SNF blend. Obtained results showed that only pure PO was a better frying medium than its blends with SBO and SNF. However, a prepared blend had a better fatty acid composition for human health and was more stable than pure SBO and SNF.
Literature review of the epidemiology of influenza B disease in 15 countries in the Asia‐Pacific region
Authors: Jennings Lance , Huang Qiu Sue , Barr Ian , Lee Ping‐Ing , Kim Woo Joo , Buchy Philippe , Sanicas Melvin , Mungall Bruce A. , Chen Jing
Published: November 2017

Influenza control strategies focus on the use of trivalent influenza vaccines containing two influenza A virus subtypes and one of the two circulating influenza type B lineages (Yamagata or Victoria). Mismatches between the vaccine B lineage and the circulating lineage have been regularly documented in many countries, including those in the Asia‐Pacific region. We conducted a literature review with the aim of understanding the relative circulation of influenza B viruses in Asia‐Pacific countries. PubMed and Western Pacific Region Index Medicus were searched for relevant articles on influenza type B published since 1990 in English language for 15 Asia‐Pacific countries. Gray literature was also accessed. From 4834 articles identified, 121 full‐text articles were analyzed. Influenza was reported as an important cause of morbidity in the Asia‐Pacific region, affecting all age groups. In all 15 countries, influenza B was identified and associated with between 0% and 92% of laboratory‐confirmed influenza cases in any one season/year. Influenza type B appeared to cause more illness in children aged between 1 and 10 years than in other age groups. Epidemiological data for the two circulating influenza type B lineages remain limited in several countries in the Asia‐Pacific, although the co‐circulation of both lineages was seen in countries where strain surveillance data were available. Mismatches between circulating B lineages and vaccine strains were observed in all countries with available data. The data suggest that a shift from trivalent to quadrivalent seasonal influenza vaccines could provide additional benefits by providing broader protection.