bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunogenicity of meningococcal polysaccharide ACWY vaccine in primary immunized or revaccinated adults
Authors: Ferlito C , Biselli R , Cattaruzza M S , Teloni R , Mariotti S , Tomao E , Salerno G , Peragallo M S , Lulli P , Caporuscio S , Autore A , Bizzarro G , Germano V , Biondo M I , Picchianti Diamanti A , Salemi S , Nisini R , D'Amelio R
Published: August 2018

Meningococcal polysaccharide (Men-Ps) vaccine immunogenicity following either primary immunization or revaccination in adults was evaluated. The study population consisted of subjects who have received tetravalent Men-Ps vaccine once (group 1) or at least twice, with a 2–6 dose range (group 2). Human leucocyte antigen (HLA)-typing was performed by polymerase chain reaction and specific immunoglobulin (Ig)G was measured by enzyme-linked immunosorbent assay. Nine months post-immunization, the percentages of individuals with levels of anti-Men-Ps IgG ≥ 2 µg/ml were comparable in both groups, with the exception of anti-Men-PsW135 IgG, which were significantly higher in group 2. The percentage of subjects doubling IgG levels at 9 months was significantly higher in group 1. The high baseline anti-Men-Ps antibody levels negatively influenced the response to revaccination, suggesting a feedback control of specific IgG. The calculated durability of anti-Men-Ps IgG was 2·5–4·5 years, depending on the Men-Ps, following a single vaccine dose. No interference by other vaccinations nor HLA alleles association with immune response were observed. This study confirms that Men-Ps vaccine in adults is immunogenic, even when administered repeatedly, and underlines the vaccine suitability for large-scale adult immunization programmes that the higher costs of conjugate vaccines may limit in developing countries.
Comorbidities and complications of polycystic ovary syndrome: An overview of systematic reviews
Authors: Gilbert Emily W. , Tay Chau T. , Hiam Danielle S. , Teede Helena J. , Moran Lisa J.
Published: August 2018

Background

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting reproductive‐aged women with adverse reproductive, metabolic and psychological outcomes. It has a complex pathophysiology and therefore requires a multidiscipline clinical approach. However, there remains limited research synthesizing the broad clinical implications of PCOS which would assist clinicians in the management of PCOS.

Objective

To summarize and appraise methodological quality of systematic reviews and meta‐analyses evaluating complications and comorbidities associated with PCOS.

Methods

A literature search from MEDLINE, EMBASE, CINAHL PLUS and PROSPERO was performed until 15 September 2017. Article selection, data extraction and quality appraisal of included reviews using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool were performed in duplicate. A narrative synthesis of the findings was conducted.

Results

Twenty‐three reviews were included. All reviews were of low (n = 2) to moderate quality (n = 21). PCOS was associated with adverse pregnancy outcomes (n = 2), impaired glucose tolerance (n = 6), insulin resistance (n = 6), increased risk of type 2 diabetes (n = 1), cardiovascular disease (n = 10), metabolic syndrome (n = 2), psychological stress (n = 7), endometrial cancer (n = 1) and vitamin D deficiency (n = 1). Obesity exacerbates many of these outcomes.

Conclusions

There is a large body of reliable evidence for adverse metabolic outcomes and smaller, but consistent evidence for psychological issues in PCOS. We identified a shortage of systematic reviews regarding pregnancy outcomes of PCOS and significant gaps in knowledge of the association between PCOS and subclinical hyperthyroidism, vitamin D levels and cancers which future studies could aim to address.
Glucose and lipid metabolism, bone density, and body composition in individuals with Williams syndrome
Authors: Shaikh Sofia , Waxler Jessica L. , Lee Hang , Grinke Kathy , Garry Jamie , Pober Barbara R. , Stanley Takara L.
Published: August 2018

Objective

We assessed body composition, bone mineral density (BMD), glucose and lipids in Williams syndrome (WS), a rare microdeletion disorder.

Design

Individuals with WS had outpatient assessment at Massachusetts General Hospital. Controls were selected from the National Health and Nutrition Examination Survey (NHANES 2005‐2006).

Patients

A total of 22 individuals with WS, each matched by age, sex and race to four NHANES controls.

Measurements

Blood sampling, oral glucose tolerance test, dual‐energy X‐ray absorptiometry scan.

Results

WS and control groups were 59% female and 29 ± 8 years old. Compared to controls, individuals with WS were shorter but had similar body weight, with more fat and less lean mass. Per cent body fat was higher in WS even after adjusting for BMI (+2.1% [95% CI 0.4, 3.9%]). Four WS patients had abnormal lower extremity fat accumulation resembling lipedema. HbA1c (+0.5% [0.2, 0.7]) and 2‐hour glucose (+68 mg/dL [44, 93]) were higher in WS vs controls, differences which persisted after adjusting for BMI. Fasting glucose was comparable between groups. LDL (−18 mg/dL [−35, −2]) and triglycerides (−45 mg/dL [−87, −2]) were significantly lower in WS. Whole‐body BMD was significantly lower (−0.15 g/cm2 [−0.20, −0.11]) in WS, and this remained true controlling for height (−0.06 g/cm2 [−0.11, −0.02]). Vitamin D was <30 ng/mL in 81% of those with WS.

Conclusions

On average, adults with WS have increased fat, decreased lean mass, impaired glucose homeostasis and reduced BMD. Clinical efforts to build muscle and bone mass, and to ensure vitamin D sufficiency, are warranted. Genotype–phenotype research efforts are also warranted.
Progranulin is a novel biomarker for predicting an acute exacerbation of chronic obstructive pulmonary disease
Authors: Chen Xiaoyan , Liu Jinguo , Zhu Mengchan , Hu Bijie , Bai Fengxi , Jin Wenting , Zhou Jian , Chen Cuicui , Song Yuanlin , Pan Jue
Published: August 2018

Background

Progranulin is a pleiotropic glycosylated protein precursor that plays an important role in inflammation. Limited data exist regarding the role of progranulin in the acute exacerbation of chronic obstructive pulmonary disease (AECOPD).

Objectives

The study is to assess the efficiency of progranulin as a circulating biomarker of AECOPD.

Methods

The plasma progranulin levels were measured and compared in patients with AECOPD (n = 52), patients with stable COPD (n = 56), and healthy controls (n = 36). In patients with AECOPD, plasma progranulin levels were measured repeatedly on the last day of hospitalization. Demographical data, pulmonary function, and laboratory parameters were recorded.

Results

Patients with AECOPD had higher plasma progranulin levels than both stable COPD patients and healthy controls (158.77 ± 48.17, 109.00 ± 25.05, 93.67 ± 14.71 ng/mL, respectively; P < .001). In patients with AECOPD, the plasma progranulin levels significantly decreased on the last day of hospitalization compared with those on the first day of hospitalization (138.51 ± 44.68 vs. 158.77 ± 48.17 ng/mL, P = .042). The progranulin levels were negatively correlated to FEV1%pred but positively correlated to neutrophil‐to‐lymphocyte ratio and C‐reactive protein in all patients with COPD. Multivariate logistic regression and ROC analysis revealed progranulin (odds ratio 1.05, 95% confidence interval 1.03‐1.08, P < .001) as an independent predictor of AECOPD, with an area under the curve of 0.82.

Conclusions

Progranulin may be a valuable blood biomarker of AECOPD and progranulin may be involved in the pathogenesis of AECOPD by disturbing inflammatory responses.
Racial disparities in preemptive referral for kidney transplantation in Georgia
Authors: Gander Jennifer C. , Zhang Xingyu , Plantinga Laura , Paul Sudeshna , Basu Mohua , Pastan Stephen O. , Gibney Eric , Hartmann Erica , Mulloy Laura , Zayas Carlos , Patzer Rachel E.
Published: August 2018

Background

Racial disparities persist in access to kidney transplantation. Racial differences in preemptive referral, or referral prior to dialysis start, may explain this discrepancy.

Methods

Patient‐level data on kidney transplant referrals (2005‐2012) from all Georgia transplant centers were linked to the United States Renal Data System to examine racial disparities in preemptive referral, waitlisting, and living donor transplant. Adjusted logistic regression and Cox proportional hazard models determined the associations between race (African American vs white) and preemptive referral, and placement on the waitlist and receipt of a living donor kidney, respectively.

Results

Among 7752 adults referred for transplant evaluation, 20.38% (n = 1580) were preemptively referred. The odds of African Americans being preemptively referred for transplant evaluation were 37% (OR = 0.63; [95% CI: 0.55 0.71]) lower than white patients. Among preemptively referred patients, there was no racial difference (African Americans compared to white patients. HR = 0.96; [95% CI: 0.88, 1.04]) in waitlisting. However, African Americans were 70% less likely than white patients to receive a living donor transplant (HR = 0.30; [95% CI: 0.21, 0.42]).

Conclusion

Racial disparities in transplant receipt may be partially explained by disparities in preemptive referral. Interventions to reduce racial disparities in kidney transplant access may need to be targeted earlier in the disease process.
Racial disparity in kidney transplant survival relates to late rejection and is independent of steroid withdrawal
Authors: Liu Angela , Woodside Kenneth J. , Augustine Joshua J. , Sarabu Nagaraju
Published: August 2018

Black kidney transplant recipients have more acute rejection (AR) and inferior graft survival. We sought to determine whether early steroid withdrawal (ESW) had an impact on AR and death‐censored graft loss (DCGL) in blacks. From 2006 to 2012, AR and graft survival were analyzed in 483 kidney recipients (208 black and 275 non‐black). Rates of ESW were similar between blacks (65%) and non‐blacks (67%). AR was defined as early (≤3 months) or late (>3 months). The impact of black race, early AR, and late AR on death‐censored graft failure was analyzed using univariate and multivariate Cox models. Blacks had greater dialysis vintage, more deceased donor transplants, and less HLA matching, yet rates of early AR were comparable between blacks and non‐blacks. However, black race was a risk factor for late AR (HR: 3.48 (95% CI: 1.87‐6.47)) Blacks had a greater rate of DCGL, partially driven by late AR (HR with late AR: 5.6; 95% CI: 3.3‐9.3). ESW had no significant interaction with black race for risk of early AR, late AR, or DCGL. Independent of ESW, black kidney recipients had a higher rate of late AR after kidney transplantation. Late AR was highly predictive of DCGL and contributed to inferior graft survival in blacks.
Bilateral intraorbital masses in a child
Authors: Gupta Parikshaa , Kaur Gurwinder , Rajwanshi Arvind , Bansal Sandeep , Kamble Rajeev , R. Ranjini
Published: August 2018

The present case demonstrates the characteristic cytomorphological features of an uncommon condition involving an usual site ‐ presenting as bilateral orbital soft tissue masses in a child. The case leads the reader through a series of questions to a diagnosis and discusses that condition. It also highlights the diagnostic role of fine needle aspiration cytology in such cases.
Sleep deprivation versus melatonin to induce sleep during paediatric electroencephalography
Authors: Zaiwalla Zenobia
Published: August 2018

This commentary is on the original article by Alix et al. on pages 181–185 of this issue.
Giant coronary artery aneurysms in an infant with Kawasaki disease: Evaluation by echocardiography and computed tomographic angiography
Authors: Cameron Scott A. , Robinson Joshua D. , Carr Michael R. , Patel Angira
Published: August 2018

Kawasaki disease (KD) is a vasculitis that affects medium‐sized arteries and can lead to coronary artery aneurysms. KD should be considered in any infant presenting with prolonged fever. Delaying treatment beyond Day 10 of fever portends a high risk of coronary artery aneurysms. Echocardiography is often necessary to diagnose KD in young infants who frequently present without classic physical examination findings. We report on a case of KD with giant aneurysms in a 2‐month‐old infant. A combination of transthoracic echocardiography and CT angiography was utilized in the diagnosis as well as in the management of this infant.
Deformation imaging of the atria using 2D strain: A noninvasive modality to characterize operating compliance?
Authors: Saha Samir K. , Kiotsekoglou Anatoli , Gopal Aasha S.
Published: August 2018

This viewpoint with two illustrated case summaries of biventricular and biatrial mechanical function/dysfunction emphasizes the importance of continued research in deformation imaging beyond the left ventricle, as there are no Cinderellas in the heart and we just cannot afford to be nonchalant toward the atria, particularly the right atrium.
Unusual sequelae of a subluxated primary incisor on its permanent successor tooth
Authors: Cho Vanessa Y. Y. , Anthonappa Robert P. , King Nigel M.
Published: August 2018

Traumatic dental injuries (TDIs) such as subluxations of primary teeth can have significant consequences on their developing successors. The purpose of this report is to present a 3‐year‐old boy who encountered subluxation injuries to his primary incisors which subsequently had an unusual consequence on the permanent successor. On the day of the TDI, based on clinical and radiographic examinations, a diagnosis of subluxation of teeth 52, 51 and 61 was made. By age 5, the patient reported that tooth 51 had exfoliated, and consequently, tooth 11 had erupted into the oral cavity, but it was very loose. Eventually, the patient lost the crown of tooth 11 during his routine daily activities. Furthermore, radiographic examination at age 11 revealed a small root‐like structure in the tooth 11 region. It is very unusual to have premature loss of a permanent incisor following subluxation to its predecessor. Therefore, the present case serves as a good example to emphasize that even minor TDIs are of considerable importance as they may lead to unexpected consequences.
Granulocyte‐macrophage colony‐stimulating factor improves mouse peripheral nerve regeneration following sciatic nerve crush
Authors: Bombeiro André Luis , Pereira Bruna Toledo Nunes , de Oliveira Alexandre Leite Rodrigues
Published: August 2018

Peripheral nerve injuries severely impair patients’ quality of life as full recovery is seldom achieved. Upon axonal disruption, the distal nerve stump undergoes fragmentation, and myelin breaks down; the subsequent regeneration progression is dependent on cell debris removal. In addition to tissue clearance, macrophages release angiogenic and neurotrophic factors that contribute to axon growth. Based on the importance of macrophages for nerve regeneration, especially during the initial response to injury, we treated mice with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) at various intervals after sciatic nerve crushing. Sciatic nerves were histologically analyzed at different time intervals after injury for the presence of macrophages and indicators of regeneration. Functional recovery was followed by an automated walking track test. We found that GM‐CSF potentiated early axon growth, as indicated by the enhanced expression of growth‐associated protein at 7 days postinjury. Inducible nitric oxide synthase expression increased at the beginning and at the end of the regenerative process, suggesting that nitric oxide is involved in axon growth and pruning. As expected, GM‐CSF treatment stimulated macrophage infiltration, which increased at 7 and 14 days; however, it did not improve myelin clearance. Instead, GM‐CSF stimulated early brain‐derived neurotrophic factor (BDNF) production, which peaked at 7 days. Locomotor recovery pattern was not improved by GM‐CSF treatment. The present results suggest that GM‐CSF may have beneficial effects on early axonal regeneration.
Dopamine and opioids inhibit synaptic outputs of the main island of the intercalated neurons of the amygdala
Authors: Gregoriou Gabrielle C. , Kissiwaa Sarah A. , Patel Sahil D. , Bagley Elena E.
Published: August 2018

Neural circuits in the amygdala are important for associating the positive experience of drug taking with the coincident environmental cues. During abstinence, cue re‐exposure activates the amygdala, increases dopamine release in the amygdala and stimulates relapse to drug use in an opioid dependent manner. Neural circuits in the amygdala and the learning that underlies these behaviours are inhibited by GABAergic synaptic inhibition. A specialised subtype of GABAergic neurons in the amygdala are the clusters of intercalated cells. We focussed on the main‐island of intercalated cells because these neurons, located ventromedial to the basolateral amygdala, express very high levels of dopamine D1‐receptor and μ‐opioid receptor, release enkephalin and are densely innervated by the ventral tegmental area. However, where these neurons project to was not fully described and their regulation by opioids and dopamine was incomplete. To address this issue we electrically stimulated in the main‐island of the intercalated cells in rat brain slices and made patch‐clamp recordings of GABAergic synaptics from amygdala neurons. We found that main‐island neurons had a strong GABAergic inhibitory output to pyramidal neurons of the basolateral nucleus and the medial central nucleus, the major output zones of the amygdala. Opioids inhibited both these synaptic outputs of the intercalated neurons and thus would disinhibit these target zones. Additionally, dopamine acting at D1‐receptors inhibited main‐island neuron synapses onto other main‐island neurons. This data indicates that the inhibitory projections from the main‐island neurons could influence multiple aspects of addiction and emotional processing in an opioid and dopamine dependent manner.
Binge drinking is associated with attenuated frontal and parietal activation during successful response inhibition in fearful context
Authors: Herman Aleksandra M. , Critchley Hugo D. , Duka Theodora
Published: August 2018

Binge drinking is associated with increased impulsivity and altered emotional processing. This study investigated, in a group of university students who differed in their level of binge drinking, whether the ability to inhibit a pre‐potent response and to delay gratification is disrupted in the presence of emotional context. We further tested whether functional connectivity within intrinsic resting‐state networks was associated with alcohol use. Higher incidence of binge drinking was associated with enhanced activation of the lateral occipital cortex, angular gyrus, the left frontal pole during successful response inhibition irrespective of emotional context. This observation suggests a compensatory mechanism. However, higher binge drinking attenuated frontal and parietal activation during successful response inhibition within a fearful context, indicating the selective emotional facilitation of inhibitory control. Similarly, higher binge drinking was associated with attenuated frontopolar activation when choosing a delayed reward over an immediate reward within the fearful, relative to the neutral, context. Resting‐state functional data analysis revealed that binge drinking decreased coupling between the right supramarginal gyrus and Ventral Attention Network, indicating alcohol‐associated disruption of functional connectivity within brain substrates directing attention. Together, our results suggest that binge drinking makes response inhibition more effortful, yet emotional (more arousing) contexts may mitigate this; disrupted functional connectivity between regions underlying adaptive attentional control, is a likely mechanism underlying these response inhibition effects associated with binge drinking.
Cell‐based therapy for Parkinson's disease: A journey through decades toward the light side of the Force
Authors: Parmar Malin , Torper Olof , Drouin‐Ouellet Janelle
Published: August 2018

This review describes the history, development, and evolution of cell‐based replacement therapy for Parkinson's disease (PD), from the first pioneering trials with fetal ventral midbrain progenitors to future trials using stem cells as well as reprogrammed cells. In the spirit of Tom Isaacs, the review takes parallels to the storyline of Star Wars, including the temptations from the dark side and the continuous fight for the light side of the Force. It is subdivided into headings based on the original movies, spanning from A New Hope to the Last Jedi.
Systematic review of the effects of acute stress in binge eating disorder
Authors: Naish Katherine R. , Laliberte Michele , MacKillop James , Balodis Iris M.
Published: August 2018

Binge eating disorder (BED) is characterized by recurrent episodes of eating an excessive amount of food over a discrete time period, while feeling a loss of control over one's eating. Although stress is one of the most commonly reported triggers of binge eating in individuals with BED, there has been little work examining the stress response specifically in individuals with the disorder. In this review, we examine what is known about how individuals with BED respond to acute stressors. A systematic literature search identified 14 relevant articles that report on the effects of experimentally induced stress on objective measures. Dependent measures that have been examined include changes in the levels of hormones such as cortisol and ghrelin, cardiovascular function, ad libitum food intake and eating rate. In this review, we describe the published findings and discuss their implications in the context of the wider literature. Overall, we found partial evidence that BED is associated with a heightened response to stress. Given the inconsistencies between studies, we suggest that reported differences between individuals with and without BED might be driven by factors that are correlated with, but not specific to, BED. We suggest that two priorities for this research area are to identify factors that modulate the stress response in individuals with BED, and to address the underrepresentation of males in this literature.
A 6‐month prospective randomized controlled trial of remotely delivered group format epilepsy self‐management versus waitlist control for high‐risk people with epilepsy
Authors: Sajatovic Martha , Colon‐Zimmermann Kari , Kahriman Mustafa , Fuentes‐Casiano Edna , Liu Hongyan , Tatsuoka Curtis , Cassidy Kristin A. , Lhatoo Samden , Einstadter Douglas , Chen Peijun
Published: August 2018

Objective

Despite advances in care, many people with epilepsy have negative health events (NHEs) such as accidents, emergency department visits, and poor quality of life. “Self‐management forpeople with epilepsy and a history of negative health events” (SMART) is a novel group format epilepsy self‐management intervention. A community participatory approach informed the refinement ofSMART, which was then tested in a 6‐month randomized controlled trial ofSMART(n = 60) versus waitlist control (WL, n = 60).

Methods

Participants were adults aged ≥18 years with epilepsy and anNHEwithin the past 6 months (seizure, accident, self‐harm attempt, emergency department visit, or hospitalization). Assessments were conducted at screening, baseline, 10 weeks, and 24 weeks (6 months). Primary outcome was 6‐month change in totalNHEcount. Additional outcomes included depression on the nine‐item Patient Health Questionnaire and Montgomery‐Asberg Depression Rating Scale, quality of life on the 10‐item Quality of Life in Epilepsy, functioning on the 36‐item Short‐Form Health Survey, and seizure severity on the Liverpool Seizure Severity Scale.

Results

Mean age was 41.3 years (SD = 11.82), 69.9% were African American, 74.2% were unemployed, and 87.4% had an annual income < US$25 000; 57.5% had a seizure within 30 days of enrollment. MostNHEs were seizures. Six‐month study attrition was 14.2% overall and similar between arms. Individuals randomized toSMARThad greater reduction in total medianNHEs from baseline to 6 months compared toWL(P = 0.04).SMARTwas also associated with improved nine‐item Patient Health Questionnaire (P = 0.032), Montgomery‐Asberg Depression Rating Scale (P = 0.002), 10‐item Quality of Life in Epilepsy (P < 0.001), and 36‐item Short‐Form Health Survey (P = 0.015 physical health,P = 0.003 mental health) versusWL. There was no difference in seizure severity.

Significance

SMARTis associated with reduced health complications and improved mood, quality of life, and health functioning in high‐risk people with epilepsy. Additional efforts are needed to investigate potential for scale‐up.
Differential expression of lncRNAs and predicted target genes in normal mouse melanocytes and B16 cells
Authors: Ji Kaiyuan , Zhang Junzhen , Fan Ruiwen , Yang Shanshan , Dong Changsheng
Published: August 2018

Melanoma is a highly invasive and metastatic malignant skin tumor with poor prognosis. Although several widely studied pure melanoma cell lines are available, the precise mechanism underlying transformation of melanocyte to melanoma remains unclear. Long non‐coding RNAs (lncRNAs) represent a vast category of non‐coding RNA molecules, and increasing evidence suggests that lncRNAs are crucial for various biological processes, including those in the skin. Herein, lncRNA sequencing was performed on an Illumina HiSeq platform to identify lncRNAs expressed differently in murine B16 melanoma cells compared to normal mouse melanocytes. Using four computational approaches, 2319 lncRNAs were expressed in both normal melanocytes and B16 cells, with 373 being differentially expressed at a significant level. Of these, 136 lncRNAs were upregulated and 237 were downregulated. KEGG analyses revealed that 467 genes were target genes in the Wnt signalling pathway, TGF‐beta signalling pathway, MAPK signalling pathway, NF‐kappa B signalling pathway, melanoma and several other cancer‐related regulatory pathways. From among the differentially expressed lncRNAs, lnc‐13317.1 was found to play a role in the cell cycle in melanoma by targeting BRCA1. Thus, lnc‐13317.1 might have therapeutic potential in melanoma treatment. The lncRNA profile described here highlights the importance of elucidating the exact function of these lncRNAs in the transformation of melanoma. Lnc‐13317.1 might have therapeutic potential in melanoma treatment by targeting BRCA1.
Decorin promotes proliferation and migration of ORS keratinocytes and maintains hair anagen in mice
Authors: Zhou Lijuan , Jing Jing , Wang Han , Wu Xianjie , Lu Zhongfa
Published: August 2018

DECORIN is a prototypical member of the small leucine‐rich proteoglycan (SLRP) family that plays important roles in numerous biological processes and cellular biological pathways. We previously showed that Decorin expression was highly enhanced in mouse dorsal hair follicles (HFs) during the anagen phase and was reduced during the catagen and telogen phases, suggesting that Decorin might modulate follicular cycling and morphogenesis. In this study, to further clarify the effects of DECORIN on hair cells and the cycling transition, an in vitro overexpression strategy and Decorin‐null (Dcn−/−) mice were used to investigate the effects of DECORIN on outer root sheath (ORS) keratinocytes. DECORIN overexpression significantly enhanced proliferation and migration in ORS keratinocytes in vitro. Moreover, DECORIN overexpression upregulated the mRNA and protein expression levels of WNT10b, β‐CATENIN and LEF1. The DECORIN overexpression‐induced increase in the proliferation and migration of ORS keratinocytes was partially inhibited by a Wnt/β‐catenin inhibitor. Furthermore, Dcn−/− mice had a shortened anagen phase and lower levels of β‐catenin expression than were observed in wild‐type mice in imaging and histological analyses. Taken together, these findings suggest that DECORIN promotes the proliferation and migration of ORS keratinocytes in vitro and maintains hair anagen in mice.
Pushing the limit: Resilience of an Arctic copepod to environmental fluctuations
Authors: Kvile Kristina Øie , Ashjian Carin , Feng Zhixuan , Zhang Jinlun , Ji Rubao
Published: August 2018

Life history strategies such as multiyear life cycles, resting stages, and capital breeding allow species to inhabit regions with extreme and fluctuating environmental conditions. One example is the zooplankton species Calanus hyperboreus, whose life history is considered an adaptation to the short and unpredictable growth season in the central Arctic Ocean. This copepod is commonly described as a true Arctic endemic; however, by statistically analyzing compiled observational data, we show that abundances are relatively low and later stages and adults dominate in the central Arctic Ocean basins, indicating expatriation. Combining data analyses with individual‐based modeling and energy requirement estimation, we further demonstrate that while C. hyperboreus can reach higher abundances in areas with greater food availability outside the central Arctic basins, the species’ resilience to environmental fluctuations enables the life cycle to be completed in the central Arctic basins. Specifically, the energy level required to reach the first overwintering stage—a prerequisite for successful local production—is likely met in some—but not all—years. This fine balance between success and failure indicates that C. hyperboreus functions as a peripheral population in the central Arctic basins and its abundance will likely increase in areas with improved growth conditions in response to climate change. By illustrating a key Arctic species’ resilience to extreme and fluctuating environmental conditions, the results of this study have implications for projections of future biogeography and food web dynamics in the Arctic Ocean, a region experiencing rapid warming and sea ice loss.
Adenomatoid tumour of the uterus is frequently associated with iatrogenic immunosuppression
Authors: Tamura Daisuke , Maeda Daichi , Halimi Sultan Ahmad , Okimura Masato , Kudo‐Asabe Yukitsugu , Ito Satoru , Sato Naoki , Shibahara Junji , Nanjo Hiroshi , Terada Yukihiro , Goto Akiteru
Published: August 2018

Aims

Uterine adenomatoid tumour (AT) is a benign proliferation of cells showing mesothelial differentiation within the myometrium that usually presents as a single nodule. Rare diffuse uterine ATs have been reported, often in patients undergoing immunosuppressive therapy. Herein, we aimed to elucidate the general association between the incidence of uterine AT and iatrogenic immunosuppression by cohort analysis.

Methods and results

We analysed 611 consecutive hysterectomy specimens to determine the incidence of AT and its correlation with the immunosuppressive status. Mesothelial lineage, p16 expression, mismatch repair (MMR) protein alterations, and the possible integration of tumorigenic viruses were examined by in situ hybridizasion and immunohistochemistry. ATs were detected in 14 of 611 hysterectomy cases (2.3%). The incidence of AT was significantly higher in the immunosuppressed (IS) group (5/20, 25.0%) than in the non‐IS group (9/591, 1.52%), with a relative risk of 16.4. Of the five ATs in the IS group, three were multifocal or diffuse. Latent uterine AT was detected, by in toto sectioning, in one of four immunosuppressed autopsy cases. The tumor cells of ATs commonly expressed calretinin and podoplanin. Characteristic block‐type (≥90%) positivity for p16 was observed in most ATs. None of the ATs were positive for human herpes virus type 8, Merkel cell polyomavirus, SV40 large T antigen, Epstein‐Barr virus, and human papilloma virus, and the MMR proteins were retained. A TRAF7 mutation was identified from macrodissected tissue in one of 12 ATs by Sanger sequencing.

Conclusion

Uterine AT is an immunosuppression‐associated mesothelial lesion characterised by p16 overexpression.
Bacterial species associated with persistent apical periodontitis exert differential effects on osteogenic differentiation
Authors: Chow A. T. , Quah S. Y. , Bergenholtz G. , Lim K. C. , Yu V. S. H. , Tan K. S.
Published: August 2018

Aim

To determine if bacteria associated with persistent apical periodontitis induce species‐specific pro‐inflammatory cytokine responses in macrophages, and the effects of this species‐specific microenvironment on osteogenic differentiation.

Methodology

Macrophages were exposed to Enterococcus faecalis, Streptococcus oralis, Streptococcus mitis, Fusobacterium nucleatum, Treponema denticola or Tannerella forsythia, and levels of TNF‐α and IL‐1β elicited were determined by immunoassay. Following treatment of MG‐63 pre‐osteoblasts with conditioned media from bacteria‐exposed macrophages, osteogenic differentiation and viability of osteoblasts were analyzed by Alizarin Red Staining and MTS assay, respectively. Statistical analysis was carried out by one‐way anova with the Tukey post‐hoc test. Differences were considered to be significant if P < 0.05.

Results

Macrophages exposed to Gram‐positive bacteria did not produce significant amounts of cytokines. F. nucleatum‐challenged macrophages produced up to four‐fold more TNF‐α and IL‐1β compared to T. denticola or T. forsythia. Only conditioned media from macrophages treated with Gram‐negative bacteria decreased mineralization and viability of osteoblasts.

Conclusions

Gram‐positive bacteria did not impact osteogenic differentiation and appeared innocuous. Gram‐negative bacteria, in particular F. nucleatum elicited an enhanced pro‐inflammatory response in macrophages, inhibited osteogenic differentiation and reduced cell viability. The findings suggest that the presence of this organism could potentially increase the severity of persistent apical periodontitis.
Effectiveness of technology‐enhanced learning in Endodontic education: a systematic review and meta‐analysis
Authors: Nagendrababu V. , Pulikkotil S. J. , Sultan O. S. , Jayaraman J. , Soh J. A. , Dummer P. M. H.
Published: August 2018

The aim of the present systematic review was to evaluate the effectiveness of technology‐enhanced learning (TEL) in the field of Endodontics to improve educational outcomes compared to traditional learning methods. Randomized controlled studies published in English were identified from two electronic databases (PubMed and Scopus) up to May 2018. Two authors independently performed study selection, data extraction and assessed the risk of bias (ROB). Any teaching method using TEL was considered as the intervention, and this was compared to traditional methods. The outcome measuring the effectiveness of learning activities was evaluated by Kirkpatrick's four‐level training evaluation model. The four levels of training outcomes are as follows: Reaction, Learning, Behaviour and Results. A meta‐analysis was performed to estimate the standardized mean difference (SMD) by the random effects model. In total, 13 studies were included in the systematic review. Only three studies were assessed as ‘low’ ROB. A meta‐analysis could not be performed in the domains of Reaction and Behaviour. No significant difference was observed in knowledge gain (Learning domain) between TEL and traditional methods (SMD, 0.14 (95% CI −0.10 to 0.39) I2 = 62.7%). Similarly, no difference was observed in performance (Behaviour domain). A variable response was found in attitude (Reaction domain). From the available evidence, it can be concluded that TEL is equally as effective as traditional learning methods.
Evidence for changing nerve growth factor signalling mechanisms during development, maturation and ageing in the rat molar pulp
Authors: Mahdee A. , Eastham J. , Whitworth J. M. , Gillespie J. I.
Published: August 2018

Aim

To examine rat molar pulp innervation and identify complex cellular signalling systems involving nerve growth factor (NGF) and its p75 receptors (NGFR) at different stages of development, maturation and ageing.

Methodology

Decalcified mandibular first molar mesial cusps from Wistar rats of ages 0 day; 1, 2, 3, 4, 6, 9, 12 and 24 weeks (n = 5 per group) were sectioned (10 μm) and incubated with antibodies for NGF, NGFR, calcitonin gene‐related peptide (CGRP) and neurofilament. Nerve densities in worn and intact regions of 3‐ to 24‐week‐old rats were compared by anova, Bonferroni and t‐tests.

Results

During odontogenesis, differences in NGF and NGFR expression were observed, with no evidence of nerve fibres, suggesting a signalling mechanism controlling cellular differentiation and dentine formation. Tooth wear in 4‐week rats was associated with reduced NGF expression and significantly decreased CGRP axons within affected odontoblast regions. The underlying subodontoblasts started expressing NGF which continued until 9 weeks. This may promote a significant increase in CGRP nerve density in affected regions. Nerve density in intact odontoblast regions increased gradually and reached significant levels in 12‐week rats. Reduction in nerve densities within worn and intact regions of cusps was observed at 24 weeks.

Conclusions

Age‐related changes and responses to tooth wear may be controlled by the NGF signalling mechanism, with roles in odontoblast/subodontoblast communication and control of sensory innervation at different stages of tooth development, maturation and ageing. Greater understanding of cellular and nerve regulation in the injured pulp may promote therapeutic strategies for pulp survival.
Prevalence, risk factors, and mortality outcome in the drug reaction with eosinophilia and systemic symptoms patients with cardiac involvement
Authors: Intarasupht Julphat , Kanchanomai Anchisa , Leelasattakul Wuttirak , Chantrarat Thoranis , Nakakes Artit , Tiyanon Waraporn
Published: August 2018

Background

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous drug reaction that can affect multiple internal organ systems. Cardiac involvement in DRESS syndrome (CiDs) is uncommon but can be life‐threatening.

Objective

To determine the prevalence, risk factors, and mortality outcome of CiDs.

Material and methods

Forty‐one patients who were diagnosed with probable and definite DRESS syndrome according to the RegiSCAR criteria were recruited. Cardiac involvement was evaluated by two independent cardiologists.

Results

The cardiac involvement was found in 8/41 (19.5%) patients. Specifically, myocardial involvement was found in five patients, while three patients had pericardial involvement. The majority of culprit drugs were antibiotics followed by anti‐epileptic medications. The hemoglobin and albumin levels were significantly lower in the patients with CiDs when compared to the patients without CiDs (P‐value = 0.005 for both factors). The mortality rate at 30 and 90 days was significantly higher among CiDs patients, that is, 3/8 (37.5%) versus 2/28 (6.1%); P‐value = 0.02 and 4/8 (50.0%) versus 2/33 (6.1%); P‐value = 0.002 respectively.

Conclusion

Our study showed the prevalence of CiDs was as high as 19.5% with high mortality rate. We suggest a thorough cardiac evaluation in all DRESS patients with RegiSCAR score ≥4. The patients with CiDs had significantly lower hemoglobin and albumin levels, which might imply poor health condition, when compared to those without CiDs.
Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology
Authors: Cicchese Joseph M. , Evans Stephanie , Hult Caitlin , Joslyn Louis R. , Wessler Timothy , Millar Jess A. , Marino Simeone , Cilfone Nicholas A. , Mattila Joshua T. , Linderman Jennifer J. , Kirschner Denise E.
Published: August 2018

Immune responses to pathogens are complex and not well understood in many diseases, and this is especially true for infections by persistent pathogens. One mechanism that allows for long‐term control of infection while also preventing an over‐zealous inflammatory response from causing extensive tissue damage is for the immune system to balance pro‐ and anti‐inflammatory cells and signals. This balance is dynamic and the immune system responds to cues from both host and pathogen, maintaining a steady state across multiple scales through continuous feedback. Identifying the signals, cells, cytokines, and other immune response factors that mediate this balance over time has been difficult using traditional research strategies. Computational modeling studies based on data from traditional systems can identify how this balance contributes to immunity. Here we provide evidence from both experimental and mathematical/computational studies to support the concept of a dynamic balance operating during persistent and other infection scenarios. We focus mainly on tuberculosis, currently the leading cause of death due to infectious disease in the world, and also provide evidence for other infections. A better understanding of the dynamically balanced immune response can help shape treatment strategies that utilize both drugs and host‐directed therapies.
Herpes simplex virus‐2 dynamics as a probe to measure the extremely rapid and spatially localized tissue‐resident T‐cell response
Authors: Schiffer Joshua T. , Swan David A. , Prlic Martin , Lund Jennifer M.
Published: August 2018

Herpes simplex virus‐2 infection is characterized by frequent episodic shedding in the genital tract. Expansion in HSV‐2 viral load early during episodes is extremely rapid. However, the virus invariably peaks within 18 hours and is eliminated nearly as quickly. A critical feature of HSV‐2 shedding episodes is their heterogeneity. Some episodes peak at 108 HSV DNA copies, last for weeks due to frequent viral re‐expansion, and lead to painful ulcers, while others only reach 103 HSV DNA copies and are eliminated within hours and without symptoms. Within single micro‐environments of infection, tissue‐resident CD8+ T cells (TRM) appear to contain infection within a few days. Here, we review components of TRM biology relevant to immune surveillance between HSV‐2 shedding episodes and containment of infection upon detection of HSV‐2 cognate antigen. We then describe the use of mathematical models to correlate large spatial gradients in TRM density with the heterogeneity of observed shedding within a single person. We describe how models have been leveraged for clinical trial simulation, as well as future plans to model the interactions of multiple cellular subtypes within mucosa, predict the mechanism of action of therapeutic vaccines, and describe the dynamics of 3‐dimensional infection environment during the natural evolution of an HSV‐2 lesion.
Modeling the dynamics of hepatitis B infection, immunity, and drug therapy
Authors: Ciupe Stanca M
Published: August 2018

Hepatitis B virus infection is the cause of liver diseases such as cirrhosis and liver cancer. Understanding the host‐virus mechanisms that mediate virus pathogenesis can help design better preventive measures for disease control. Mathematical models have been used alongside experimental data to provide insight into the role of immune responses during the acute and chronic hepatitis B infections as well as virus dynamics following administration of combined drug therapy. In this paper, we review several modeling studies on virus‐host interactions during acute infection, the virus‐host characteristics responsible for transition to chronic disease, and the efficacy and optimal control measures of drug therapy. We conclude by presenting our opinion on the future directions of the field.
Mathematical modeling of within‐host Zika virus dynamics
Authors: Best Katharine , Perelson Alan S
Published: August 2018

Recent Zika virus outbreaks have been associated with severe outcomes, especially during pregnancy. A great deal of effort has been put toward understanding this virus, particularly the immune mechanisms responsible for rapid viral control in the majority of infections. Identifying and understanding the key mechanisms of immune control will provide the foundation for the development of effective vaccines and antiviral therapy. Here, we outline a mathematical modeling approach for analyzing the within‐host dynamics of Zika virus, and we describe how these models can be used to understand key aspects of the viral life cycle and to predict antiviral efficacy.
Virus dynamics and phyloanatomy: Merging population dynamic and phylogenetic approaches
Authors: Bons Eva , Regoes Roland R
Published: August 2018

In evolutionary biology and epidemiology, phylodynamic methods are widely used to infer population biological characteristics, such as the rates of replication, death, migration, or, in the epidemiological context, pathogen spread. More recently, these methods have been used to elucidate the dynamics of viruses within their hosts. Especially the application of phylogeographic approaches has the potential to shed light on anatomical colonization pathways and the exchange of viruses between distinct anatomical compartments. We and others have termed this phyloanatomy. Here, we review the promise and challenges of phyloanatomy, and compare them to more classical virus dynamics and population genetic approaches. We argue that the extremely strong selection pressures that exist within the host may represent the main obstacle to reliable phyloanatomic analysis.
Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon‐free treatment era
Authors: Raja Rubesh , Baral Subhasish , Dixit Narendra M.
Published: August 2018

The advent of powerful direct‐acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA‐based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment‐naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA‐based treatments.
Molecular mechanisms of T cell sensitivity to antigen
Authors: Siller‐Farfán Jesús A. , Dushek Omer
Published: August 2018

T cells initiate and regulate adaptive immune responses that can clear infections. To do this, they use their T cell receptors (TCRs) to continually scan the surfaces of other cells for cognate peptide antigens presented on major histocompatibility complexes (pMHCs). Experimental work has established that as few 1‐10 pMHCs are sufficient to activate T cells. This sensitivity is remarkable in light of a number of factors, including the observation that the TCR and pMHC are short molecules relative to highly abundant long surface molecules, such as CD45, that can hinder initial binding, and moreover, the TCR/pMHC interaction is of weak affinity with solution lifetimes of approximately 1 second. Here, we review experimental and mathematical work that has contributed to uncovering molecular mechanisms of T cell sensitivity. We organize the mechanisms by where they act in the pathway to activate T cells, namely mechanisms that (a) promote TCR/pMHC binding, (b) induce rapid TCR signaling, and (c) amplify TCR signaling. We discuss work showing that high sensitivity reduces antigen specificity unless molecular feedbacks are invoked. We conclude by summarizing a number of open questions.