bluuebunny/crossref_metadata_2025 huggingface dataset:
Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis
Authors: Refardt Julie , Winzeler Bettina , Christ‐Crain Mirjam
Published: April 2019

Copeptin is secreted in an equimolar amount to arginine vasopressin (AVP) but can easily be measured in plasma or serum with a sandwich immunoassay. The main stimuli for copeptin are similar to AVP, that is an increase in osmolality and a decrease in arterial blood volume and pressure. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation. Copeptin has, therefore, been evaluated as diagnostic biomarker in vasopressin‐dependent disorders of body fluid homeostasis. Disorders of body fluid homeostasis are common and can be divided into hyper‐ and hypoosmolar circumstances: the classical hyperosmolar disorder is diabetes insipidus, while the most common hypoosmolar disorder is the syndrome of inappropriate antidiuresis (SIAD). Copeptin measurement has led to a “revival” of the direct test in the differential diagnosis of diabetes insipidus. Baseline copeptin levels, without prior thirsting, unequivocally identify patients with nephrogenic diabetes insipidus. In contrast, for the difficult differentiation between central diabetes insipidus and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is clearly superior to the classical water deprivation test. On the contrary, in the SIAD, copeptin measurement is of only little diagnostic value. Copeptin levels widely overlap in patients with hyponatraemia and emphasize the heterogeneity of the disease. Additionally, a variety of factors lead to unspecific copeptin elevations in the acute setting further complicating its interpretation. The broad use of copeptin as diagnostic marker in hyponatraemia and specifically to detect cancer‐related disease in SIADH patients can, therefore, not be recommended.
The values of shear wave elastography in avoiding repeat fine‐needle aspiration for thyroid nodules with nondiagnostic and undetermined cytology
Authors: Chen Lin , Shi Yi‐xin , Liu Ying‐chun , Zhan Jia , Diao Xue‐hong , Chen Yue , Zhan Wei‐wei
Published: April 2019

Objective

To evaluate the value of shear wave elastography (SWE) in avoiding repeat fine‐needle aspiration of thyroid nodules with nondiagnostic and undetermined cytology.

Methods

A total of 232 thyroid nodules with nondiagnostic (n = 132) and undetermined (n = 100) cytology underwent ultrasound (US) and SWE, followed by repeat ultrasound (US)‐guided fine‐needle aspiration cytology (FNAC). The final diagnosis was based on cytological or pathological findings. The US and SWE characteristics of benign and malignant nodules were compared using the χ2‐test. The receiver operating characteristic (ROC) curves of the thyroid imaging reporting and data system (TI‐RADS) categories from the US and the EMean and ESD from the SWE were graphed, and the areas under the curves (AUCs) were compared using a Z test.

Results

There were significant differences between the benign and malignant nodules in terms of the echogenicity, shape, margin, calcification and TI‐RADS categories (all P < 0.05). The differences were significant between the malignant and benign nodules for EMean [(34.57 ± 14.81) kPa vs. (19.18 ± 7.09) kPa] and ESD [(13.68 ± 13.01) kPa vs. (3.97 ± 2.58) kPa] (both P < 0.001). Though the difference in the AUCs of EMean (0.864) and ESD (0.876) was not significant (P = 0.745), they both had higher diagnostic performances in comparison with TI‐RADS categories (0.762) (all P < 0.05). Moreover, ESD attained a sensitivity of 100% with a relatively higher specificity of 49.75% when its cut‐off value was 3.3 kPa.

Conclusions

Shear wave elastography is a promising imaging method for reducing repeat FNAC for benign thyroid nodules with nondiagnostic and undetermined cytology when using ESD as an index.
Establishing reproductive potential and advances in fertility preservation techniques for XY individuals with differences in sex development
Authors: Islam Rumana , Lane Sheila , Williams Suzannah A. , Becker Christian M. , Conway Gerard S. , Creighton Sarah M.
Published: April 2019

Background

Discordance between gonadal type and gender identity has often led to an assumption of infertility in patients with differences in sex development (DSD). However, there is now greater recognition of fertility being an important issue for this group of patients. Currently, gonadal tissue that may have fertility potential is not being stored for individuals with DSD and, where gonadectomy forms part of management, is often discarded. The area of fertility preservation has been predominantly driven by oncofertility which is a field dedicated to preserving the fertility of patients undergoing gonadotoxic cancer treatment. The use of fertility preservation techniques could be expanded to include individuals with DSD where functioning gonads are present.

Methods

This is a systematic literature review evaluating original research articles and relevant reviews between 1974 and 2018 addressing DSD and fertility, in vitro maturation of sperm, and histological/ultrastructural assessment of gonadal tissue in complete and partial androgen insensitivity syndrome, 17β‐hydroxysteroid dehydrogenase type 3 and 5α‐reductase deficiency.

Conclusion

Successful clinical outcomes of ovarian tissue cryopreservation are paving the way for similar research being conducted using testicular tissue and sperm. There have been promising results from both animal and human studies leading to cryopreservation of testicular tissue now being offered to boys prior to cancer treatment. Although data are limited, there is evidence to suggest the presence of reproductive potential in the gonads of some individuals with DSD. Larger, more detailed studies are required, but if these continue to be encouraging, individuals with DSD should be given the same information, opportunities and access to fertility preservation as other patient groups.
Association of opioid receptor gene polymorphisms with drinking severity and impulsivity related to alcohol use disorder in a Korean population
Authors: Park Chun Il , Hwang Syung Shick , Kim Hae Won , Kang Jee In , Lee Sang Hak , Kim Se Joo
Published: April 2019

Aims

Recent evidence suggests that the opioid system is implicated in the pathophysiology of alcohol use disorder (AUD). We aimed to examine the genetic influence of opioid receptors on susceptibility to AUD and its clinical and psychological characteristics including harmful drinking behavior and various aspects of impulsivity in AUD patients.

Methods

Three μ‐opioid receptor gene (OPRM1) variants and two κ‐opioid receptor gene (OPRK1) variants were examined in 314 male patients with AUD and 324 male controls. We applied the Alcohol Use Disorders Identification Test (AUDIT), Obsessive Compulsive Drinking Scale (OCDS), and Alcohol Dependence Scale. AUD patients also completed the stop‐signal task, delay discounting task, balloon analogue risk task, and the Barratt Impulsiveness Scale version 11 (BIS‐11).

Results

No significant differences in genotype distributions or haplotype frequencies were found between AUD patients and controls. However, OPRK1 SNP rs6473797 was significantly related to the severity of alcohol‐related symptoms as measured by AUDIT and OCDS and a haplotype containing rs6473797 was also related to OCDS scores in AUD patients. For other psychological traits, OPRM1 SNP rs495491 was significantly associated with scores on the motor subfactor of the BIS‐11.

Conclusion

Genetic variations in opioid receptors may contribute to symptom severity and impulsivity in AUD patients.
Voice aerodynamics following office‐based hyaluronate injection laryngoplasty
Authors: Pei Yu‐Cheng , Chuang Hsiu‐Feng , Wong Alice M. K. , Fang Tuan‐Jen
Published: April 2019

Objectives

Neuromuscular control, glottal conformation and aerodynamics are the major factors affecting voice performance. We aimed to characterise the degree to which voice improvements following office‐based intracordal hyaluronate injection laryngoplasty (HIL) depend on changes in voice aerodynamics in patients with unilateral vocal fold paralysis (UVFP), by assessing the correlations between these parameters.

Design

Prospective case series.

Setting

Otolaryngology Clinics in a Medical Center.

Participants

Patients with UVFP within 6 months of their first outpatient visit who received single HIL.

Main outcome measures

Videolaryngostroboscopy, aerodynamics and laboratory voice analysis were evaluated at baseline and 1 month after HIL. Quantitative laryngeal electromyography was evaluated at baseline to confirm UVFP.

Results

Seventy‐five newly diagnosed patients with UVFP were analysed. The normalised glottal gap area (NGGA) decreased (P < 0.001) (Cohen's dz = 0.94) and all aerodynamic parameters improved (all P < 0.05) (Cohen's dz = 0.38‐1.02) following HIL. Patients undergoing thoracic surgery had more profound aerodynamic impairments both before and after HIL. After adjusting for improvements in NGGA, the improvement in aerodynamics was correlated with voice improvement and most notably with maximum phonation time and jitter/shimmer.

Conclusions

Hyaluronate injection laryngoplasty improved glottal conformation, aerodynamics and voice, highlighting the benefit of early HIL intervention for patients with UVFP. Patients with UVFP caused by thoracic surgery continued to have poorer aerodynamics post‐HIL, indicating the importance of speech therapy in these patients.
All‐trans‐retinoic acid activated mast cells via Mas‐related G‐protein‐coupled receptor‐X2 in retinoid dermatitis
Authors: Zheng Yi , Che Delu , Peng Bin , Hao Yong , Zhang Xinyue , He Langchong , Geng Songmei
Published: April 2019

Background

Retinoic acid (RA)‐induced dermatitis is the most frequent side‐effect limiting its widespread use. However, the exact mechanisms triggering dermatitis are not fully understood, including the role of skin mast cells. The newly discovered Mas‐related G‐protein‐coupled receptor‐X2 (MRGPRX2) in mast cells mediates pseudoallergic drug reactions in several types of dermatitis. A possible contribution of MRGPRX2 to contact dermatitis induced by RA has hitherto not been examined.

Objectives

To investigate whether all‐trans‐RA (ATRA) activates mast cells via MRGPRX2/MrgprB2 (the mouse orthologue), contributing to the pathogenesis of retinoid‐induced dermatitis.

Methods

Wild‐type (WT) and MrgprB2−/− mice were treated with topical ATRA to observe local inflammation and mast cell degranulation in vivo by the use of haematoxylin and eosin and immunofluorescence staining. Release of histamine and release of β‐hexosaminidase were measured and calcium influx was detected in Laboratory of Allergic Disease 2 (LAD2) cells with specific knockdown targeting MRGPRX2 by small interfering RNA (siRNA) and in primary cells from MrgprB2−/− mice.

Results

As compared with WT mice, MrgprB2−/− mice showed resistance to ATRA‐triggered contact dermatitis and local inflammatory reactions in the paws. ATRA activated mast cells via the MrgprB2 pathway in murine cells, and via the MRGPRX2 pathway in human mast cells.

Conclusions

ATRA‐induced dermatitis could be achieved by activating mast cells via MRGPRX2/MrgprB2, which may provide a potential therapy target to reduce the side‐effect.
The preservative 2‐(thiocyanomethylthio)benzothiazole: A potential allergen in leather products
Authors: Herman Anne , Goossens An , Tennstedt Dominique , Bergendorff Ola , Isaksson Marléne , Mowitz Martin , Baeck Marie
Published: April 2019

Background

Allergic contact dermatitis caused by leather is common, and several responsible allergens, such as tanning agents, glues, mercaptobenzothiazole derivatives, and dyes, but also antimicrobials and antifungals, are involved.

Material and methods

Three female patients were referred to the Departments of Dermatology in a Belgian university hospital following skin reactions caused by leather products (shoes, belt, and car seats). They were patch tested with the European baseline series and samples of suspected leather products, and additionally with 2‐(thiocyanomethylthio)benzothiazole (TCMTB), an antifungal agent previously reported to be a contact allergen in footwear. Chromatographic analyses of samples of all the leather materials tested were performed at the Department of Occupational and Environmental Dermatology in Malmö, Sweden.

Results

The patients reacting to the leather samples were shown to be sensitized to TCMTB, the presence of which could be confirmed by chemical analyses of samples obtained from the patients.

Conclusion

Patch tests with TCMTB should be considered in patients with contact dermatitis caused by leather items.
Determine safety of outpatient chemotherapy and autotransplants using refrigerated, non‐frozen grafts in persons with multiple sclerosis
Authors: Gale Robert Peter , Gómez‐Cruz Gisela Berenice , Olivares‐Gazca Juan Carlos , León‐Peña Andrés A. , Gómez‐Almaguer David , Gómez‐De‐León Andrés , González‐López Elías Eugenio , Ruiz‐Argüelles Alejandro , Soto‐Vega Elena , Muñoz‐Pérez María José , Ruiz‐Delgado Guillermo José , Ruiz‐Argüelles Guillermo José
Published: April 2019

Background

Persons with multiple sclerosis are increasingly treated with intermediate‐ or high‐dose chemotherapy and a hematopoietic cell autotransplant. This is often done in an inpatient setting using frozen blood cell grafts.

Objective

Determine if chemotherapy and a hematopoietic cell autotransplant can be safely done in an outpatient setting using refrigerated, non‐frozen grafts.

Methods

We developed an autotransplant protocol actionable in an outpatient setting using a refrigerated, non‐frozen blood graft collected after giving cyclophosphamide, 50 mg/kg/d × 2 days and filgrastim, 10 μg/kg/d. A second identical course was given 9 days later followed by infusion of blood cells stored at 4°C for 1‐4 days. The co‐primary outcomes were rates of granulocyte and platelet recovery and therapy‐related mortality.

Results

We treated 426 consecutive subjects. Median age was 47 years (range, 21‐68 years). A total of 145 (34%) were male. Median graft refrigeration time was 1 day (range, 1‐4 days). Median interval to granulocytes >0.5 × 10E + 9/L was 8 days (range, 2‐12) and to platelets >20 × 10E + 9/L, 8 days (range, 1‐12). Only 15 subjects (4%) were hospitalized, predominately for iatrogenic pneumothorax (N = 5) and neutropenic fever (N = 4). There was only 1 early death from infection.

Conclusion

Intermediate‐dose chemotherapy and a hematopoietic cell autotransplant can be safely done in an outpatient setting using, refrigerated, non‐frozen grafts.
Influence of Rifampin‐Mediated Organic Anion‐Transporting Polypeptide 1B1/1B3 Inhibition on the Pharmacokinetics of Clazosentan
Authors: Juif Pierre‐Eric , Voors‐Pette Christine , Ufer Mike , Dogterom Peter , Dingemanse Jasper
Published: April 2019

Clazosentan is a selective endothelin A receptor antagonist in development for the prevention and treatment of vasospasm postsubarachnoid hemorrhage. It is a substrate of organic anion‐transporting polypeptide 1B1/1B3 based on preclinical data. This randomized, double‐blind, two‐period, cross‐over study investigated the pharmacokinetics, safety, and tolerability of an intravenous infusion of clazosentan (15 mg/hour for 3 hours) after the intravenous administration of placebo or rifampin (600 mg/100 mL in 30 minutes). A total of 14 healthy male participants were enrolled resulting in 13 completers. Clazosentan exposure was three to four times higher after organic anion‐transporting polypeptide 1B1/1B3 inhibition, as reflected by the geometric mean ratio (90% confidence interval) of area under the plasma concentration‐time curve from zero to infinity: 3.88 (3.24–4.65). Clearance and volume of distribution decreased to a similar extent. Elimination half‐life was not affected. A similar pattern but a higher incidence and frequency of adverse events were observed when clazosentan was given with rifampin than with placebo.
Sensitivity to amplitude envelope rise time in infancy and vocabulary development at 3 years: A significant relationship
Authors: Kalashnikova Marina , Goswami Usha , Burnham Denis
Published: April 2019

Here we report, for the first time, a relationship between sensitivity to amplitude envelope rise time in infants and their later vocabulary development. Recent research in auditory neuroscience has revealed that amplitude envelope rise time plays a mechanistic role in speech encoding. Accordingly, individual differences in infant discrimination of amplitude envelope rise times could be expected to relate to individual differences in language acquisition. A group of 50 infants taking part in a longitudinal study contributed rise time discrimination thresholds when aged 7 and 10 months, and their vocabulary development was measured at 3 years. Experimental measures of phonological sensitivity were also administered at 3 years. Linear mixed effect models taking rise time sensitivity as the dependent variable, and controlling for non‐verbal IQ, showed significant predictive effects for vocabulary at 3 years, but not for the phonological sensitivity measures. The significant longitudinal relationship between amplitude envelope rise time discrimination and vocabulary development suggests that early rise time discrimination abilities have an impact on speech processing by infants.
Brittle diabetes revisited: a description of erratic and difficult‐to‐control diabetes in an elderly woman with Type 1 diabetes
Authors: Newman C. , Dinneen S. F.
Published: April 2019

Background

‘Brittle diabetes’ is frequently attributed to psychological stressors causing insulin omission in young women with Type 1 diabetes. It has received little attention in the recent medical literature.

Case report

We report the case of an 87‐year‐old woman who had recurrent episodes of unexplained diabetic ketoacidosis. Despite frequent inpatient monitoring of capillary glucose, her blood glucose levels remained erratic. She experienced a total of 12 episodes of ketoacidosis (some occurring during hospitalization), with 11 episodes occurring over a 3‐month period. Several episodes of ketoacidosis required care in a high‐dependency unit and up to 32 h of intravenous insulin and fluids. Extensive investigations failed to identify any underlying cause of the recurrent ketoacidosis. Ultimately, the introduction of a continuous subcutaneous insulin infusion pump resulted in improved glycaemic control and avoided the need for further hospitalizations.

Conclusion

Individuals of advanced age can benefit from insulin pump therapy. The original definition of ‘brittle diabetes’ referred to patients whose lives were ‘constantly disrupted by episodes of hypo‐ or hyperglycaemia’. Our case reminds us that this clinical entity can result from altered biology and is not always related to psychological stressors.
Discovering biogeographic and ecological clusters with a graph theoretic spin on factor analysis
Authors: Alroy John
Published: April 2019

Factor analysis (FA) has the advantage of highlighting each semi‐distinct cluster of samples in a data set with one axis at a time, as opposed to simply arranging samples across axes to represent gradients. However, in the case of presence–absence data it is confounded by absences when gradients are long. No statistical model can cope with this problem because the raw data simply do not present underlying information about the length of such gradients. Here I propose an easy way to tease out this information. It is a simple emendation of FA called stepping down, which involves giving an absence a negative value when the missing species nowhere co‐occurs with the species found in the relevant sample. Specifically, a binary co‐occurrence graph is created, and the magnitude of negative values is made a function of how far the graph must be traversed in order to link the missing species with each species that is present. Simulations show that standard FA yields inferior results to FA based on stepped‐down matrices in terms of mapping clusters into axes one‐by‐one. Standard FA is also uninformative when applied to a global bat inventory data set. Step‐down FA (SDFA) easily flags the main biogeographic groupings. Methods like correspondence analysis, non‐metric multidimensional scaling, and Bayesian latent variable modelling are not commensurate with SDFA because they do not seek to find a one‐to‐one mapping of axes and clusters. Stepping down seems promising as a means of illustrating clusters of samples, especially when there are subtle or complex discontinuities in gradients.
Do genetic structure and landscape heterogeneity impact color morph frequency in a polymorphic salamander?
Authors: Hantak Maggie M. , Page Robert B. , Converse Paul E. , Anthony Carl D. , Hickerson Cari‐Ann M. , Kuchta Shawn R.
Published: April 2019

Landscape heterogeneity plays an important role in population structure and divergence, particularly for species with limited vagility. Here, we used a landscape genetic approach to identify how landscape and environmental variables affect genetic structure and color morph frequency in a polymorphic salamander. The eastern red‐backed salamander, Plethodon cinereus, is widely distributed in northeastern North America and contains two common color morphs, striped and unstriped, that are divergent in ecology, behavior, and physiology. To quantify population structure, rates of gene flow, and genetic drift, we amplified 10 microsatellite loci from 648 individuals across 28 sampling localities. This study was conducted in northern Ohio, where populations of P. cinereus exhibit an unusually wide range of morph frequency variation. To test whether genetic distance was more correlated with morph frequency, elevation, canopy cover, waterways, ecological niche or geographic distance, we used resistance distance and least cost path analyses. We then examined whether landscape and environmental variables, genetic distance or geographic distance were correlated with variation in morph frequency. Tests for population structure revealed three genetic clusters across our sampling range, with one cluster monomorphic for the striped morph. Rates of gene flow and genetic drift were low to moderate across sites. Genetic distance was most correlated with ecological niche, elevation and a combination of landscape and environmental variables. In contrast, morph frequency variation was correlated with waterways and geographic distance. Thus, our results suggest that selection is also an important evolutionary force across our sites, and a balance between gene flow, genetic drift and selection interact to maintain the two color morphs.
Plants, microbes, and odorants involved in host plant location by a specialist moth: who's making the message?
Authors: Wolfin Michael S. , Volo Sara L. , Chilson Ronald R. , Liu Yuxi , Cha Dong H. , Cox Kerik D. , Loeb Gregory M. , Linn Charles E.
Published: April 2019

The grape berry moth (GBM), Paralobesia viteana (Clemens) (Lepidoptera: Tortricidae), is a specialist pest insect of cultivated grape, Vitis spp. (Vitaceae), in the eastern USA. A blend of volatile compounds has been isolated from plant material that attracts female GBM in the flight tunnel and field. However, the origin of the volatile cue is potentially complicated by the presence of microbes (bacteria and fungi) living on the surface of the plant. Microbial volatile organic compounds can affect insect behavior, and therefore must be considered to fully understand olfaction‐mediated behaviors. We report here the chemical and behavioral analysis of the volatile profiles produced from both the sanitized and control shoot treatments. The sanitization treatment removed 96.4% of the surface microbes up to 24 h, covering the duration of the behavioral assays and volatile collections. Overall, the surface microbes did not significantly contribute to the volatile profile of the grape shoots, as all of the peaks in the volatile profile of sanitized shoots were found in the profile of control shoots. In flight tunnel assays, female GBM displayed the same level of upwind oriented flight to sanitized shoots (flew upwind 57.4%, landed 30.9%) as they did to control shoots (flew upwind 57.8%, landed 31.0%), suggesting further that surface microbes did not contribute to the production of the previously identified blend of behaviorally active volatiles for GBM.
Effect of rain on trap building by Myrmeleon brasiliensis in a riparian woodland from the Cerrado biome in Brazil
Authors: Freire Luciane Gomes , Lima Tatiane do Nascimento
Published: April 2019

In areas of the Cerrado biome (Brazilian savanna) with well‐defined rainy and dry seasons, changes in climate and landscape affect the abundance and seasonality of insects. Larvae of the antlion Myrmeleon brasiliensis (Návas) (Neuroptera: Myrmeleontidae) are predators that build traps in dry sandy soil to capture prey. Here we determined the effect of rain on trap building by M. brasiliensis larvae in a riparian forest in the Cerrado biome. Differences in population size and developmental stage were found between the rainy and dry seasons. In the laboratory, the effect of rain‐soaked soil on trap building was evaluated. Fewer antlion larvae were found in the rainy season. Moreover, a greater abundance of larvae in the final stage of development (third instar) was found in the dry season, whereas more first instars were found in the rainy season. The latter revealed that wet soil affects the trap building of the larvae, as smaller traps were built in the treatment with soaked soil (simulated rain), whereas the larvae in the control treatment (no rain) continued building traps with no change in size. The findings indicate that seasonality in the Cerrado biome exerts a short‐term influence on M. brasiliensis larvae (larvae build fewer traps) as well as a long‐term influence (association with life cycle).
Molecular identification of the powdery mildew fungus infecting rubber trees in China
Authors: Wu Hua , Pan Yingwen , Di Rong , He Qiguang , Rajaofera Mamy Jayne Nelly , Liu Wenbo , Zheng Fucong , Miao Weiguo
Published: April 2019

Powdery mildew is a foliar disease of rubber trees. It is one of the most important leaf diseases in rubber plantations worldwide. The causal agent of this powdery mildew, previously known as Oidium heveae, has been identified under various names. To precisely identify the causal agents of this disease, 57 conidial samples were collected from 2013 to 2017 in Hainan, Yunnan and Guangdong provinces, the main rubber tree planting regions in China. Based on morphological observations using light and scanning electron microscopy, pathogenicity testing, and nrDNA ITS and 28S sequences, Erysiphe quercicola is suggested as the only causal agent of rubber tree powdery mildew in China.
First‐in‐man study of ACT‐709478, a novel selective triple T‐type calcium channel blocker
Authors: Richard Muriel , Kaufmann Priska , Kornberger Rüdiger , Dingemanse Jasper
Published: April 2019

Objective

Increased activity of T‐type Ca2+ channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. ACT‐709478 is an orally available triple T‐type Ca2+ channel blocker. The aim of this first‐in‐man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of ACT‐709478 in healthy subjects.

Methods

This double‐blind, placebo‐controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1‐400 mg ACT‐709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60 mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests.

Results

The maximum plasma concentration (Cmax) was reached within 3 to 4 hours (≤60 mg) and within 20 to 28 hours (>60 mg), and across all dose levels the terminal half‐life (95% confidence interval) ranged from 36 (29‐45) to 43 (22‐86) hours. Multiple peaks were observed and Cmax and area under the plasma concentration‐time curve (AUC)0‐∞ increased in a less than dose‐proportional manner. A 1.6‐fold increase in Cmax and no change in AUC0‐∞ was observed in fed compared to fasted conditions. A significant correlation (P < 0.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment‐related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo.

Significance

ACT‐709478 exhibits good tolerability and safety after single‐dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.
Natural Wolbachia infections are common in the major malaria vectors in Central Africa
Authors: Ayala Diego , Akone‐Ella Ousman , Rahola Nil , Kengne Pierre , Ngangue Marc F. , Mezeme Fabrice , Makanga Boris K. , Nigg Martha , Costantini Carlo , Simard Frédéric , Prugnolle Franck , Roche Benjamin , Duron Olivier , Paupy Christophe
Published: April 2019

During the last decade, the endosymbiont bacterium Wolbachia has emerged as a biological tool for vector disease control. However, for long time, it was believed that Wolbachia was absent in natural populations of Anopheles. The recent discovery that species within the Anopheles gambiae complex host Wolbachia in natural conditions has opened new opportunities for malaria control research in Africa. Here, we investigated the prevalence and diversity of Wolbachia infection in 25 African Anopheles species in Gabon (Central Africa). Our results revealed the presence of Wolbachia in 16 of these species, including the major malaria vectors in this area. The infection prevalence varied greatly among species, confirming that sample size is a key factor to detect the infection. Moreover, our sequencing and phylogenetic analyses showed the important diversity of Wolbachia strains that infect Anopheles. Co‐evolutionary analysis unveiled patterns of Wolbachia transmission within some Anopheles species, suggesting that past independent acquisition events were followed by co‐cladogenesis. The large diversity of Wolbachia strains that infect natural populations of Anopheles offers a promising opportunity to select suitable phenotypes for suppressing Plasmodium transmission and/or manipulating Anopheles reproduction, which in turn could be used to reduce the malaria burden in Africa.
Species interactions mediate thermal evolution
Authors: Tseng M. , Bernhardt Joey R. , Chila Alexander E.
Published: April 2019

Understanding whether populations and communities can evolve fast enough to keep up with ongoing climate change is one of the most pressing issues in biology today. A growing number of studies have documented rapid evolutionary responses to warming, suggesting that populations may be able to persist despite temperature increases. The challenge now is to better understand how species interactions, which are ubiquitous in nature, mediate these population responses to warming. Here, we use laboratory natural selection experiments in a freshwater community to test hypotheses related to how thermal evolution of Daphnia pulex to two selection temperatures (12 and 18°C) is mediated by rapid thermal evolution of its algal resource (Scenedesmus obliquus) or by the presence of the zooplankton predator Chaoborus americanus. We found that cold‐evolved algae (a high‐quality resource) facilitated the evolution of increased thermal plasticity in Daphnia populations selected at 12°C, for both body size and per capita growth rates (r). Conversely, warm‐evolved algae facilitated the evolution of increased r thermal plasticity for Daphnia selected at 18°C. Lastly, we found that the effect of selection temperature on evolved Daphnia body size was more pronounced when Daphnia were also reared with predators. These data demonstrate that trait evolution of a focal population to the thermal environment can be affected by both bottom‐up and top‐down species interactions and that rapid temperature evolution of a resource can have cascading effects on consumer thermal evolution. Our study highlights the importance of incorporating species interactions when estimating ecological and evolutionary responses of populations and communities to ongoing temperature warming.
Turning a potent family‐9 free cellulase into an operational cellulosomal component and vice versa
Authors: Vita Nicolas , Borne Romain , Perret Stéphanie , de Philip Pascale , Fierobe Henri‐Pierre
Published: April 2019

Ruminiclostridium cellulolyticum and Lachnoclostridium phytofermentans are cellulolytic clostridia either producing extracellular multienzymatic complexes termed cellulosomes or secreting free cellulases respectively. In the free state, the cellulase Cel9A secreted by L. phytofermentans is much more active on crystalline cellulose than any cellulosomal family‐9 enzyme produced by R. cellulolyticum. Nevertheless, the incorporation of Cel9A in vitro in hybrid cellulosomes was formerly shown to generate artificial complexes with altered activity, whereas its incorporation in vivo in native R. cellulolyticum cellulosomes resulted in a strain displaying a weakened cellulolytic phenotype. In this study, we investigated why Cel9A is so potent in the free state but functions poorly as a cellulosomal component, in contrast to the most similar enzyme synthesized by R. cellulolyticum, Cel9G, weakly active in the free state but whose activity on crystalline cellulose is drastically increased in cellulosomes. We show that the removal of the C‐terminal moiety of Cel9A encompassing the two X2 modules and the family‐3b carbohydrate binding module (CBM3b), reduces its activity on crystalline cellulose. Grafting a dockerin module further diminishes the activity, but this truncated cellulosomal form of Cel9A displays important synergies in hybrid cellulosomes with the pivotal family‐48 cellulosomal enzyme of R. cellulolyticum. The exact inverse approach was applied to the cellulosomal Cel9G. Grafting the two X2 modules and the CBM3b of Cel9A to Cel9G strongly increases its activity on crystalline cellulose, to reach Cel9A activity levels. Altogether these data emphasize the specific features required to generate an efficient free or cellulosomal family‐9 cellulase.
Colorectal cancer‐associated ~ 6 kDa hyaluronan serves as a novel biomarker for cancer progression and metastasis
Authors: Zhang Guoliang , Lu Renquan , Wu Man , Liu Yiwen , He Yiqing , Xu Jing , Yang Cuixia , Du Yan , Gao Feng
Published: April 2019

Low molecular weight hyaluronan (LMW‐HA) is believed to accumulate in tumors and to exert protumor effects. This study aimed to identify colorectal cancer (CRC)‐associated LMW‐HA, precisely determine its MW, and elucidate its role in predicting tumor progression. The MW distribution of HA extracted from CRC and paired noncancerous tissues was evaluated. We found that the level of HA with a MW below 30 kDa was markedly elevated in CRC tissues, and we defined HA with a MW of ~ 6 kDa as CRC‐associated LMW‐HA. In line with this finding, ~ 6 kDa HA was significantly accumulated in cancer tissues relative to total HA, and this LMW‐HA played a critical role in tumor metastasis. Moreover, serum ~ 6 kDa HA levels in CRC patients were significantly increased and positively correlated with the levels in matched cancer tissues. Elevated serum ~ 6 kDa HA levels could be used to discriminate patients with or without CRC and was associated with early relapse, advanced tumor–node–metastasis stage, lymphovascular invasion, and lymph node (LN) metastasis. Notably, serum ~ 6 kDa HA levels were significantly reduced after tumor resection. Our study suggests that ~ 6 kDa HA may serve as a new biomarker for estimating tumor progression, predicting LN metastasis, and monitoring tumor recurrence.
Effectiveness of acute in‐hospital occupational therapy for older patients with hip fracture
Authors: Uruma Makiko , Momosaki Ryo , Chono Masayuki , Fukumoto Miki , Watanabe Tomomi , Nakamura Mikako , Abo Masahiro
Published: April 2019

Aim

To test the hypothesis that hip fracture patients who receive occupational therapy (OT) have better functional ability than those who do not.

Methods

This retrospective observational study utilized data from the Japan Rehabilitation Database spanning 2005–2015. In‐hospital hip fracture patients admitted to acute hospitals were identified. In total, 1266 patients were eligible based on the exclusion criteria. The primary outcome was motor Functional Independence Measure (FIM) efficiency.

Results

Patients who received OT were 50.9% of hip fracture patients. Patients who received OT had significantly higher scores in motor FIM efficiency (mean 0.79 vs 0.70; P = 0.02) and FIM effectiveness (mean 0.49 vs 0.41; P < 0.01) than the patients who did not receive OT. From multivariate linear regression analysis, OT was identified as a significant factor in motor FIM efficiency (coefficient 1.29, 95% confidence interval 1.14–1.47; P < 0.01) and FIM effectiveness (coefficient 1.07, 95% confidence interval 1.02–1.12; P < 0.01).

Conclusions

The present cohort analysis showed that OT for hip fracture patients in the acute phase likely contributes to improved functional ability. Geriatr Gerontol Int 2019; 19: 611–615.
Black porcelain solar plate and its thermal performance
Authors: Xiu Dapeng , Zhao Guochen , Zhou Jixue , Zhang Suqing
Published: April 2019

In this study, a new percentage named “A value” was proposed, which was the key to evaluate whether solar thermal systems could be put into massive industrial application. A novel type of solar energy collector—black porcelain solar plate was developed. The solar absorptance of black coating was as high as 0.95 and did not decay against time. The performance of black porcelain solar roof systems (BPRSs) was investigated, which could be integrated with buildings and had the A value 2.49‐2.67 times higher than traditional solar thermal systems. The experimental results showed that the thermal efficiencies of BPRSs were more than 50%, which was about 20% higher than traditional solar thermal systems. BPRSs were widely known as low cost, long lifetime, no corrosion, and no aging. They could provide many applications for civil buildings, such as hot water of four seasons, summer air conditioning and winter heating. Once applied widely, solar energy collected by black porcelain solar plates might prospectively be the major source of human energy demand.
The effect of gelation on statically and dynamically freeze‐cast structures
Authors: Christiansen Cathrine D. , Nielsen Kaspar K. , Bordia Rajendra K. , Bjørk Rasmus
Published: April 2019

Freeze‐casting is a technique used to produce structures with anisotropic porosity in the form of well‐defined microchannels throughout a sample. Here, this technique is used on the magnetocaloric ceramic La0.66Ca0.26Sr0.07 Mn1.05O3. We show that a dynamic freezing profile, where the temperature is decreased continuously at −10 K/min, results in homogeneous, lamellar channels with widths of ∼15 µm, while static freezing, where the temperature is kept constant at 177 K, results in channels of increasing size away from the initial ice crystal nucleation site. The effect of gelation before freeze‐casting is also investigated. Gelation inhibits ice crystal growth, which significantly changes the morphology by making channel cross sections less elongated, while additionally introducing more dendrites and ceramic bridges in the structure. The latter significantly dominates the flow path through the gelated structures, affecting the calculated tortuosity, which increases to τ ≈ 4 when compared to non‐gelated samples where calculated tortuosities are in the range of ∼1.3 to ∼3. Finally, we present a systematic and automatic approach for evaluating channel and wall sizes and calculating tortuosities. This is based on analysis of images obtained by scanning electron microscopy using a continuous particle size distribution method and the TauFactor application in MATLAB®.
Thermally stable high strain and piezoelectric characteristics of (Li, Na, K)(Nb, Sb)O3‐CaZrO3 ceramics for piezo actuators
Authors: Lee Ku‐Tak , Lee Tae‐Gon , Kim Sun‐Woo , Chae Seok‐June , Kim Eun‐Ji , Kim Jeong‐Seog , Choi Ji‐Won , Nahm Sahn
Published: April 2019

The 0.97(Na0.5K0.5)(Nb1−xSbx)O3‐0.03CaZrO3 ceramic with x = 0.09 exhibits a high d33 of 518 pC/N and a strain of 0.13% at 4.0 kV/mm owing to its orthorhombic‐pseudocubic polymorphic phase boundary (PPB) structure. However, these values decreased considerably above 90°C owing to its low Curie temperature (TC), indicating that its thermal stability is not sufficient for practical applications. Li2O was added to the specimen with x = 0.11 to improve its thermal stability of the strain and d33 by increasing the TC without degrading the actual d33 and strain values. The 0.97(Li0.04Na0.46K0.5)(Nb0.89Sb0.11)O3‐0.03CaZrO3 ceramic, having an orthorhombic‐tetragonal PPB structure, exhibits a d33 of 502 pC/N and a strain of 0.16%. This large strain was maintained up to 150°C and the d33 slightly decreased to 475 pC/N at 130°C. Therefore, this lead‐free ceramic displays excellent piezoelectric characteristics with improved thermal stability, indicating that it can be applied to piezoelectric actuators.
Densification, microstructure, and mechanical properties of ZrC–SiC ceramics
Authors: Feng Lun , Fahrenholtz William G. , Hilmas Gregory E. , Watts Jeremy , Zhou Yue
Published: April 2019

ZrC–SiC ceramics were fabricated by high‐energy ball milling and reactive hot pressing of ZrH2, carbon black, and varying amounts of SiC. The ceramics were composed of nominally pure ZrC containing 0 to 30 vol% SiC particles. The relative density increased as SiC content increased, from 96.8% for nominally pure ZrC to 99.3% for ZrC‐30 vol% SiC. As SiC content increased from 0 to 30 vol%, Young's modulus increased from 404 ± 11 to 420 ± 9 GPa and Vickers hardness increased from 18.5 ± 0.7 to 23.0 ± 0.5 GPa due to a combination of the higher relative density of ceramics with higher SiC content and the higher Young's modulus and hardness of SiC compared to ZrC. Flexure strength was 308 ± 11 MPa for pure ZrC, but increased to 576 ± 49 MPa for a SiC content of 30 vol%. Fracture toughness was 2.3 ± 0.2 MPa·m1/2 for pure ZrC and increased to about 3.0 ± 0.1 MPa·m1/2 for compositions containing SiC additions. The combination of high‐energy ball milling and reactive hot pressing was able to produce ZrC–SiC ceramics with sub‐micron grain sizes and high relative densities with higher strengths than previously reported for similar materials.
Ferric citrate, nitrate, saponin and their combinations affect in vitro ruminal fermentation, production of sulphide and methane and abundance of select microbial populations
Authors: Wu H. , Meng Q. , Zhou Z. , Yu Z.
Published: April 2019

Aims

This study investigated the effects of ferric citrate, nitrate and saponin, both individually and in combination, on sulphidogenesis, methanogenesis, rumen fermentation and abundances of select microbial populations using in vitro rumen cultures.

Methods and Results

Ferric citrate (50 mg l−1), Quillaja saponin (0·6 g l−1) and sodium nitrate (5 mmol l−1) were used in in vitro ruminal fermentation. Ferric citrate alone, its combination with saponin and/or nitrate lowered the aqueous sulphide concentration and total sulphide production. Methane production was suppressed by nitrate alone (by up to 32·92%), its combination with saponin (25·04%) and with both saponins with nitrate (25·92%). None of the treatments adversely affected feed digestion or rumen fermentation. The population of sulphate-reducing bacteria was increased by nitrate and saponin individually, while that of total Archaea was decreased by nitrate alone and the combination of the three inhibitors.

Conclusions

Nitrate and its combination with saponin or both ferric citrate and saponin substantially decreased methane production. Most importantly, the decreased methane production was not at the expense of feed digestion or fermentation. Sulphidogenesis from the sulphate present in the high-sulphur diets can be suppressed competitively by ferric citrate, although it was elevated by saponin and nitrate.

Significance and Impact of the Study

The results of this study demonstrated that combinations of certain methane inhibitors, which have different mechanisms of antimethanogenic actions or inhibit different guilds of microbes involved in methane production and sulphate reduction, can be more effective and practical than individual inhibitors, not only in mitigating enteric methane emission but also in lowering the risk of sulphur-associated polioencephalomalacia in feedlot cattle fed high sulphur diets.
Dermatoscopy in leprosy and its correlation with clinical spectrum and histopathology: a prospective observational study
Authors: Vinay K. , Kamat D. , Chatterjee D. , Narang T. , Dogra S.
Published: April 2019

Background

Leprosy, a chronic granulomatous infection has varied clinical presentations spanning across different spectrums. The scope of dermatoscopy is vast and has been studied for other granulomatous disorders like sarcoidosis.

Objectives

The objective of this study was to describe the dermatoscopic features of the entire spectrum of leprosy and to correlate with clinical and histopathological findings.

Methods

This was a prospective observational study of treatment naïve leprosy patients over a period of 1 year. The study patients were categorized as per Ridley‐Jopling classification based on clinical, slit skin smear and histopathological findings. Most representative lesions were photographed, evaluated by dermatoscopy and were biopsied.

Results

A total of 30 patients (21 males and 9 females) were recruited; 2 cases of tuberculoid leprosy, 12 cases of borderline tuberculoid (3 with type 1 reaction), 8 cases of borderline lepromatous, 6 cases of lepromatous leprosy (3 with type 2 reaction) and 2 cases of Histoid leprosy. The dermatoscopic featues consistently seen were yellowish orange areas and vascular structures like linear branching vessels and crown vessels correlating with the presence of dermal granulomas and dilated vessels. Broken pigment network, white chrysalis like areas were seen in addition. Tuberculoid spectrum also had absence of or diminished hair follicles and eccrine duct openings correlating with presence of peri‐appendageal granuloma and appendageal destruction. Scaling and follicular plugs were other features in lesions of type 1 reaction.

Conclusion

Yellowish‐orange areas and vascular structures are the common dermatoscopic features of leprosy. Broken pigment network and paucity of appendageal structures are additional specific features.