bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved menstrual function in obese women with polycystic ovary syndrome after behavioural modification intervention—A randomized controlled trial
Authors: Oberg Emma , Gidlöf Sebastian , Jakson Ivika , Mitsell Marja , Tollet Egnell Petra , Hirschberg Angelica Lindén
Published: December 2018

Objective

Lifestyle intervention is the recommended first‐line treatment for overweight women with polycystic ovary syndrome (PCOS). However, the efficacy of lifestyle change in improving reproductive function is still unclear.

Design

A randomized controlled trial (RCT) with allocation to a behavioural modification programme (intervention) or minimal intervention (control) for 4 months with a follow‐up at 12 months.

Patients

Sixty‐eight women, aged 18‐40 years, body mass index (BMI) ≥ 27 kg/m2, fulfilling all Rotterdam PCOS criteria were randomized to treatment.

Measurements

The primary outcome was improved menstrual regularity. Secondary outcomes were ovulation and pregnancy rates.

Results

At 4 months, the weight loss was significant in the intervention group (−2.1%, P = 0.002) and nonsignificant in the control group (−1.0%). A higher proportion of patients in the intervention group improved menstrual regularity compared to the control group, mean difference 35% (95% CI: 16‐60), P = 0.003. There was no difference in ovulation rate between groups. Logistic regression analysis showed that intervention was the only predictor of improved menstrual function, OR 3.9 (95% CI: 1.3‐11.9). At 12 months, a total of 54% of the women improved menstrual regularity compared to baseline (P = 0.000) and 43% (P = 0.000) had confirmed ovulation. 38% of the women wishing to become pregnant succeeded within 1 year of study completion.

Conclusions

This is the first RCT in overweight women with PCOS showing efficacy in improving reproductive function following behavioural modification intervention in comparison with minimal intervention. Although extensive weight loss is difficult to achieve in these women, behavioural modification intervention can help improve reproductive function.
The relationship between mesorectal grading and oncological outcome in rectal adenocarcinoma
Authors: Silva‐Velazco J. , Stocchi L. , Valente M. A. , Church J. M. , Liska D. , Gorgun E. , Kalady M. F. , Kessler H. , Steele S. R. , Delaney C. P.
Published: December 2018

Aim

The prognostic association between mesorectal grading and oncological outcome in patients undergoing resection for rectal adenocarcinoma is controversial. The aim of this retrospective chart review was to determine the individual impact of mesorectal grading on rectal cancer outcomes.

Method

We compared oncological outcomes in patients with complete, near‐complete and incomplete mesorectum who underwent rectal excision with curative intent from 2009 to 2014 for Stage cI–III rectal adenocarcinoma. We also assessed the independent association of mesorectal grading and oncological outcome using multivariate models including other relevant variables.

Results

Out of 505 patients (339 men, median age of 60 years), 347 (69%) underwent a restorative procedure. There were 452 (89.5%), 33 (6.5%) and 20 (4%) patients with a complete, near‐complete and incomplete mesorectum, respectively. Local recurrence was seen in 2.4% (n = 12) patients after a mean follow‐up of 3.1 ± 1.7 years. Unadjusted 3‐year Kaplan–Meier analysis by mesorectal grade showed decreased rates of overall, disease‐free and cancer‐specific survival and increased rates of overall and distant recurrence with a near‐complete mesorectum, while local recurrence was increased in cases of an incomplete mesorectum (all P < 0.05). On multivariate analyses, a near‐complete mesorectum was independently associated with decreased cancer‐specific survival (hazard ratio 0.26, 95% CI 0.1–0.7; P = 0.007). There were no associations between mesorectal grading and overall survival, disease‐free survival, overall recurrence or distant recurrence (all P > 0.05).

Conclusion

Mesorectal grading is independently associated with oncological outcome. It provides unique information for optimizing surgical quality in rectal cancer.
Layer‐to‐layer closure of a large gastric artificial ulcer using side‐channel tube
Authors: Nishiyama Noriko , Kobara Hideki , Masaki Tsutomu
Published: December 2018

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Stability of insulin and C‐peptide measurement with long‐term frozen storage of serum: Implications for diabetes research studies
Authors: Retnakaran Ravi , Ye Chang , Kramer Caroline K.
Published: December 2018

The current era of large‐scale clinical trials in diabetes has generated thousands of biological samples from study participants that are being stored long‐term under frozen conditions for the future measurement of analytes of interest. Insulin and C‐peptide are two such analytes that can provide insight into underlying pathophysiological processes (insulin sensitivity and β‐cell function). However, the validity of the inferences that may be drawn from such future measurements is contingent on the stability of these analytes after long‐term frozen storage. We conducted the present study to determine the stability of insulin and C‐peptide concentrations that were first measured on fresh serum at the time of collection, followed by frozen storage at –80°C for >5 years and then repeat measurement. Bland–Altman analyses revealed good agreement between the repeated insulin measurements and between the repeated C‐peptide measurements. The concordance correlation coefficient (CCC) confirmed reproducibility for both insulin (CCC 0.98, 95% confidence interval [CI] 0.96‐0.99) and C‐peptide (CCC 0.91, 95% CI 0.84‐0.95); thus, insulin and C‐peptide measurements are both stable and reproducible after long‐term frozen storage of serum samples.
A multinational observational study assessing insulin use: Understanding the determinants associated with progression of therapy
Authors: Ray Kausik K. , Kendall David M. , Zhao Zhenxiang , Peng Xiaomei , Caballero A. Enrique , Polonsky William H. , Nordstrom Beth L. , Fan Ludi , Curtis Bradley H. , Davies Melanie J.
Published: December 2018

Aims

To describe global patterns of insulin treatment and to assess the impact of patient, provider, health system and economic influences on treatment decisions for patients with insulin‐treated type 2 diabetes (T2D).

Methods

This prospective cohort study of insulin‐treated patients with T2D was conducted across 18 countries categorized as high, upper‐middle or lower‐middle income regions. Information collected from patients included knowledge of diabetes, experiences and interactions with their healthcare provider. Physician information included specialty, practice size, availability of diabetes support services, volume of diabetes patients treated and time spent per patient. Physicians determined an individualized haemoglobin A1c (HbA1c) target for each patient by the start of the study. Changes in T2D therapies and HbA1c were recorded for 2 years.

Results

Complete treatment data were available for 2528 patients. Median age was 61 years and median duration of diabetes was 11.4 years. Changes to treatment regimen occurred in 90.0% of patients, but changes were less common in countries with a higher economic status (P < 0.001). Most treatment changes involved insulin, with changes in dose the most common. Overall predictors of change in insulin therapy included younger age, use of any insulin regimen other than basal only, higher mean baseline HbA1c and longer duration of T2D. HbA1c levels remained constant regardless of regional economic status. At baseline, 20.6% of patients were at their HbA1c target; at 2 years this was 26.8%.

Conclusions

Among insulin‐treated patients with T2D, treatment changes were common; however, only approximately one‐fourth of individuals achieved their HbA1c target.
Kalirin‐7 prevents dendritic spine dysgenesis induced by amyloid beta‐derived oligomers
Authors: Xie Zhong , Shapiro Lauren P. , Cahill Michael E. , Russell Theron A. , Lacor Pascale N. , Klein William L. , Penzes Peter
Published: December 2018

Synapse degeneration and dendritic spine dysgenesis are believed to be crucial early steps in Alzheimer's disease (AD), and correlate with cognitive deficits in AD patients. Soluble amyloid beta (Aβ)‐derived oligomers, also termed Aβ‐derived diffusible ligands (ADDLs), accumulate in the brain of AD patients and play a crucial role in AD pathogenesis. ADDLs bind to mature hippocampal neurons, induce structural changes in dendritic spines and contribute to neuronal death. However, mechanisms underlying structural and toxic effects are not fully understood. Here, we report that ADDLs bind to cultured mature cortical pyramidal neurons and induce spine dysgenesis. ADDL treatment induced the rapid depletion of kalirin‐7, a brain‐specific guanine‐nucleotide exchange factor for the small GTPase Rac1, from spines. Kalirin‐7 is a key regulator of dendritic spine morphogenesis and maintenance in forebrain pyramidal neurons and here we show that overexpression of kalirin‐7 prevents ADDL‐induced spine degeneration. Taken together, our results suggest that kalirin‐7 may play a role in the early events leading to synapse degeneration, and its pharmacological activation may prevent or delay synapse pathology in AD.
Positive morality and the realization of freedom in Kant's moral philosophy
Authors: Biss Mavis
Published: December 2018

This paper argues that recent accounts of Kantian virtue as “strengthened” inner freedom apply much more clearly to the avoidance of violations of perfect duties than to the fulfillment of imperfect duties, leaving us with the question of how inadequate commitment to morally required ends impacts the exercise of inner freedom. The question is answered through the development of a model of inner freedom that emphasizes the relationship between moral self‐governance and participation in an ethical community.
Study of the NR4A family gene expression in patients with multiple sclerosis treated with Fingolimod
Authors: Montarolo F. , Perga S. , Martire S. , Brescia F. , Caldano M. , Lo Re M. , Panzica G. , Bertolotto A.
Published: December 2018

Background and purpose

Fingolimod is a drug approved for treatment of relapsing‐remitting multiple sclerosis (RRMS) that exerts its effects via sequestering lymphocytes within the lymph nodes. The drug, acting on the sphingosine‐1‐phosphate pathway, is involved in a plethora of processes and, to date, its mechanism of action is not completely understood.

Recently, it has been demonstrated that Fingolimod increases the expression of transcription factor NR4A2 in murine brain. NR4A2 belongs to nuclear receptor family 4, group A (NR4A) along with NR4A1 and NR4A3. The role of NR4A2 in the pathogenesis of multiple sclerosis is already known and supported by its down‐regulation observed in blood obtained from patients with RRMS compared with healthy controls (HCs). It is notable that NR4A2 impairment is reversed in patients with RRMS during pregnancy, which represents a transitory state of immune tolerance, associated with reduced disease activity. An inverse correlation between NR4A2 gene expression levels and clinical parameters indicates that more aggressive forms of the disease are characterized by lower levels of NR4A2.

Methods

Gene expression levels of NR4A in blood obtained from HCs, treatment‐naive (T0) and Fingolimod‐treated patients with RRMS were evaluated to determine their contribution to drug response.

Results

Gene expression levels of NR4A were down‐regulated in T0 patients compared with HCs. Patients treated with Fingolimod for >2 years were characterized by higher levels of NR4A2 compared with the T0 group, approaching those of HCs. NR4A1 and NR4A3 levels were not altered.

Conclusions

Involvement of the NR4A family in the pathogenesis of multiple sclerosis and a role of Fingolimod in the recovery from NR4A2 deficit can be hypothesized based on our data.
Intravenous thrombolysis in wake‐up stroke: real‐world data from the Austrian Stroke Unit Registry
Authors: Krebs S. , Posekany A. , Ferrari J. , Lang W. , Sommer P. , Gattringer T. , Boehme C. , Sykora M. ,   the Austrian Stroke Unit Registry Collaborators
Published: December 2018

Background and purpose

Data on real‐world experience with intravenous thrombolysis (IV tPA) in wake‐up stroke (WUS) are limited. The aim of this study was to examine the efficacy and safety of IV tPA in patients with WUS included in the Austrian Stroke Unit Registry.

Methods

Data from a large nationwide stroke unit registry including initial stroke severity, vascular risk factors, comorbidities, treatment with IV tPA, symptomatic intracerebral haemorrhage (sICH) and functional outcome were extracted and analysed. Patients with WUS were compared with patients with known‐onset stroke (KOS) regarding the frequency of IV tPA treatment, neurological improvement (National Institutes of Health Stroke Scale score ≥4), sICH and 3‐month functional outcome by modified Rankin Scale score using standard statistical tests.

Results

A total of 107 895 stroke patients entered the analysis, including 12 534 with WUS and 91 899 with KOS. Altogether, 904 (7.2%) patients with WUS received IV tPA as compared with 16 694 (18.2%) patients with KOS. Patients with WUS who received IV tPA treatment had twofold higher initial National Institutes of Health Stroke Scale score (median 8 vs. median 4) as compared with patients with KOS. There was no statistical difference in functional outcome by modified Rankin Scale score 0–1 at 3 months between patients with WUS and patients with KOS treated with IV tPA (adjusted odds ratio, 1.08; 95% confidence interval, 0.9–1.31). Also, the rate of sICH did not differ (4.1% vs. 4%, P = 0.852).

Conclusions

In this large non‐randomized comparison, the safety and efficacy of IV tPA in patients with WUS in the real‐world setting seems to be comparable to patients with KOS.
The ADAN scale: a proposed scale for pre‐hospital use to identify status epilepticus
Authors: Requena M. , Fonseca E. , Olivé M. , Abraira L. , Quintana M. , Mazuela G. , Toledo M. , Salas‐Puig X. , Santamarina E.
Published: December 2018

Background and purpose

The prognosis of status epilepticus (SE) depends on the time between onset and the diagnosis and start of treatment. Our aim was to design a scale with predictive value for pre‐hospital diagnosis of SE.

Methods

This was a retrospective study of 292 patients who attended the emergency department for an epileptic seizure. A total of 49 patients fulfilled the criteria for SE. We recorded the patients’ history and clinical features. Variables independently associated with SE were combined to design a clinical scale. The performance of the scale was evaluated in a validation dataset of 197 patients.

Results

A total of 50.3% of the patients were male and the mean age was 55.9 years. The following features were more prevalent in patients with SE: abnormal speech (79.6% vs. 18.9%, P < 0.001), eye deviation (69.4% vs. 14.0%, P < 0.001), automatism (22.4% vs. 6.3%, P < 0.001), hemiparesis (24.5% vs. 10.9%, P = 0.011), state of stupor/coma (46.9% vs. 4.2%, P < 0.001) and number of pre‐hospital seizures, i.e. two (34.7% vs. 4.5%, P < 0.001) or more than two (51.0% vs. 0.4%, P < 0.001). Based on these findings, we designed a scale that scored 1 point each for presence of abnormal speech, eye deviation, automatism and two seizures, and 2 points for more than two seizures. The predictive capacity of the scale for identifying SE in the validation dataset was 98.7% (95% confidence interval, 97.3%–100%) and 85.4% of patients with a score >1 had SE.

Conclusions

A score >1 on the ADAN scale is a robust predictor of the diagnosis of SE in patients who experience an epileptic seizure. This scale may be a useful tool for clinical use and warrants further investigation.
Postictal electroencephalographic (EEG) suppression: A stereo‐EEG study of 100 focal to bilateral tonic–clonic seizures
Authors: Marchi Angela , Giusiano Bernard , King Mark , Lagarde Stanislas , Trébuchon‐Dafonseca Agnès , Bernard Christophe , Rheims Sylvain , Bartolomei Fabrice , McGonigal Aileen
Published: December 2018

Objectives

We aimed to describe intracerebral aspects of postictal generalized electroencephalography suppression (PGES) following focal to bilateral tonic–clonic (“secondarily generalized tonic–clonic”) seizures (GTCS) recorded using stereoelectroencephalographic (SEEG), and to correlate these with electroclinical features.

Methods

Three independent observers scored semiologic and SEEG features. Patient and epilepsy characteristics were collected. Descriptive statistics and multivariate analysis were performed. The operational definition of PGES on SEEG used strict criteria (absence of visible signal at 20 μV/mm amplitude, in all readable channels). Postictal regional suppression (RS) was identified if only a subset of implanted electrodes showed absence of signal.

Results

We evaluated 100 seizures in 52 patients. Interobserver agreement was good (κ 0.72 for clinical features and 0.73 for EEG features). PGES was present in 27 of 100 and RS without PGES present in 42 of 100 seizures. Region of RS included epileptogenic zone in 43 of 51 (86%). No effect of sampling (multilobar or bilateral exploration) was seen. Oral tonicity (mouth opening and/or tonic vocalization during the tonic phase of GTCS) was associated with the presence of PGES (P = 0.029; negative predictive value [NPV] 0.91). Bilateral upper limb extension during the tonic phase correlated with PGES (P = 0.041; NPV 0.85). Association of both oral tonicity and bilateral upper limb extension had a high NPV of 0.96.

Significance

SEEG recordings confirm true absence of signal during postictal EEG suppression. PGES is unlikely when both upper limb extension and oral tonicity are absent. We hypothesize that bilateral tonic seizure discharge at bulbar level brainstem regions is associated with the production of oral signs and may relate to mechanisms of PGES.
Tissue microenvironment initiates an immune response to structural components of Staphylococcus aureus
Authors: Mainzer Carine , Packard Thomas , Bordes Sylvie , Closs Brigitte , Greene Warner C. , Elias Peter M. , Uchida Yoshikazu
Published: December 2018

Cell‐to‐cell communication in skin participates to the maintenance of homeostatic responses to foreign substances. Certain strains of Staphylococcus (S) aureus are vicious pathogens that cause deleterious effects in host cells and tissues. Both secreted toxins and structural components of S. aureus trigger an immune response, though how S. aureus stimulates host immune responses is poorly understood. We explored here how keratinocytes and fibroblasts initiate the first steps of an immune response by activating dendritic cells (DCs) through recognition of structural components of S. aureus. We treated monocyte‐derived Langerhans cells (moLCs) and monocyte‐derived DCs (moDCs) with conditioned media from keratinocytes (K‐CM) and fibroblasts (F‐CM) treated with heat‐killed S. aureus (HKSA) respectively, or directly with HKSA. Immune and inflammatory responses from keratinocytes, fibroblasts, moLCs and moDCs were assessed by analysis of cell surface markers and cytokine production using flow cytometry, real‐time PCR and ELISA assays. K‐CM and F‐CM increased the expression of CD86 and HLA‐DR on moLCs and moDCs, in association with a specific cytokine profile. K‐CM upregulated TNFA, IL‐1B and GM‐CSF mRNA expression in moLCs, while F‐CM upregulated IL‐12 and downregulated TNFA and TGFB mRNA expression in moDCs. Additionally, F‐CM attenuated the induction of an inflammatory profile in monocytes. The recognition of structural components from S. aureus by cutaneous microenvironment induces the activation and the expression of specific cytokines from LCs and DCs.
Oral health‐related quality of life in older adults—Longitudinal study
Authors: Echeverria Mariana S. , Wünsch Isadora S. , Langlois Caroline O. , Cascaes Andreia M. , Ribeiro Silva Alexandre E.
Published: December 2018

Objective

The aim of the present study was to investigate oral health‐related quality of life (OHRQoL) and determine associations with demographic, socio‐economic and oral health variables at two evaluation times (2009 and 2015) among older adults assisted by Family Health Units in the Brazil.

Methods

A longitudinal study was conducted involving the evaluation (2009) and re‐evaluation (2015) of 161 older adults (≥60 years of age). Demographic, socio‐economic and general health variables were collected using a standardised questionnaire. Clinical oral health variables were also collected. OHRQoL was measured using the Oral Health Impact Profile‐14 (OHIP‐14). Multiple regression analysis was employed for the evaluation of OHRQoL considering the variables from the two evaluations.

Results

The severity of impact (mean OHIP‐14) was 9.12 (SD: 10.81) in 2009 and 8.50 (10.52) in 2015. The greatest impact regarded the psychological discomfort domain at both evaluations (28.8% in 2009 and 22.9% in 2015). In the adjusted multiple linear regression, the mean OHIP‐14 score increased 4.8 points (95% CI: 0.11‐9.49) among individuals who experienced tooth loss between the two evaluations in comparison with those who maintained the same number of teeth. An increase in the OHIP‐14 score occurred between 2009 and 2015 among 40.6% of the older adults.

Conclusions

The findings of the present study reveal that the oral health status of older adults exerts an influence on OHRQoL, indicating the need for oral health policies directed at this portion of the population.
Predictors of mortality in older patients admitted to a geriatric hospital
Authors: Agrawal Siddarth , Luc Mateusz , Winkowski Filip , Lindner Karolina , Agrawal Anil Kumar , Wozniak Marta , Sobieszczanska Malgorzata
Published: December 2018

Aim

The identification of older patients at risk of mortality is important to provide properly tailored care and effectively manage healthcare resources. The present study aimed to identify predictors of all‐cause mortality related to geriatric patients’ clinical, functional and sociodemographic status at admission.

Methods

A retrospective study was carried out of patients admitted to a geriatric hospital from January to May 2013. A total of 208 patients were enrolled in the study. The outcome measure was 4‐year mortality.

Results

The mortality rate was 26%. We found that age, red blood cells count and white blood cells count, as well as C‐reactive protein level, albumin level and high‐density lipoprotein cholesterol level significantly correlated with mortality. Furthermore, the presence of clinical symptoms, such as pressure ulcers and depressed level of consciousness, was predictive of poor outcome. Multidimensional aspects of aging that are assessed in the Comprehensive Geriatric Assessment – activities of daily living, instrumental activities of daily living, Barthel scale, Mini‐Mental State Examination and The Clock Drawing Test – appeared to be strong predictors of 4‐year mortality. The expression to estimate the probability of mortality based on the examined variables correctly classified nearly 85% of the analyzed cases.

Conclusions

Early detection of high‐risk patients is of particular significance to reach a better survival rate among older adults. Clinicians should put more stress on the comprehensive surveillance of geriatric patients, rather than focusing solely on the treatment of chronic diseases.Geriatr Gerontol Int 2019; 19: 70–75.
Analysis of 307 cases with drug‐induced liver injury between 2010 and 2018 in Japan
Authors: Aiso Mitsuhiko , Takikawa Hajime , Tsuji Keiji , Kagawa Tatehiro , Watanabe Masaaki , Tanaka Atsushi , Sato Ken , Sakisaka Shotaro , Hiasa Yoichi , Takei Yoshiyuki , Ohira Hiromasa , Ayada Minoru , Hashimoto Etsuko , Kaneko Shuichi , Ueno Yoshiyuki , Ohmoto Kenji , Takaki Akinobu , Torimura Takuji , Matsuzaki Yasushi , Tajiri Kazuto , Yoneda Masashi , Ito Takayoshi , Kato Naoya , Ikejima Kenichi , Mochida Satoshi , Yasuda Hiroshi , Sakamoto Naoya
Published: December 2018

Aim

In order to know the present status of drug‐induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals.

Methods

Drug‐induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level

≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria.

Results

In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug‐induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty‐three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)‐Japan 2004 workshop, 93.8% of cases were diagnosed as “highly probable”, and 5.9% as “possible”.

Conclusions

Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW‐Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI.
“I kind of gave up on it after a while, became too hard, closed my eyes, didn't want to know about it”—adults with type 1 diabetes mellitus describe defeat in the context of low social support
Authors: Hill Kathleen , Ward Paul , Gleadle Jonathan
Published: December 2018

Background

Type 1 diabetes mellitus (T1DM) is a lifelong condition that requires diligent self‐management to avoid complications. Living with T1DM is a considerable challenge and the inability to follow a prescribed regimen is often termed non‐compliance. However, this fails to acknowledge that for some people the barriers to glycaemic control may be insurmountable.

Objective

This qualitative study explores the structural determinants, social context and lived experience of T1DM with 17 adults to understand influences on patterns of self‐care, engagement with and trust in health‐care services, and health outcomes.

Results

Their stories tell us that strong social support is vital to disease adaptation and ongoing management. When social support is absent, the story is one of struggling with intensive diabetes management alone and difficulty controlling blood glucose levels. When confronted with suboptimal glycaemic control, participants isolated from social support developed combative relationships with health‐care providers and disengaged from health care. Their subsequent slide to chronic comorbid illness is steep and this study reveals the heartache and loss experienced when difficult life circumstances and low levels of social support have led to irreparable kidney damage.

Conclusion

Patterns of poor glycaemic control viewed in the health‐care encounter without an understanding of the context or life circumstances in which they are occurring can lead to an inability to engage with health‐care services. Disengagement from services and the absence of specialist care further isolates people, leaving them managing their diabetes alone with limited success.
Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?
Authors: Batavia Aashil A , Schraml Peter , Moch Holger
Published: December 2018

The current World Health Organisation (WHO) classification of renal tumours is based on characteristic histological features or specific molecular alterations. von Hippel‐Lindau (VHL) alteration is the hallmark of clear cell renal cell carcinoma (RCC). After identification of the MiT translocation family of tumours, clear cell papillary renal cancer and others, the group of ccRCC with wild‐type VHL is small. TCEB1 mutation combined with chromosome 8q loss is an emerging tumour entity with wild‐type VHL. Inactivation of TCEB1 increases HIF stabilisation via the same mechanism as VHL inactivation. Importantly, recent molecular analyses suggest the existence of another ‘VHL wild‐type’ evolutionary subtype of clear cell RCC in addition to TCEB1 mutated RCC and clear cell papillary renal cancer. These tumours are characterised by an aggressive behaviour, high tumour cell proliferation rate, elevated chromosomal instability and frequent presence of sarcomatoid differentiation. Future clinicopathological studies will have to provide data to determine whether TCEB1 tumours and clear cell RCC with wild‐type VHL are separate tumour entities or represent variants of a clear cell RCC tumour family.
Somatic genetic alterations in synchronous and metachronous low‐grade serous tumours and high‐grade carcinomas of the adnexa
Authors: Murali Rajmohan , Selenica Pier , Brown David N , Cheetham R Keira , Chandramohan Raghu , Claros Nidia L , Bouvier Nancy , Cheng Donavan T , Soslow Robert A , Weigelt Britta , McCluggage W Glenn
Published: December 2018

Aims

Low‐grade serous carcinomas (LGSCs) and their precursors serous borderline tumours (SBTs) characteristically harbour mutations in BRAF, KRAS or NRAS but rarely in TP53, whereas high‐grade serous carcinomas (HGSCs) are characterised by frequent TP53 mutations but rare BRAF, KRAS or NRAS mutations. In a small subset of cases, LGSCs and/or SBTs develop into high‐grade tumours, including HGSCs and poorly differentiated carcinomas (PDCs). Here, we sought to define the repertoire of somatic genetic alterations in low‐grade serous tumours and synchronous or metachronous high‐grade adnexal carcinomas.

Methods and results

DNA extracted from five SBTs/LGSCs and synchronous or metachronous HGSCs/PDCs and matched normal tissue was subjected to massively parallel sequencing targeting all exons and selected non‐coding regions of 341 cancer‐related genes. The low‐grade and high‐grade tumours from a given case were related, and shared mutations and copy number alterations. Progression from low‐grade to high‐grade lesions was observed, and involved the acquisition of additional mutations and/or copy number alterations, or shifts from subclonal to clonal mutations. Only two (an HGSC and a PDC) of the five high‐grade tumours investigated harboured TP53 mutations, whereas NRAS and KRAS hotspot mutations were seen in two HGSCs and one HGSC, respectively.

Conclusions

Our results suggest that progression from SBT to HGSC may take place in a subset of cases, and that at least some of the rare HGSCs lacking TP53 mutations may be derived from a low‐grade serous precursor.
A biological study of supernumerary teeth derived dental pulp stem cells based on RNA‐seq analysis
Authors: Lu X. , Liu S‐F. , Wang H‐H. , Yu F. , Liu J‐J. , Zhao Y‐M. , Zhao S‐L.
Published: December 2018

Aim

To identify the basic characteristics and gene expression profiles of supernumerary teeth derived stem cells (SNTSCs) and compare them with those of normal dental pulp stem cells (DPSCs).

Methodology

Flow cytometry was conducted to identify the protein expression of stem cell markers. Cell proliferation, migration and differentiation abilities of both SNTSCs and DPSCs were determined by CCK8, transwell and differentiation assays, respectively. Gene expression profiles were studied by RNA sequencing analyses. After knocking down the expression of certain differential expression genes (DEGs), the function of DEGs was investigated by CCK8 and transwell assays. Statistical differences were determined using a two‐tailed t‐test and P values below 0.05 were considered significant.

Results

Supernumerary teeth derived stem cells were capable of differentiating into adipocyte, chondrocyte and osteoblast lineage cells, and compared to ordinary DPSCs, SNTSCs had a significantly higher cell proliferation rate (P < 0.01) and significantly lower migration rate (P < 0.01). RNA‐seq results revealed the differential expression genes (DEGs) between SNTSCs and DPSCs. A principal component analysis (PCA) and cluster analysis revealed that the gene expression patterns of SNTSCs and DPSCs were different from each other. A total of 12 861 genes were differentially expressed at a significant P value (P ≤ 0.01), and 5292 of these increased in SNTSCs and 7569 decreased. Further study on the selected DEGs revealed that FUT11, FAM155A and BRD2 inhibited the cell proliferation rate of SNTSCs, and FUT11 and GLUD1 inhibited the cell migration rate, whilst FAM155A promoted the migration rate.

Conclusions

The biological characteristics and gene expression profile of SNTSCs was revealed. The stem cell properties of SNTSCs were similar to normal DPSCs but they had a high cell proliferation rate and may have greater potential for cell differentiation.
Current understanding of transport and bioavailability of bioactive peptides derived from dairy proteins: a review
Authors: Xu Qingbiao , Yan Xianghua , Zhang Yangdong , Wu Jianping
Published: December 2018

Dairy protein‐derived bioactive peptides (DBPs) have potential benefits for human health. However, their transport mechanisms and bioavailability from intestinal lumen to bloodstream are not well understood. This review summarises current understanding of their transport mechanisms across the intestinal membrane (peptide transport 1, paracellular route, transcytosis and passive transcellular diffusion) and the bioavailability of DBPs in animal and human studies. Some DBPs can escape the degradation of peptidase and reach the bloodstream at concentrations of micromolar range, and keep intact for several minutes to hours. The presences of brush‐border peptidases at the site of absorption and other peptidases in the blood, along with the peptide properties, such as molecular size and weight, stability to proteases, hydrophobicity and charge, determine their bioavailability. Developing novel analytical tools for accurate measurement and study of the transport, metabolism, and bioavailability of DBPs in vivo are expected.
Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy
Authors: Constantine Gregory M. , Lionakis Michail S.
Published: December 2018

The discovery of the autoimmune regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire‐deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.
CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease
Authors: Ozen Ahmet
Published: December 2018

Primary intestinal lymphangiectasia (PIL) or Waldmann's disease was described in 1961 as an important cause of protein‐losing enteropathy (PLE). PIL can be the sole finding in rare individuals or occur as part of a multisystemic genetic syndrome. Although genetic etiologies of many lymphatic dysplasia syndromes associated with PIL have been identified, the pathogenesis of isolated PIL (with no associated syndromic features) remains unknown. Familial cases and occurrence at birth suggest genetic etiologies in certain cases. Recently, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (the CHAPLE syndrome) has been identified as a monogenic form of PIL. Surprisingly, loss of CD55, a key regulator of complement system leads to a predominantly gut condition. Similarly to other complement disorders, namely paroxysmal nocturnal and hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), CHAPLE disease involves pathogenic cross‐activation of the coagulation system, predisposing individuals to severe thrombosis. The observation that complement system is overly active in CHAPLE disease introduced a novel concept into the management of PLE; anti‐complement therapy. While CD55 deficiency constitutes a treatable subgroup in the larger pool of patients with isolated PIL, the etiology remains to be identified in the remaining patients with intact CD55.
WHIM syndrome: Immunopathogenesis, treatment and cure strategies
Authors: McDermott David H. , Murphy Philip M.
Published: December 2018

WHIM syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It results from heterozygous gain‐of‐function mutations in the chemokine receptor CXCR4 which is widely expressed on leukocytes and has profound influences on immune system homeostasis and organogenesis. New treatments for the disease using drugs to reduce CXCR4 function are excellent examples of precision medicine. Since CXCR4 and its ligand CXCL12 play an important role in a variety of infectious, inflammatory, autoimmune, and malignant diseases, the study of WHIM syndrome provides important insights into both the physiologic and disease roles of these molecules.
Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome
Authors: Su Helen C. , Jing Huie , Angelus Pam , Freeman Alexandra F.
Published: December 2018

DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination‐mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV‐associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered the roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.
Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms
Authors: Pazmandi Julia , Kalinichenko Artem , Ardy Rico Chandra , Boztug Kaan
Published: December 2018

Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.
The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism
Authors: Lyons Jonathan J. , Milner Joshua D.
Published: December 2018

Dynamic changes in metabolism have long been understood as critical for both the initiation and maintenance of innate and adaptive immune responses. A number of recent advances have clarified details of how metabolic pathways can specifically affect cellular function in immune cells. Critical to this understanding is ongoing study of the congenital disorders of glycosylation and other genetic disorders of metabolism that lead to altered immune function in humans. While there are a number of immune phenotypes associated with metabolic derangements caused by single gene disorders, several genetic mutations have begun to link discrete alterations in metabolism and growth specifically with allergic disease. This subset of primary atopic disorders is of particular interest as they illuminate how hypomorphic mutations which allow for some residual function of mutated protein products permit the “abnormal” allergic response. This review will highlight how mutations altering sugar metabolism and mTOR activation place similar constraints on T lymphocyte metabolism to engender atopy, and how alterations in JAK/STAT signaling can impair growth and cellular metabolism while concomitantly promoting allergic diseases and reactions in humans.
Randomised controlled trials as part of clinical care: A seven‐step routinisation framework proposal
Authors: Team Victoria , Weller Carolina D.
Published: December 2018

Evidence translation in wound care relies on the need for evidence generation. Clinical practice may generate evidence only if evidence‐generating research projects, such as randomised controlled trials (RCTs), became routinised in clinical settings. The aim of this study was to identify optimal trial‐related practices to routinise trial‐related activities in Melbourne‐located wound clinics as reported by clinicians and researchers. We conducted a secondary analysis of the available data on how to routinise RCTs in clinical care, with a focus on enablers and suggestions provided by the participants during face‐to‐face and telephone interviews. Data were obtained from a qualitative observational study nested within a randomised, double‐blinded, placebo‐controlled trial on clinical effectiveness of aspirin as an adjunct to compression therapy in healing chronic venous leg ulcers (ASPiVLU). We developed a seven‐step Routinisation of Trials in Clinical Care Framework. These steps include: (1) pre‐trial clinical site assessment, (2) optimising pre‐recruitment arrangements, (3) developing and updating trial‐related skills, (4) embedding RCT recruitment as part of routine clinical care, (5) promoting teamwork and trial‐related collaboration, (6) addressing trial‐related financial issues, and (7) communicating trial results to clinicians.
Functionally richer communities improve ecosystem functioning: Dung removal and secondary seed dispersal by dung beetles in the Western Palaearctic
Authors: Milotić Tanja , Baltzinger Christophe , Eichberg Carsten , Eycott Amy E. , Heurich Marco , Müller Jörg , Noriega Jorge A. , Menendez Rosa , Stadler Jutta , Ádám Réka , Bargmann Tessa , Bilger Isabelle , Buse Jörn , Calatayud Joaquín , Ciubuc Constantin , Boros Gergely , Jay‐Robert Pierre , Kruus Märt , Merivee Enno , Miessen Geoffrey , Must Anne , Ardali Elham , Preda Elena , Rahimi Iraj , Rohwedder Dirk , Rose Rob , Slade Eleanor M. , Somay László , Tahmasebi Pejman , Ziani Stefano , Hoffmann Maurice
Published: December 2018

Aim

In several ecosystems, the diversity of functional species traits has been shown to have a stronger effect on ecosystem functioning than taxonomic diversity alone. However, few studies have explored this idea at a large geographical scale. In a multisite experiment, we unravelled the relationship between ecosystem function and functional completeness of species assemblages using dung beetles as a model group, focusing on dung removal and secondary seed dispersal.

Location

Seventeen grassland locations across the Western Palaearctic.

Methods

We used a randomized block design with different exclosure types to control the dung and seed removing activities of individual functional groups of the local dung beetle assemblage. We classified dung beetle species according to resource specialization and into functional groups based on dung processing behaviour (dwellers, tunnellers, rollers) and body size (small, large). Additionally, we assessed the role of other soil macro‐invertebrates. By sampling the dung beetle community and measuring the remaining dung and seeds after the experiment, the impact of each functional group was estimated.

Results

Dung beetle assemblages differed along a north–south and east–west gradient. Dwellers dominated northernmost sites, whereas at lower latitudes we observed more tunnellers and rollers indicating a functional shift. Resource specialists were more abundant in southern and eastern areas. Overall, functional group diversity enhanced dung removal. More dung (+46.9%) and seeds (+32.1%) were removed in the southern sites and tunnellers and rollers were more effective. At the northernmost sites, where tunnellers were scarce or absent, other soil macro‐invertebrates removed the majority of dung.

Main conclusions

The conservation of functionally complete dung beetle assemblages is crucial to maintain the ecosystem functions provided by dung beetles. Given the latitudinal variation in functional group diversity, it is reasonable to expect compositional changes due to climate change. These changes could lead to increased dung removal and a higher secondary seed dispersal rate in northern regions.