bluuebunny/crossref_metadata_2025 huggingface dataset:
IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation
Authors: Abdullah Ahmad , Talwar Priti , d'Hellencourt Christian Lefebvre , Ravanan Palaniyandi
Published: February 2019

Neuroblastoma is an embryonic malignancy that arises out of the neural crest cells of the sympathetic nervous system. It is the most common childhood tumor known for its spontaneous regression via the process of differentiation. The induction of differentiation using small molecules such as retinoic acid is one of the therapeutic strategies to treat the residual disease. In this study, we have reported the effect of kaempferol (KFL) in inducing differentiation of neuroblastoma cells in vitro. Treatment of neuroblastoma cells with KFL reduced the proliferation and enhanced apoptosis along with the induction of neuritogenesis. Analysis of the expression of neuron‐specific markers such as β‐III tubulin, neuron‐specific enolase, and N‐myc downregulated gene 1 revealed the process of differentiation accompanying KFL‐induced apoptosis. Further analysis to understand the molecular mechanism of action showed that the effect of KFL is mediated by the activation of the endoribonuclease activity of inositol‐requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum‐resident transmembrane protein. In silico docking analysis and biochemical assays using recombinant human IRE1α confirm the binding of KFL to the ATP‐binding site of IRE1α, which thereby activates IRE1α ribonuclease activity. Treatment of cells with the small molecule STF083010, which specifically targets and inhibits the endoribonuclease activity of IRE1α, showed reduced expression of neuron‐specific markers and curtailed neuritogenesis. The knockdown of IRE1α using plasmid‐based shRNA lentiviral particles also showed diminished changes in the morphology of the cells upon KFL treatment. Thus, our study suggests that KFL induces differentiation of neuroblastoma cells via the IRE1α ‐XBP1 pathway.
Evaluating ecosystem effects of climate change on tropical island streams using high spatial and temporal resolution sampling regimes
Authors: Frauendorf Therese C. , MacKenzie Richard A. , Tingley Ralph W. , Frazier Abby G. , Riney Michael H. , El‐Sabaawi Rana W.
Published: February 2019

Climate change is expected to alter precipitation patterns worldwide, which will affect streamflow in riverine ecosystems. It is vital to understand the impacts of projected flow variations, especially in tropical regions where the effects of climate change are expected to be one of the earliest to emerge. Space‐for‐time substitutions have been successful at predicting effects of climate change in terrestrial systems by using a spatial gradient to mimic the projected temporal change. However, concerns have been raised that the spatial variability in these models might not reflect the temporal variability. We utilized a well‐constrained rainfall gradient on Hawaii Island to determine (a) how predicted decreases in flow and increases in flow variability affect stream food resources and consumers and (b) if using a high temporal (monthly, four streams) or a high spatial (annual, eight streams) resolution sampling scheme would alter the results of a space‐for‐time substitution. Declines in benthic and suspended resource quantity (10‐ to 40‐fold) and quality (shift from macrophyte to leaf litter dominated) contributed to 35‐fold decreases in macroinvertebrate biomass with predicted changes in the magnitude and variability in the flow. Invertebrate composition switched from caddisflies and damselflies to taxa with faster turnover rates (mosquitoes, copepods). Changes in resource and consumer composition patterns were stronger with high temporal resolution sampling. However, trends and ranges of results did not differ between the two sampling regimes, indicating that a suitable, well‐constrained spatial gradient is an appropriate tool for examining temporal change. Our study is the first to investigate resource to community wide effects of climate change on tropical streams on a spatial and temporal scale. We determined that predicted flow alterations would decrease stream resource and consumer quantity and quality, which can alter stream function, as well as biomass and habitat for freshwater, marine, and terrestrial consumers dependent on these resources.
Behaviour and characteristics of low‐grade ductal carcinoma in situ of the breast: literature review and single‐centre retrospective series
Authors: Koh Valerie Cui Yun , Lim Jeffrey Chun Tatt , Thike Aye Aye , Cheok Poh Yian , Thu Minn Minn Myint , Li Huihua , Tan Veronique Kiak Mien , Ong Kong Wee , Tan Benita Kiat Tee , Ho Gay Hui , Thilagaratnam Shyamala , Wong Jill Su Lin , Wong Fuh Yong , Ellis Ian Ogilvie , Tan Puay Hoon
Published: February 2019

Aims

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease that has risen to prominence and more recently controversy, with the advent of screening mammography. Debate concerning the true biological potential of low nuclear grade DCIS continues to challenge therapeutic considerations. In this study, we carried out a comprehensive literature review of the behaviour, outcomes and current management trials of low‐grade DCIS, as well as a retrospective study of a large single institutional series of low‐grade DCIS diagnosed at our hospital.

Methods and results

The study cohort comprised 195 cases of low‐grade DCIS diagnosed at the Singapore General Hospital from 1994 to 2010. Clinicopathological parameters and follow‐up data were retrieved and compared between screen‐detected and symptomatic low‐grade DCIS. Immunohistochemistry was performed for ER, PR and HER2. Among 195 cases, 123 (63.1%) were screen‐detected, while 72 (36.9%) were symptomatic. Screen‐detected cases had frequent calcifications (P < 0.001) and were smaller (P = 0.018) than symptomatic cases. All cases were ER‐positive and rate of PR expression was high. No HER2 overexpression was observed. Mean and median follow‐up periods were 107.8 and 109.6 months, respectively. Six patients recurred ipsilaterally, and one patient developed direct distant metastasis. One breast cancer‐related death was recorded. Positive surgical margins (P = 0.023) were significantly associated with a higher risk of ipsilateral recurrences, as well as poorer disease‐free survivals (P = 0.010).

Conclusion

Our data indicate that low‐grade DCIS may be followed by invasive recurrences and even metastatic disease, requiring more study before being regarded as innocuous and indolent.
NLRP6 suppresses the inflammatory response of human periodontal ligament cells by inhibiting NF‐κB and ERK signal pathways
Authors: Lu W. L. , Zhang L. , Song D. Z. , Yi X. W. , Xu W. Z. , Ye L. , Huang D. M.
Published: February 2019

Aim

To explore the function and mechanisms of NLRP6 (NOD‐, LRR‐ and pyrin domain‐containing 6) in the inflammatory response of human periodontal ligament cells (HPDLCs).

Methodology

Tissues associated with apical periodontitis were obtained from three patients who underwent endodontic microsurgery. The expression of NLRP6 in 3 human apical periodontitis tissues and HPDLCs was examined by immunohistochemistry and immunofluorescence, respectively. The expressions of NLRP6, Phospho(p)‐ p65, p65, IκB‐α, p‐ IκB‐α, ERK, p‐ ERK, NLRP3, Pro interleukin (IL)‐1β, Pro caspase‐1 and apoptosis‐associated speck‐like protein containing a CARD (ASC) were examined by western blot. The gene expression and secretion of proinflammatory cytokines were detected using quantitative real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay. Data were analysed statistically with independent sample t‐tests.

Results

NLRP6 was expressed in inflammatory periapical tissues and HPDLCs. Lipopolysaccharide (LPS) from Escherichia coli induced NLRP6 in HPDLCs (P < 0.05). After silencing NLRP6, E. coli LPS‐induced activation of NF‐κB and ERK signalling was enhanced, which was also accompanied by elevated levels of IL‐6 and tumour necrosis factor‐α (TNF‐α) (P < 0.05). Moreover, knockdown of NLRP6 led to up‐regulation of NLRP3, Pro IL‐1β and Pro caspase‐1 (P < 0.05), whereas down‐regulation of ASC (P < 0.05), which may contribute to unchanged levels of IL‐1β in HPDLCs inflammation.

Conclusion

NLRP6 was functionally expressed in inflamed periapical tissues and HPDLCs. NLRP6 negatively regulated the production of IL‐6 and TNF‐α in HPDLCs inflammation by inhibiting NF‐κB and ERK signal pathways.
Autologous platelet‐rich plasma covering urethroplasty versus dartos flap in distal hypospadias repair: A prospective randomized study
Authors: Mahmoud Abdelaziz Yehya , Gouda Samir , Gamaan Ibrahim , Baky Fahmy Mohamed A
Published: February 2019

Objective

To compare the outcome and complication rate of the platelet‐rich plasma applied as a coverage layer and dartos flap layer during primary repair of distal hypospadias.

Methods

A prospective randomized study was carried out comprising 180 boys (age range 12–65 months) from October 2011 to December 2016 at Al‐Azhar University Hospitals, Cairo, Egypt. A single surgeon carried out all urethroplasty. Patients were randomly divided into two groups: group A (tubularized incised plate urethroplasty with platelet‐rich plasma coverage layer) and group B (ventral dartos flap). Complication rates were compared between two groups.

Results

There was a significant difference in the occurrence of complications between the two groups. A total of 36 (20%) complications were recorded in 26 patients, just 12 (13.3%) reported in group A, but 24 (26.7%) complications were reported in group B. Urethrocutaneous fistula was observed in nine patients (10%) in group A, and 12 (13.3%) in group B. Partial glans dehiscence occurred in one patient in group A, and four patients in group B. No patient in group A had a superficial wound infection, compared with six patients in group B. One case of meatal stenosis and urethral stricture was recorded in each group, all of which were managed conservatively. The resultant urinary stream was single and good in 154 patients of both groups.

Conclusions

Platelet‐rich plasma sheet might be considered as an alternative coverage layer for distal hypospadias repair, especially in the absence of a healthy layer.
The midgut V‐ATPase subunit A gene is associated with toxicity to crystal 2Aa and crystal 1Ca‐expressing transgenic rice in Chilo suppressalis
Authors: Qiu L. , Sun Y. , Jiang Z. , Yang P. , Liu H. , Zhou H. , Wang X. , Zhang W. , Lin Y. , Ma W.
Published: February 2019

Insecticidal crystal (Cry) proteins produced by the bacterium Bacillus thuringiensis (Bt) are toxic to a diverse range of insects. Transgenic rice expressing Cry1A, Cry2A and Cry1C toxins have been developed that are lethal to Chilo suppressalis, a devastating insect pest of rice in China. Identifying the mechanisms underlying the interactions of Cry toxins with susceptible hosts will improve both our understanding of Cry protein toxicology and long‐term efficacy of Bt crops. In this study, we tested the hypothesis that V‐ATPase subunit A contributes to the action of Cry1Ab/1Ac, Cry2Aa and Cry1Ca toxins in C. suppressalis. The full‐length V‐ATPase subunit A transcript was initially cloned from the C. suppressalis larval midgut and then used to generate double‐stranded RNA (dsRNA)‐producing bacteria. Toxicity assays using transgenic rice lines TT51 (Cry1Ab and Cry1Ac fusion genes), T2A‐1 (Cry2Aa), and T1C‐19 (Cry1Ca) in conjunction with V‐ATPase subunit A dsRNA‐treated C. suppressalis larvae revealed significantly reduced larval susceptibility to T2A‐1 and T1C‐19 transgenic rice, but not to TT51 rice. These results suggest that the V‐ATPase subunit A plays a crucial role in mediating Cry2Aa and Cry1Ca toxicity in C. suppressalis. These findings will have significant implications on the development of future resistance management tools.
Eritrean Refugees’ Utilization of Antenatal Services in Israel
Authors: van den Bos Nellie , Sabar Galia
Published: February 2019

This study analyzes Eritrean refugee women's utilization of antenatal services in Israel by means of retrospective self‐reports surveys (N = 63) targeting women's service utilization (array of services used, frequency rates, facility rates and demographic correlates) and semi‐structured interviews (N = 10) targeting women's experienced barriers for service utilization. Findings show that Eritrean women make substantive use of the full array of services, with user rates increasing over time. However, frequency rates are low, although increasing when women have more experience with the system. Facility rates are not in keeping with the recommendations of the Israeli Ministry of Health. Interviews reveal that the barriers of work and a complex system of antenatal care limit women's frequent service utilization in the right facility, while the barrier of miscommunication limits their understanding of the services they actually utilized. Findings stress the importance of analyzing different facets of utilization and their demographic correlates.
Complex dietary polysaccharide modulates gut immune function and microbiota, and promotes protection from autoimmune diabetes
Authors: Gudi Radhika , Perez Nicolas , Johnson Benjamin M. , Sofi M. Hanief , Brown Robert , Quan Songhua , Karumuthil‐Melethil Subha , Vasu Chenthamarakshan
Published: February 2019

The dietary supplement and prebiotic values of β‐glucan‐rich products have been widely recognized and dietary approaches for modulating autoimmunity have been increasingly explored, we assess the impact of oral administration of high‐purity yeast β‐glucan (YBG) on gut immune function, microbiota and type 1 diabetes (T1D) using mouse models. Oral administration of this non‐digestible complex polysaccharide caused a dectin‐1‐dependent immune response involving increased expression of interleukin‐10 (IL‐10), retinaldehyde dehydrogenase (Raldh) and pro‐inflammatory cytokines in the gut mucosa. YBG‐exposed intestinal dendritic cells induced/expanded primarily Foxp3+, IL‐10+ and IL‐17+ T cells, ex vivo. Importantly, prolonged oral administration of low‐dose YBG at pre‐diabetic stage suppressed insulitis and significantly delayed the appearance of T1D in non‐obese diabetic (NOD) mice. Further, prolonged treatment with YBG showed increased Foxp3+ T‐cell frequencies, and a significant change in the gut microbiota, particularly an increase in the abundance of Bacteroidetes and a decrease in the Firmicute members. Oral administration of YBG, together with Raldh‐substrate and β‐cell antigen, resulted in better protection of NOD mice from T1D. These observations suggest that YBG not only has a prebiotic property, but also an oral tolerogenic‐adjuvant‐like effect, and these features could be exploited for modulating autoimmunity in T1D.
Development of a data registry to evaluate the quality and safety of nursing practice
Authors: Sim Jenny , Joyce‐McCoach Joanne , Gordon Rob , Kobel Conrad
Published: February 2019

Aim

To describe the development, testing, and implementation of a data registry of nursing‐sensitive indicators for measuring the quality and safety of nursing practice.

Background

Recent research has established causal links between nurse staffing and patient outcomes. Unit level data is necessary for implementation of evidence‐based strategies on nurse staffing and nursing care processes.

Design

Multi‐site, cross‐sectional design.

Methods

Retrospective data were collected from administrative data sets on nurse staffing, patient flow, and adverse events in three hospitals in 2016. Periodic observational surveys on pressure injury prevalence, hand hygiene practices, and documentation of processes of care were also conducted. Prospective data were collected from patients at time of discharge using the Caring Assessment Tool. Nurses’ perceptions of their practice environment were assessed using the Nursing Work Index – Revised: Australian. Data from annual Press Ganey® surveys on patient satisfaction/experience were obtained.

Results

The Australian Nursing Outcomes Collaborative (AUSNOC) data registry was developed in three phases. Phase 1 involved development of a data codebook; phase 2 involved development and testing of data collection methods; and phase 3 involved development of data reports and data dissemination strategies. This paper gives an overview of these phases and includes a summary of the descriptive statistics from the indicator set.

Conclusion

Unit level data is pivotal for measuring the quality and safety of nursing care. Data from the Australian Nursing Outcomes Collaborative (AUSNOC) can be feasibly collected and used to benchmark nursing performance, evaluate patient outcomes, and identify areas for practice improvement.
Metasynthesis: Dying adults’ transition process from cure‐focused to comfort‐focused care
Authors: Meeker Mary Ann , McGinley Jacqueline M. , Jezewski Mary Ann
Published: February 2019

Aim

To describe and explain the process of transition from cure‐focused to comfort‐focused health care as perceived and reported by patients, family members, and healthcare providers.

Background

Moving into the last phase of life due to advanced illness constitutes a developmental transition with increased vulnerability for patients and family.

Design

Qualitative metasynthesis.

Data sources

Medline, CINAHL, and PsycInfo databases searched from inception through March 2016. Primary research reports published from 1990 to 2015, using qualitative designs to report transition experiences of patients, family members, and/or healthcare providers were included.

Review methods

Key elements were extracted and organized into matrices. Findings from each report were analysed using qualitative coding.

Results

The sample was 56 unique reports from 50 primary studies. Patients and families emphasized the importance of receiving understandable information, emotional support, respect for personhood and control. The critical juncture of ‘realizing terminality’ preceded a transition to comfort‐focused care. Subsequently, a shift in goals of care emphasizing comfort and quality of life could occur. Continued provision of information, effective support, respect and control promoted ‘reframing perceptions’ and capacity to embrace a changed identity. Reframing allowed patient and family to find meaning and value in this last phase of life and to embrace the opportunity to prepare for death, nurture relationships, and focus on quality of living.

Conclusion

Understanding the developmental process that can be engaged by patients and families at the end of life provides a theoretical basis that can inform choice and timing of interventions to reduce suffering and enhance positive outcomes.
Paracellular and transcellular migration of metastatic cells through the cerebral endothelium
Authors: Herman Hildegard , Fazakas Csilla , Haskó János , Molnár Kinga , Mészáros Ádám , Nyúl‐Tóth Ádám , Szabó Gábor , Erdélyi Ferenc , Ardelean Aurel , Hermenean Anca , Krizbai István A. , Wilhelm Imola
Published: February 2019

Breast cancer and melanoma are among the most frequent cancer types leading to brain metastases. Despite the unquestionable clinical significance, important aspects of the development of secondary tumours of the central nervous system are largely uncharacterized, including extravasation of metastatic cells through the blood‐brain barrier. By using transmission electron microscopy, here we followed interactions of cancer cells and brain endothelial cells during the adhesion, intercalation/incorporation and transendothelial migration steps. We observed that brain endothelial cells were actively involved in the initial phases of the extravasation by extending filopodia‐like membrane protrusions towards the tumour cells. Melanoma cells tended to intercalate between endothelial cells and to transmigrate by utilizing the paracellular route. On the other hand, breast cancer cells were frequently incorporated into the endothelium and were able to migrate through the transcellular way from the apical to the basolateral side of brain endothelial cells. When co‐culturing melanoma cells with cerebral endothelial cells, we observed N‐cadherin enrichment at melanoma‐melanoma and melanoma‐endothelial cell borders. However, for breast cancer cells N‐cadherin proved to be dispensable for the transendothelial migration both in vitro and in vivo. Our results indicate that breast cancer cells are more effective in the transcellular type of migration than melanoma cells.
Subordinate Resolution ‐‐ An Empirical Analysis of European Union Subsidiary Banks
Authors: Conlon Thomas , Cotter John
Published: February 2019

To help curtail future sovereign exposures to banking losses, the European Union (EU) introduced the Bank Resolution and Recovery Directive, which mandates bail‐in of creditors in the event of significant bank losses. In this article, we examine the impact of resolution on subsidiary banks, notable in terms of their substantial role throughout the EU. Significant differences in risk and funding characteristics are apparent between domestic and cross‐border European bank subsidiaries. Subsidiary banks are found to possess a larger proportion of loss absorbing capacity than underlying parent banks. Results indicate the suitability of single point of entry resolution in the case of domestic subsidiaries and multiple points of entry resolution for cross‐border subsidiaries. Our findings highlight a worrying decline in loss absorbing capacity in European banks more generally since 2006, pointing to a necessary future focus on broad capital thresholds to ensure the success of the resolution model.
Chronic periodontitis and reduced respiratory function
Authors: Winning Lewis , Patterson Christopher C. , Cullen Kathy M. , Kee Frank , Linden Gerard J.
Published: February 2019

Objective

To investigate whether there was an association between chronic periodontitis (CP) and reduced respiratory function.

Methods

A group of dentate 58‐ to 72‐year‐old men in Northern Ireland had a comprehensive periodontal examination. Parallel to the periodontal examination, participants completed questionnaires gathering information on their medical history, social circumstances, demographic background and tobacco use. A physical examination assessed anthropometric measures. Fasting blood samples were obtained and analysed for high‐sensitivity C‐reactive protein (hs‐CRP). Spirometry measures were performed using a wedge bellows spirometer (Vitalograph S Model). The primary outcome variable of interest was the percentage predicted forced expiratory volume in one‐second (% predictedFEV1). Analysis included multiple linear regression with adjustment for various confounders and a regression‐based mediation analysis.

Results

A total of 1,380 men were included in the analysis. The mean age was 63.7 years (SD3.0). Multiple linear regression analysis showed that a doubling in mean clinical attachment loss (CAL) equated to a −3.33% (95%CI: −4.80, −1.86),p < 0.001 change in % predictedFEV1after adjustment for all other potential confounding variables. Systemic inflammation, as measured by hs‐CRP, only accounted for a minor mediating pathway effect (9%).

Conclusions

In this homogenous group of dentate men, CP was significantly associated with a reduced respiratory function.
Variable response to low‐dose naltrexone in patients with Darier disease: a case series
Authors: Boehmer D. , Eyerich K. , Darsow U. , Biedermann T. , Zink A.
Published: February 2019

Background

Darier disease is a rare autosomal‐dominant genodermatosis with a loss of function of a Ca2+‐ATPase pump (SERCA2‐pump). Clinically, the disease is characterized by red–brown keratotic papules mainly in seborrhoeic areas and has only limited and unsatisfactory treatment options. Previously, low‐dose naltrexone was described as a successful treatment option in Hailey–Hailey disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca2+‐ATPase pump (hSPCA1‐pump).

Objective

To assess the efficacy of low‐dose naltrexone as a treatment option in Darier disease.

Methods

Six patients with biopsy‐proven Darier disease (four had severe, one had moderate and one mild clinical manifestations). The patients received off‐label therapy with naltrexone [5 mg per os (p.o.)] and magnesium [200 mg p.o.]. Patients were followed up every 4 weeks for minimally 12 weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained.

Results

The clinical response to naltrexone varied after 12 weeks. The four patients with severe Darier disease showed worsening after initial improvement during the first 4 weeks, whereas the two patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12 weeks with complete flattening of the keratotic papules.

Conclusion

Low‐dose naltrexone did not have an effect on severe Darier disease compared to Hailey–Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses.
Application of deep brief network in transmission spectroscopy detection of pesticide residues in lettuce leaves
Authors: Wu Minmin , Sun Jun , Lu Bing , Ge Xiao , Zhou Xin , Zou Mengli
Published: February 2019

To realize the quick, nondestructive detection of pesticide residues in lettuce leaves, a new method based on deep brief network (DBN) combined with near‐infrared transmission spectroscopy, was studied in this article. Two kinds of pesticide residues (fenvalerate and triazoline) and distilled water were sprayed on the surface of lettuce leaves, respectively. In addition, near infrared transmission spectroscopy was used for collecting spectral data of 240 lettuce samples. Furthermore, Savitzky–Golay combined with multiplicative scatter correction was used to denoise the raw spectral data. Then, after preprocessing spectral data, DBN was used to extract features and identify kinds of pesticide residues in lettuce leaves. Moreover，successive projection algorithm (SPA) was used to select characteristic wavelengths. After all, support vector machine (SVM), PLS‐DA, and k‐nearest neighbor were carried out to establish classification models based on full spectral data, data extracted by DBN and data extracted by SPA. Consequently, DBN–SVM performed best and the accuracy of training set and test set reached 98.89 and 95.00%, respectively. Hence, the method of near infrared transmission spectroscopy combined with DBN–SVM is practical for the qualitative analysis of pesticide residues in lettuce leaves.

Practical applications

Using near infrared spectroscopy could detect the kinds of pesticide residues in lettuce leaves quickly and effectively. A new method involving deep brief network (DBN) was proposed to extract the features of spectral data. Results in this study showed that the DBN is feasible and effective for building classification models of different pesticide residues.
Endogenous transient receptor potential ankyrin 1 and vanilloid 1 activity potentiates glutamatergic input to spinal lamina I neurons in inflammatory pain
Authors: Huang Yuying , Chen Shao‐Rui , Chen Hong , Pan Hui‐Lin
Published: February 2019

Inflammatory pain is associated with peripheral and central sensitization, but the underlying synaptic plasticity at the spinal cord level is poorly understood. Transient receptor potential (TRP) channels expressed at peripheral nerve endings, including TRP subtypes ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), can detect nociceptive stimuli. In this study, we determined the contribution of presynaptic TRPA1 and TRPV1 at the spinal cord level to regulating nociceptive drive in chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in rats. CFA treatment caused a large increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in lamina I, but not lamina II outer zone, dorsal horn neurons. However, blocking NMDA receptors had no effect on spontaneous EPSCs in lamina I neurons of CFA‐treated rats. Application of a specific TRPA1 antagonist, AM‐0902, or of a specific TRPV1 antagonist, 5′‐iodoresiniferatoxin, significantly attenuated the elevated frequency of spontaneous EPSCs and miniature EPSCs, the amplitude of monosynaptic EPSCs evoked from the dorsal root in lamina I neurons of CFA‐treated rats. AM‐0902 and 5′‐iodoresiniferatoxin had no effect on evoked or miniature EPSCs in lamina I neurons of vehicle‐treated rats. In addition, intrathecal injection of AM‐0902 or 5′‐iodoresiniferatoxin significantly reduced pain hypersensitivity in CFA‐treated rats but had no effect on acute nociception in vehicle‐treated rats. Therefore, unlike neuropathic pain, chronic inflammatory pain is associated with NMDA receptor–independent potentiation in glutamatergic drive to spinal lamina I neurons. Endogenous presynaptic TRPA1 and TRPV1 activity at the spinal level contributes to increased nociceptive input from primary sensory nerves to dorsal horn neurons in inflammatory pain.

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NDP‐MSH reduces oxidative damage induced by palmitic acid in primary astrocytes
Authors: Ramírez Delia , Saba Julieta , Turati Juan , Carniglia Lila , Imsen Mercedes , Mohn Claudia , Scimonelli Teresa , Durand Daniela , Caruso Carla , Lasaga Mercedes
Published: February 2019

Recent findings relate obesity to inflammation in key hypothalamic areas for body weight control. Hypothalamic inflammation has also been related to oxidative stress. Palmitic acid (PA) is the most abundant free fatty acid found in food, and in vitro studies indicate that it triggers a pro‐inflammatory response in the brain. Melanocortins are neuropeptides with proven anti‐inflammatory and neuroprotective action mediated by melanocortin receptor 4 (MC4R), but little is known about the effect of melanocortins on oxidative stress. The aim of this study was to investigate whether melanocortins could alleviate oxidative stress induced by a high fat diet (HFD) model. We found that NDP‐MSH treatment decreased PA‐induced reactive oxygen species production in astrocytes, an effect blocked by the MC4R inhibitor JKC363. NDP‐MSH abolished nuclear translocation of Nrf2 induced by PA and blocked the inhibitory effect of PA on superoxide dismutase (SOD) activity and glutathione levels while it also per se increased activity of SOD and γ‐glutamate cysteine ligase (γ‐GCL) antioxidant enzymes. However, HFD reduced hypothalamic MC4R and brain derived neurotrophic factor mRNA levels, thereby preventing the neuroprotective mechanism induced by melanocortins.
A role for taste receptors in (neuro)endocrinology?
Authors: Behrens Maik , Meyerhof Wolfgang
Published: February 2019

The sense of taste is positioned at the forefront when it comes to the interaction of our body with foodborne chemicals. However, the role of our taste system, and in particular its associated taste receptors, is not limited to driving food preferences leading to ingestion or rejection before other organs take over responsibility for nutrient digestion, absorption and metabolic regulation. Taste sensory elements do much more. On the one hand, extra‐oral taste receptors from the brain to the gut continue to sense nutrients and noxious substances after ingestion and, on the other hand, the nutritional state feeds back on the taste system. This intricate regulatory network is orchestrated by endocrine factors that are secreted in response to taste receptor signalling and, in turn regulate the taste receptor cells themselves. The present review summarises current knowledge on the endocrine regulation of the taste perceptual system and the release of hunger/satiety regulating factors by gastrointestinal taste receptors. Furthermore, the regulation of blood glucose levels via the activation of pancreatic sweet taste receptors and subsequent insulin secretion, as well as the influence of bitter compounds on thyroid hormone release, is addressed. Finally, the central effects of tastants are discussed briefly.
Short‐ and long‐term responsiveness to low dose growth hormone (GH) in adult GH deficiency: Role of GH receptor polymorphism
Authors: Bianchi Antonio , Giampietro Antonella , Tartaglione Linda , Chiloiro Sabrina , Gentilella Raffaella , Bima Chiara , Anile Carmelo , Olivi Alessandro , Pontecorvi Alfredo , De Marinis Laura
Published: February 2019

In patients with growth hormone (GH) deficiency (GHD), low doses of recombinant human GH (rhGH) have a similar or better long‐term clinical effect than higher doses. Pharmacogenetic studies suggest that GH receptor (GHR) polymorphism only influences some metabolic parameters. Nonetheless, there is no clear scientific evidence proving the effects of lower rhGH dose regimens on metabolic parameters. The aim of our prospective study was to evaluate the effects of GHR polymorphism in adult GHD patients treated with low rhGH dose during short‐ (6 and 12 months) and long‐term (5 years) follow‐up. Sixty‐nine GHD adult patients were studied, before and during treatment with rhGH, using a standardised low‐dose protocol calculated on the basis of body weight (0.01‐0.03 mg kg‐1 week‐1) and monitored by an insulin‐like growth factor (IGF)‐I plasma assay, as well as anthropometric and metabolic parameters. The GHR genotype (flfl, fld3 or d3d3) was determined from the peripheral blood. d3‐GHR carriers showed a more effective short‐ and long‐term response to low rhGH dose with respect to low‐density lipoprotein reduction, body composition and blood pressure (homozygous patients only); d3‐GHR homozygosity is related to a significant IGF‐I increase during short‐term follow‐up. Regression analysis demonstrated that rhGH dose, age at diagnosis and GHR genotype are the major determinants of IGF‐I increase at 6 and 12 months of replacement therapy. The d3d3‐GHR genotype may influence some metabolic effects during the short‐ and long‐term follow‐up of low rhGH dose and could be an independent determinant of the increase of IGF‐ I during short‐term follow‐up.
A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next‐generation sequencing and review of the literature
Authors: Lerat Justine , Magdelaine Corinne , Beauvais‐Dzugan Hélène , Espil Caroline , Ghorab Karima , Latour Philippe , Derouault Paco , Sturtz Franck , Lia Anne‐Sophie
Published: February 2019

Neurofilaments are neuron‐specific intermediate filaments essential for the radial growth of axons during development and the maintenance of axonal diameter. Pathogenic variants of Neurofilament Light (NEFL) are associated with CMT1F, CMT2E, and CMTDIG and have been observed in less than 1% of Charcot‐Marie‐Tooth (CMT) cases, resulting in the reporting of 35 variants in 173 CMT patients to date. However, only six variants have been reported in 17 patients with impaired hearing. No genotype‐phenotype correlations have yet been established.

Here, we report an additional case: a 69‐year‐old female, who originally presented with axonal sensory and motor neuropathy at the age of 45, associated with moderate sensorineural hearing loss, with a slight slope at high frequencies. Next‐generation sequencing identified a novel pathogenic variant: c.269A > G, p.(Glu90Gly).

Hearing impairment is often linked to CMT due to pathogenic variants of NEFL, especially p.(Glu90Lys) and p.(Asn98Ser), and in our case p.(Glu90Gly). These pathogenic variants are all located at hot spots, in the head domain and the two ends of the rod domain of the protein.
Quality of care assessment for people with multimorbidity
Authors: Valderas J. M. , Gangannagaripalli J. , Nolte E. , Boyd C. M. , Roland M. , Sarria‐Santamera A. , Jones E. , Rijken M.
Published: February 2019

Multimorbidity, the simultaneous presence of multiple health conditions in an individual, is an increasingly common phenomenon globally. The systematic assessment of the quality of care delivered to people with multimorbidity will be key to informing the organization of services for meeting their complex needs. Yet, current assessments tend to focus on single conditions and do not capture the complex processes that are required for providing care for people with multimorbidity. We conducted a scoping review on quality of care and multimorbidity in selected databases in June 2018 and identified 87 documents as eligible for review, predominantly original research and reviews from North America, Europe and Australasia and mostly frequently related to primary care settings. We synthesized data qualitatively in terms of perceived challenges, evidence and proposed metrics. Findings reveal that the association between quality of care and multimorbidity is complex and depends on the conditions involved (quality appears to be higher for those with concordant conditions, and lower in the presence of discordant conditions) and the approach used for measuring quality (quality appears to be higher in people with multimorbidity when measured using condition/drug‐specific process or intermediate outcome indicators, and worse when using patient‐centred reports of experiences of care). People with discordant multimorbidity may be disadvantaged by current approaches to quality assessment, particularly when they are linked to financial incentives. A better understanding of models of care that best meet the needs of this group is needed for developing appropriate quality assessment frameworks. Capturing patient preferences and values and incorporate patients’ voices in the form of patient‐reported experiences and outcomes of care will be critical towards the achievement of high‐performing health systems that are responsive to the needs of people with multimorbidity.
Plasma levels of melatonin in dilated cardiomyopathy
Authors: Misaka Tomofumi , Yoshihisa Akiomi , Yokokawa Tetsuro , Sato Takamasa , Oikawa Masayoshi , Kobayashi Atsushi , Yamaki Takayoshi , Sugimoto Koichi , Kunii Hiroyuki , Nakazato Kazuhiko , Takeishi Yasuchika
Published: February 2019

Background

Melatonin is a multifunctional indolamine and has a cardioprotective role in a variety of cardiovascular processes via antioxidant, anti‐inflammatory, antihypertensive, antithrombotic, and antilipemic effects. It has been reported that lower levels of circulating melatonin are significantly associated with a higher risk of acute myocardial infarction (AMI) and later cardiac remodeling. However, levels of melatonin in patients with dilated cardiomyopathy (DCM) and associations between melatonin levels and cardiac function remain unclear.

Methods and Results

We measured and compared plasma levels of melatonin in 61 control subjects, 81 AMI patients, and 77 DCM patients. Plasma levels of melatonin were progressively decreased from 71.9 pg/mL in the control group to 52.6 pg/mL in the DCM group and 21.9 pg/mL in the AMI group. Next, we examined associations of melatonin levels with parameters of laboratory data, echocardiography, and right‐heart catheterization. In the DCM patients, circulating melatonin showed significant correlations with both high‐sensitivity troponin T (R = −0.422, P < 0.001) and cardiac output (R = 0.431, P = 0.003), but not with B‐type natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), pulmonary artery wedge pressure, or pulmonary artery pressure.

Conclusion

Patients with not only AMI but also DCM had lower circulating melatonin levels. Circulating melatonin levels appear to correlate with myocardial injury and cardiac output in DCM patients.
High prevalence and poor linkage to care of transfusion‐transmitted infections among blood donors in Dar‐es‐Salaam, Tanzania
Authors: Mohamed Zameer , Kim Jin U. , Magesa Alex , Kasubi Mabula , Feldman Sarah F. , Chevaliez Stephane , Mwakale Promise , Taylor‐Robinson Simon D. , Thursz Mark R. , Shimakawa Yusuke , Rwegasha John , Lemoine Maud
Published: February 2019

Blood transfusion is one of the most commonly relied upon therapies in sub‐Saharan Africa. Existing safeguards recommended include systematic screening for transfusion‐transmitted infections and restricted voluntary nonremunerated blood donor selection. We report the transfusion‐transmitted infection screening and notification practice at a large urban blood transfusion centre in Dar‐es‐Salaam, Tanzania. Between October 2016 and March 2017 anonymized records of all donors registered at the blood transfusion unit were accessed to retrospectively note demographic information, donor status, first‐time status, transfusion‐transmitted infection result and notification. 6402 consecutive donors were screened for transfusion‐transmitted infections; the majority were family/replacement blood donors (88.0%) and male (83.8%). Overall transfusion‐transmitted infections prevalence was 8.4% (95% CI 7.8‐9.1), with hepatitis B being the most prevalent infection (4.1% (95% CI 3.6‐4.6)). Transfusion‐transmitted infections were more common in family/replacement blood donors (9.0% (95% CI 8.3‐9.8)) as compared to voluntary nonremunerated blood donor (4.1% (95% CI 2.8‐5.7)). A minority of infected‐donors were notified of a positive result (8.5% (95% CI 6.3‐11.2)). Although transfusion‐transmitted infections are more prevalent among family/replacement blood donors, overall risk of transfusion‐transmitted infections across all groups is considerable. In addition, existing efforts to notify donors of a positive transfusion‐transmitted infection are poor. Future policies must focus on improving linkage to care for newly diagnosed patients with transfusion‐transmitted infections.
Impact of antiretroviral therapy containing tenofovir disoproxil fumarate on the survival of patients with HBV and HIV coinfection
Authors: Tsai Wan‐Chen , Hsu Wei‐Ting , Liu Wang‐Da , Sun Hsin‐Yun , Chuang Yu‐Chung , Huang Yu‐Shan , Cheng Aristine , Lin Kuan‐Yin , Huang Yi‐Chia , Chen Guan‐Jhou , Huang Sung‐Hsi , Sheng Wang‐Huei , Hsieh Szu‐Min , Hung Chien‐Ching , Chang Shan‐Chwen
Published: February 2019

Background

Tenofovir disoproxil fumarate (TDF) is active against both HBV and HIV. Whether the introduction of TDF‐containing combination antiretroviral therapy (cART) has improved the outcome of HIV/HBV‐coinfected patients remains unclear in areas of higher HBV endemicity.

Methods

We retrospectively reviewed medical records of newly diagnosed antiretroviral‐naïve HIV‐infected patients between 2007 and 2015. Four groups of patients were defined, according to the HBV status and availability of TDF for HIV treatment in Taiwan in 2011. The primary outcome was all‐cause mortality.

Results

During the 9‐year study period, 1,723 HIV‐infected patients were included, with a median age of 31 years and baseline CD4 count of 273 cells per μL. The HBV seroprevalence had declined from 18.1% (125/692) in the pre‐TDF era to 10.1% (104/1031) in the post‐TDF era. The respective mortality rate for HIV/HBV‐coinfected and HIV‐monoinfected patients in the pre‐TDF era was 23.2 (95% CI, 12.5‐43.1) and 9.6 (95% CI, 6.1‐15.0) deaths per 1000 person‐years of follow‐up [PYFU], and the respective mortality rate in the post‐TDF era was 15.7 (95% CI, 7.0‐34.8) and 8.0 (95% CI, 5.5‐11.6) deaths per 1000 PYFU. The adjusted hazard ratio for mortality in multivariate Cox proportional‐hazards regression analysis among HIV/HBV‐coinfected patients compared to HIV‐monoinfected patients was 2.79 (95% CI, 1.25‐6.22) in pre‐TDF era and 1.11 (95% CI, 0.45‐2.72) in post‐TDF era.

Conclusions

In this country of high HBV endemicity, the adverse impact of chronic HBV infection on the survival observed in the pre‐TDF era has significantly diminished among HIV/HBV‐coinfected patients compared to HIV‐monoinfected patients in the era of TDF‐containing cART.
Ideal cardiovascular health metrics and the risk of non‐alcoholic fatty liver disease: A cross‐sectional study in northern China
Authors: Liu Huamin , Yao Yan , Wang Youxin , Ma Likun , Liu Xuezhen , Guo Shasha , Feng Xia , Chen Yanru , Chen Xueyu , Liu Zhongni , Ji Long , Li Dong , Zhou Yong
Published: February 2019

Background and purpose

The components of ideal cardiovascular health (CVH) metrics have been shown to be associated with non‐alcoholic fatty liver disease (NAFLD). The present study aimed to determine the association between ideal CVH metrics and NAFLD.

Methods

A total of 10,511 participants (47.26% men) aged 18 to 92 years were selected from the Jidong and Kailuan communities. Ideal CVH was based on 7 ideal CVH metrics: smoking, body mass index (BMI), physical activity, diet, total cholesterol, blood pressure and fasting blood glucose. NAFLD was determined by abdominal ultrasonography. All participants underwent questionnaire assessments and clinical and laboratory examinations. Logistic regression models were used to analyse the relationship of CVH metrics and the number of ideal CVH metrics with NAFLD.

Results

The prevalence rates of NAFLD by CVH summary score quartiles were 64.38% (2,015/3,130), 50.16% (786/1,567), 33.28% (1,194/3,588) and 20.89% (465/2,226). Participants in the highest quartile showed a lower odds ratio (OR) than those in the lowest quartile (fully adjusted OR: 0.17, 95% CI: 0.17‐0.20, P < 0.001). Similar results were observed in subjects stratified by sex and age (45 years). The ORs were progressively decreased with an increased number of ideal CVH metrics (all P < 0.001).

Conclusions

NAFLD was significantly associated with both the summary score of CVH metrics and the number of ideal CVH metrics. The combined evaluation of ideal CVH may contribute to the prevention of NAFLD.
Autoimmune hepatitis: Current and future therapeutic options
Authors: Doycheva Iliana , Watt Kymberly D. , Gulamhusein Aliya F.
Published: February 2019

Autoimmune hepatitis (AIH) is a rare immune‐mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post‐transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first‐line therapy, but results from a randomized trial are awaited. MMF as a second‐line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second‐line option particularly in non‐responders, but data remain limited. Management of recurrent AIH post‐liver transplantation remains controversial with insufficient data to support long‐term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B‐cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.