bluuebunny/crossref_metadata_2025 huggingface dataset:
The blockade of interleukin‐33 released by hepatectomy would be a promising treatment option for cholangiocarcinoma
Authors: Nagaoka Satoshi , Yamada Daisaku , Eguchi Hidetoshi , Yokota Yuki , Iwagami Yoshifumi , Asaoka Tadafumi , Noda Takehiro , Kawamoto Koichi , Gotoh Kunihito , Kobayashi Shogo , Miyoshi Eiji , Doki Yuichiro , Mori Masaki
Published: October 2020

Interleukin‐33 (IL‐33), an alarmin released during tissue injury, facilitates the development of cholangiocarcinoma (CCA) in a murine model. However, it is unclear whether IL‐33 is associated with human CCA. The aim of this study was to support the following hypothesis: IL‐33 is released during hepatectomy for CCA, subsequently facilitating the development of subclinical CCA and eventually leading to recurrent disease. IL‐33 expression was assessed in various samples from both humans and mice including resected liver and paired plasma samples collected at hepatectomy and after surgery, and its influences on recurrent disease and patient prognosis were determined. Homogenized human liver samples with high or low IL‐33 expression were added to the culture medium of human CCA cells, and the changes in proliferation and migration were evaluated. To examine the effects of inhibiting the IL‐33 release induced by hepatectomy, syngraft transplantation of murine CCA cells was performed in C57BL/6J mice with or without IL‐33 blockade. The amount of IL‐33 released into the plasma during hepatectomy correlated with the background liver expression. High expression of IL‐33 in the liver was an independent risk factor for recurrence. Homogenized liver tissue strongly expressing IL‐33 increased both the proliferation and migration of tumor cells. Mice who underwent hepatectomy exhibited CCA progression in the remnant liver, whereas blockade of IL‐33 during hepatectomy inhibited tumor progression. Thus, we concluded that surgery for CCA with curative intent paradoxically induced IL‐33 release, which facilitated CCA recurrence, and anti–IL‐33 therapy during hepatectomy might reduce the risk of CCA recurrence.
Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort
Authors: Jullien Nicolas , Saveanu Alexandru , Vergier Julia , Marquant Emeline , Quentien Marie Helene , Castinetti Frederic , Galon‐Faure Noémie , Brauner Raja , Marrakchi Turki Zinet , Tauber Maité , El Kholy Mohamed , Linglart Agnès , Rodien Patrice , Fedala Nora Soumeya , Bergada Ignacio , Cortet‐Rudelli Christine , Polak Michel , Nicolino Marc , Stuckens Chantal , Barlier Anne , Brue Thierry , Reynaud Rachel ,   the Genhypopit Network
Published: October 2020

Context

The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non‐acquired hypopituitarism.

Aims

To describe main phenotype patterns and their evolution through life.

Design

Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.

Results

Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.

Conclusion

This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long‐term follow‐up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.
Differential incorporation of scientific advances affects coastal habitat restoration practice
Authors: Hughes A. Randall , Edwards Peter , Grabowski Jonathan H. , Scyphers Steven , Williams Susan L.
Published: October 2020

Understanding the diffusion of innovative ideas, behaviors, and technologies could reduce disconnects between conservation science and management, such as the science‐practice gap between biodiversity research and restoration practice. To assess knowledge uptake as an indicator of diffusion of innovation in restoration practice, we conducted an online survey of two organizations focused on coastal habitat restoration: Coastal and Estuarine Research Federation (CERF) and International Coral Reef Society (ICRS). We evaluated experience restoring particular habitats, along with perceptions of the purpose of restoration, the metrics used to evaluate restoration success, and the challenges to successful restoration. We then examined the perceived importance of genetic diversity for restoration success as an indicator of knowledge‐practice transfer in conservation strategy. The practice of coastal habitat restoration diverged by organization and habitat: a higher percentage of CERF members had restored oysters, marshes, and seagrasses compared to ICRS, whereas the reverse was true for corals. Views of the purpose of restoration, the site selection process, and the challenges to successful restoration were similar. Despite similarities in perceptions of the restoration process, the two organizations had variable indications of knowledge‐practice transfer: ICRS respondents ranked the importance of genetic diversity as a restoration strategy higher than did CERF respondents. The perceived importance of genetic diversity also differed by habitat, with both CERF and ICRS respondents ranking diversity as more important for corals. The more successful transfer of knowledge to practice in the coral community indicates that the disconnect between genetic diversity research and restoration practice is surmountable. In addition, it serves as a potential strategy for promoting the spread of innovative restoration practices to achieve long‐term recovery of ecosystems.
Pediatric lung transplantation as standard of care
Authors: Werner Raphael , Benden Christian
Published: October 2020

For infants, children, and adolescents with progressive advanced lung disease, lung transplantation represents the ultimate therapy option. Fortunately, outcomes after pediatric lung transplantation have improved in recent years now producing good long‐term outcomes, no less than comparable to adult lung transplantation. The field of pediatric lung transplantation has rapidly advanced; thus, this review aims to update on important issues such as transplant referral and assessment, and extra‐corporal life support as “bridge to transplantation”. In view of the ongoing lack of donor organs limiting the success of pediatric lung transplantation, donor acceptability criteria and surgical options of lung allograft size reduction are discussed. Post‐transplant, immunosuppression is vital for prevention of allograft rejection; however, evidence‐based data on immunosuppression are scarce. Drug‐related side effects are frequent, close therapeutic drug monitoring is highly advised with an individually tailored patient approach. Chronic lung allograft dysfunction (CLAD) remains the Achilles' heel of pediatric lung transplant limiting its long‐term success. Unfortunately, therapy options for CLAD are still restricted. The last option for progressive CLAD would be consideration for lung re‐transplant; however, numbers of pediatric patients undergoing lung re‐transplantation are very small and its success depends highly on the optimal selection of the most suitable candidate.
Defusing Land Disputes? The Politics of Land Certification and Dispute Resolution in Burundi
Authors: Tchatchoua‐Djomo Rosine , van Leeuwen Mathijs , van der Haar Gemma
Published: October 2020

There is a growing interest in localized land registration, in which user rights are acknowledged and recorded through a community‐based procedure, as an alternative to centralized titling to promote secure tenure in sub‐Saharan Africa. Localized land registration is expected to reduce land disputes, yet it remains unclear how it impacts disputes in practice. This is an urgent question for war‐affected settings that experience sensitive land disputes. This article discusses findings from ethnographic fieldwork in Burundi on pilot projects for land certification. It identifies three ways in which certification feeds into land conflicts rather than preventing or resolving them. First, land certification represents a chance for local people to enter a new round of claim making, as those ignored or disenfranchised in earlier rounds see new opportunities. Second, it offers an avenue for institutional competition between different land‐governing institutions. Third, certification provides politicians with openings to interfere in tenure relations and to expand their support base. The authors conclude that these problems are not simply a matter of inadequate policy design. Rather, there are crucial political dimensions to land conflicts and land tenure in Burundi, which means that land registration programmes run the risk of inflaming conflictive property relations in rural communities.
Computational modelling of attentional bias towards threat in paediatric anxiety
Authors: Thompson Abigail , Steinbeis Nikolaus
Published: October 2020

Computational modelling can be used to precisely characterize the cognitive processes involved in attentional biases towards threat, yet so far has only been applied in the context of adult anxiety. Furthermore, studies investigating attentional biases in childhood anxiety have largely used tasks that conflate automatic and controlled attentional processes. By using a perceptual load paradigm, we separately investigate contributions from automatic and controlled processes to attentional biases towards negative stimuli and their association with paediatric anxiety. We also use computational modelling to investigate these mechanisms in children for the first time. In a sample of 60 children (aged 5‐11 years) we used a perceptual load task specifically adapted for children, in order to investigate attentional biases towards fearful (compared with happy and neutral) faces. Outcome measures were reaction time and percentage accuracy. We applied a drift diffusion model to investigate the precise cognitive mechanisms involved. The load effect was associated with significant differences in response time, accuracy and the diffusion modelling parameters drift rate and extra‐decisional time. Greater anxiety was associated with greater accuracy and the diffusion modelling parameter ‘drift rate’ on the fearful face trials. This was specific to the high load condition. These findings suggest that attentional biases towards fearful faces in childhood anxiety are driven by increased perceptual sensitivity towards fear in automatic attentional systems. Our findings from computational modelling suggest that current attention bias modification treatments should target perceptual encoding directly rather than processes occurring afterwards.
RLTPR Q575E: A novel recurrent gain‐of‐function mutation in patients with adult T‐cell leukemia/lymphoma
Authors: Uchida Yuichiro , Yoshimitsu Makoto , Hachiman Miho , Kusano Shuichi , Arima Naosuke , Shima Kodai , Hayashida Maiko , Kamada Yuhei , Nakamura Daisuke , Arai Akihiko , Tanaka Yuetsu , Hara Hiromitsu , Ishitsuka Kenji
Published: October 2020

Objectives

Adult T‐cell leukemia/lymphoma (ATL) is an intractable T‐cell malignancy caused by long‐term infection with human T‐cell leukemia virus type‐1 (HTLV‐1). While ATL pathogenesis has been associated with HTLV‐1‐derived oncogenic proteins, including Tax and HBZ, the contribution of genomic aberrations remains poorly defined.

Methods

To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL.

Results

We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11‐0.68). Despite being reported in cutaneous T‐cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF‐κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF‐κB activity and significantly increased IL‐2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax.

Conclusions

We identified, and functionally validated, a novel gain‐of‐function mutation in patients with aggressive ATL. During TCR activation by Tax or gain‐of‐function mutations, RLTPR Q575E selectively upregulates NF‐κB signaling and may exert oncogenic effects on ATL pathogenesis.
Regulation of indoleamine 2, 3‐dioxygenase in hippocampal microglia by NLRP3 inflammasome in lipopolysaccharide‐induced depressive‐like behaviors
Authors: Zhang Shanshan , Zong Ying , Ren Zhonggan , Hu Juntao , Wu Xinyuan , Xiao Honglei , Qin Song , Zhou Guomin , Ma Yuanyuan , Zhang Yaodong , Yu Jin , Wang Kaidi , Lu Guocai , Liu Qiong
Published: October 2020

In the brain, NLRP3 (Nucleotide‐binding oligomerization domain, leucine‐rich repeat, and pyrin‐domain‐containing 3) inflammasome is mainly expressed in microglia located in the hippocampus and other mood‐regulated regions, which are particularly susceptible to stress. The activation of NLRP3 inflammasome and production of the activation products may contribute to the development of depressive disorder and memory deficits. Indoleamine 2, 3‐dioxygenase (IDO) is a key factor mediating inflammation and major depressive disorder (MDD). We here generated NLRP3 and apoptosis‐associated speck‐like protein containing caspase recruitment domain (ASC)‐knockout mice, respectively, to verify the effects of NLRP3 or ASC deficiency on lipopolysaccharide (LPS)‐induced depressive‐like behaviors, neuroinflammation, and regulation of IDO expression. Furthermore, we treated these mice with the antidepressant clomipramine (CLO) to observe its effect on depressive‐like behaviors and the expression of the NLRP3 inflammasome and LPS‐induced IDO. We found that intraperitoneal LPS administration led to marked depressive‐like behavior and neuroinflammation. NLRP3 or ASC deficiency attenuated LPS‐induced depressive‐like symptoms and increased IDO gene expression, which was accompanied by inhibition of LPS‐induced microglial activation, suggesting that IDO may be a downstream mediator of the NLRP3 inflammasome in inflammation‐mediated depressive‐like behaviors. Clomipramine administration ameliorated depressive‐like behavior in LPS‐treated mice by regulating the expression of ASC and IDO. In conclusion, NLRP3 inflammasome is involved in LPS‐induced depressive‐like behaviors, and that NLRP3 and ASC may play roles in regulating IDO expression in microglia. This may be a potential mechanism for its involvement in MDD. The antidepressant effect of clomipramine may be exerted through the regulation of ASC‐mediated expression of IDO.
Testing the effect of tACS over parietal cortex in modulating endogenous alpha rhythm and temporal integration windows in visual perception
Authors: Ronconi Luca , Melcher David , Junghöfer Markus , Wolters Carsten H. , Busch Niko A.
Published: October 2020

Neural oscillations in the alpha band (8–12 Hz) have been proposed as a key mechanism for the temporal resolution of visual perception. Higher alpha frequencies have been related to improved segregation of visual events over time, whereas lower alpha frequencies have been related to improved temporal integration. Similarly, also the phase of ongoing alpha has been shown to correlate with temporal integration/segregation. To test a causal relationship between alpha oscillations and perception, we here employed multi‐channel transcranial alternating current stimulation (mc‐tACS) over the right parietal cortex, whereas participants performed a visual temporal integration/segregation task that used identical stimuli with different instructions. Before and after mc‐tACS we recorded the resting‐state electroencephalogram (EEG) to extract the individual alpha frequency (IAF) and delivered electrical stimulation at slightly slower and faster frequencies (IAF±2 Hz). We hypothesized that this would not only drive endogenous alpha rhythms, but also affect temporal integration and segregation in an opposite way. However, the mc‐tACS protocol used here did not consistently increase or decrease the IAF after the stimulation and did not affect temporal integration/segregation accuracy as expected. Although we found some preliminary evidence for an influence of tACS phase on temporal integration accuracy, the ongoing phase of mc‐tACS oscillations did not reliably modulate temporal integration/segregation accuracy in a sinusoidal way as would have been predicted by an effective entrainment of brain oscillations. These findings may guide future studies using different stimulation montages for investigating the role of cortical alpha oscillations for human vision.
Is the “end‐of‐study guess” a valid measure of sham blinding during transcranial direct current stimulation?
Authors: Turner Christopher , Jackson Catherine , Learmonth Gemma
Published: October 2020

Studies using transcranial direct current stimulation (tDCS) typically incorporate a fade‐in, short‐stimulation, fade‐out sham (placebo) protocol, which is assumed to be indistinct from a 10–30 min active protocol on the scalp. However, many studies report that participants can dissociate active stimulation from sham, even during low‐intensity 1 mA currents. We recently identified differences in the perception of an active (10 min of 1 mA) and a sham (20 s of 1 mA) protocol that lasted for 5 min after the cessation of sham. In the present study we assessed whether delivery of a higher‐intensity 2 mA current would exacerbate these differences. Two protocols were delivered to 32 adults in a double‐blinded, within‐subjects design (active: 10 min of 2 mA, and sham: 20 s of 2 mA), with the anode over the left primary motor cortex and the cathode on the right forehead. Participants were asked “Is the stimulation on?” and “How sure are you?” at 30 s intervals during and after stimulation. The differences between active and sham were more consistent and sustained during 2 mA than during 1 mA. We then quantified how well participants were able to track the presence and absence of stimulation (i.e. their sensitivity) during the experiment using cross‐correlations. Current strength was a good classifier of sensitivity during active tDCS, but exhibited only moderate specificity during sham. The accuracy of the end‐of‐study guess was no better than chance at predicting sensitivity. Our results indicate that the traditional end‐of‐study guess poorly reflects the sensitivity of participants to stimulation, and may not be a valid method of assessing sham blinding.
Dopamine D4 receptor modulates inhibitory transmission in pallido‐pallidal terminals and regulates motor behavior
Authors: Conde Rojas Israel , Acosta‐García Jackeline , Caballero‐Florán Rene Nahum , Jijón‐Lorenzo Rafael , Recillas‐Morales Sergio , Avalos‐Fuentes José Arturo , Paz‐Bermúdez Francisco , Leyva‐Gómez Gerardo , Cortés Hernán , Florán Benjamín
Published: October 2020

Two major groups of terminals release GABA within the Globus pallidus; one group is constituted by projections from striatal neurons, while endings of the intranuclear collaterals form the other one. Each neurons' population expresses different subtypes of dopamine D2‐like receptors: D2R subtype is expressed by encephalin‐positive MSNs, while pallidal neurons express the D4R subtype. The D2R modulates the firing rate of striatal neurons and GABA release at their projection areas, while the D4R regulates Globus pallidus neurons excitability and GABA release at their projection areas. However, it is unknown if these receptors control GABA release at pallido‐pallidal collaterals and regulate motor behavior. Here, we present neurochemical evidence of protein content and binding of D4R in pallidal synaptosomes, control of [3H] GABA release in pallidal slices of rat, electrophysiological evidence of the presence of D4R on pallidal recurrent collaterals in mouse slices, and turning behavior induced by D4R antagonist microinjected in amphetamine challenged rats. As in projection areas of pallidal neurons, GABAergic transmission in pallido‐pallidal recurrent synapses is under modulation of D4R, while the D2R subtype, as known, modulates striato‐pallidal projections. Also, as in projection areas, D4R contributes to control the motor activity differently than D2R. This study could help to understand the organization of intra‐pallidal circuitry.
Short‐term exposure to the simple polyphenolic compound gallic acid induces neuronal hyperactivity in zebrafish larvae
Authors: Annona Giovanni , Tarallo Andrea , Nittoli Valeria , Varricchio Ettore , Sordino Paolo , D'Aniello Salvatore , Paolucci Marina
Published: October 2020

A growing body of evidence suggests that the biological effects of polyphenols are not restricted to antioxidant activity, but they exert a wide range of modulatory effects on metabolic pathways, cellular signaling and gene expression. In this study, we tested the minimum safe concentration of gallic acid (GA) in 72 hpf zebrafish larvae in order to evaluate the effects on the central nervous system and the behavioral response. We showed that a short exposure (30 min) induces the depletion of the two main excitatory and inhibitory neurotransmitters, Glu and GABA, respectively, in the larval nervous system. The acute impairment of GABAergic‐glutamatergic balance was paralleled by an increase of thefosabneuronal activity marker in specific brain areas, such as the forebrain, olfactory bulbs, pallial area, ventral midbrain, tegmentum, and the medulla oblongata ventral area. The neuronal excitation was mirrored by the increased cumulative motor response. The inhibition of the olfactory epithelium with brief cadmium exposition suggests a direct involvement of olfaction in the larvae response to GA. Our results demonstrate that a brief exposure to GA induces motoneuronal hyperexcitability in zebrafish. The behavioral response was probably elicited through the activation of an odorous, or chemical, stimulus. The specificity of the activated neuronal territories suggests the involvement of additional signaling pathways. Although the underlying molecular mechanisms remain to be elucidated, our data support the hypothesis that GA acts as an excitatory molecule, capable of inducing a specific nerve response. These results offer a new vision on potential effects of GA.
Nonpharmacological interventions for respiratory health in Parkinson’s disease: A systematic review and meta‐analysis
Authors: McMahon L. , Blake C. , Lennon O.
Published: October 2020

Background and purpose

Respiratory dysfunction in Parkinson’s disease (PD) is often an underdiagnosed and untreated impairment associated with the disease. Clinically, a reactive approach to respiratory morbidity is taken, rather than preventative approaches that address underlying impairment/s. This systematic review identifies the current evidence to support nonpharmacological interventions to improve respiratory impairments in individuals with PD.

Methods

The relevant literature was searched using a customised and systematic strategy. Randomised and nonrandomised control trials of nonpharmacological interventions targeting respiratory outcome measures in PD were included. Outcomes of interest were respiratory morbidity and mortality, respiratory muscle strength, spirometry measures, lung volumes, peak cough flow, and perception of dyspnoea.

Results

Nonpharmacological interventions included: functional training, generalised strength training, respiratory muscle strength training, aerobic exercise, qigong, yoga, breath stacking, incentive spirometry and singing. Methodological quality of included studies varied. Meta‐analyses of nonpharmacological interventions demonstrated significant effects for inspiratory muscle strength (mean difference [MD] 19.68; confidence interval [CI] 8.49, 30.87; z = 3.45; p = 0.0006; I2 = 2%), expiratory muscle strength (MD 18.97; CI 7.79, 30.14; z = 3.33; p = 0.0009; I2 = 23%) and peak expiratory flow (MD 72.21; CI 31.19, 113.24; z = 3.45; p = 0.0006; I2 = 0%). Best‐evidence synthesis identified level 1 evidence supporting nonpharmacological interventions for improving peak cough flow and perceived dyspnoea. No studies were identified reporting outcomes of respiratory rate, inspiration:expiration ratio or respiratory morbidity or mortality in PD.

Conclusions

Nonpharmacological interventions improved respiratory muscle strength and peak expiratory flow in PD. Additional trials targeting respiratory dysfunction and longitudinal studies examining the relationship between respiratory dysfunction and morbidity and mortality rates in PD are required.
Associations between texture of T1‐weighted magnetic resonance imaging and radiographic pathologies in Alzheimer’s disease
Authors: Lee Subin , Kim Ki Woong ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2020

Background and purpose

Texture analysis of magnetic resonance imaging (MRI) brain scans have been proposed as a promising tool in the early diagnosis of Alzheimer’s disease (AD), but its biological correlates remain unknown. In this study, we examined the relationship between MRI texture features and AD pathology.

Methods

The study included 150 participants who had a 3.0T T1‐weighted image, amyloid‐β positron emission tomography (PET), and tau PET within 3 months of each other. In each of six brain regions (hippocampus, precuneus, and entorhinal, middle temporal, posterior cingulate and superior frontal cortices), linear regression analyses adjusting for age and sex was performed to examine the effects of regional amyloid‐β and tau burden on regional texture features. We also compared neuroimaging measures based on pathological severity using ANOVA.

Results

In all regions, tau burden (p < 0.05), but not amyloid‐β burden, were associated with a certain texture feature that varied with the region’s cytoarchitecture. Specifically, autocorrelation and cluster shade were associated with tau burden in allocortical and periallocortical regions, whereas entropy and contrast were associated with tau burden in neocortical regions. Mean signal intensity of each region did not show any associations with AD pathology. The values of the region‐specific textures also varied across groups of varying pathological severity.

Conclusions

Our results suggest that textures of T1‐weighted MRI reflect changes in the brain that are associated with regional tau burden and the local cytoarchitecture. This study provides insight into how MRI texture can be used for detection of microstructural changes in AD.
Association between cortical microinfarcts and total small vessel disease burden in cerebral amyloid angiopathy on 3‐Tesla magnetic resonance imaging
Authors: Ii Yuichiro , Ishikawa Hidehiro , Shindo Akihiro , Matsuyama Hirofumi , Matsuura Keita , Matsuda Kana , Yoshimaru Kimiko , Satoh Masayuki , Kogue Ryota , Umino Maki , Maeda Masayuki , Tomimoto Hidekazu
Published: October 2020

Background and purpose

Cortical microinfarcts (CMIs) are frequently found in the brains of patients with advanced cerebral amyloid angiopathy (CAA) at autopsy. The small vessel disease (SVD) score for CAA (i.e., the CAA‐SVD score) has been proposed to evaluate the severity of CAA‐associated vasculopathic changes by a combination of magnetic resonance imaging (MRI) markers. The aim of this study was to examine the association between total CAA‐SVD score and features of CMIs on in vivo 3‐Tesla MRI.

Methods

Eighty patients with probable CAA were retrospectively analyzed. Lobar cerebral microbleeds, cortical superficial siderosis, enlargement of perivascular space in the centrum semiovale and white matter hyperintensity were collectively assessed, and the total CAA‐SVD score was calculated. The presence of CMI was also examined.

Results

Of the 80 patients, 13 (16.25%) had CMIs. CMIs were detected more frequently in the parietal and occipital lobes. A positive correlation was found between total CAA‐SVD score and prevalence of CMI (ρ = 0.943; p = 0.005). Total CAA‐SVD score was significantly higher in patients with CMIs than in those without (p = 0.009). In a multivariable logistic regression analysis, the presence of CMIs was significantly associated with total CAA‐SVD score (odds ratio 2.318 [95% confidence interval 1.228–4.376]; p = 0.01, per each additional point).

Conclusions

The presence of CMIs with a high CAA‐SVD score could be an indicator of more severe amyloid‐associated vasculopathic changes in patients with probable CAA.
Spinal dural leaks in patients with infratentorial superficial siderosis of the central nervous system—Refinement of a diagnostic algorithm
Authors: Friedauer Lucie , Rezny‐Kasprzak Beata , Steinmetz Helmuth , du Mesnil de Rochemont Richard , Foerch Christian
Published: October 2020

Background and purpose

Superficial siderosis of the central nervous system is a sporadic finding in magnetic resonance imaging, resulting from recurrent bleedings into the subarachnoid space. This study aimed to determine the frequency of spinal dural cerebrospinal fluid (CSF) leaks amongst patients with a symmetric infratentorial siderosis pattern.

Methods

In all, 97,733 magnetic resonance images performed between 2007 and 2018 in our neurocenter were screened by a keyword search for “hemosiderosis” and “superficial siderosis.” Siderosis patterns on brain imaging were classified according to a previously published algorithm. Potential causative intracranial bleeding events were also assessed. Patients with a symmetric infratentorial siderosis pattern but without causative intracranial bleeding events in history were prospectively evaluated for spinal pathologies.

Results

Forty‐two patients with isolated supratentorial siderosis, 30 with symmetric infratentorial siderosis and 21 with limited (non‐symmetric) infratentorial siderosis were identified. Amyloid angiopathy and subarachnoid hemorrhage were causes for isolated supratentorial siderosis. In all four patients with a symmetric infratentorial siderosis pattern but without a causative intracranial bleeding event in history, spinal dural abnormalities were detected. Dural leaks were searched for in patients with symmetric infratentorial siderosis and a history of intracranial bleeding event without known bleeding etiology, considering that spinal dural CSF leaks themselves may also cause intracranial hemorrhage, for example by inducing venous thrombosis due to low CSF pressure. Thereby, one additional spinal dural leak was detected.

Conclusions

Persisting spinal dural CSF leaks can frequently be identified in patients with a symmetric infratentorial siderosis pattern. Diagnostic workup in these cases should include magnetic resonance imaging of the whole spine.
Atipamezole, a specific α2A antagonist, suppresses spike‐and‐wave discharges and alters Ca2⁺/calmodulin‐dependent protein kinase II in the thalamus of genetic absence epilepsy rats
Authors: Yavuz Melis , Aydın Banu , Çarçak Nihan , Akman Özlem , Raci Yananlı Hasan , Onat Filiz
Published: October 2020

Objective

The role of α2A adrenergic receptors (α2AARs) in absence epilepsy is not well characterized. Therefore, we investigated the outcomes of the specific antagonism of α2AARs on the spike‐and‐wave discharges (SWDs) in genetic absence epilepsy rats from Strasbourg (GAERSs), together with its influence on the behavior and second messenger systems, which may point to the mechanisms to which a possible SWD modulation can be related.

Methods

Atipamezole, an α2AAR antagonist, was administered intracerebroventricularly to the adult GAERSs, and electroencephalography (EEG) was conducted. The cumulative duration and number of SWDs, and the mean duration of each SWD complex were counted. The relative power of the EEG frequency bands and behavioral activity after the acute application of two doses (12 and 31 μg/5 μL) of atipamezole were evaluated. The levels of cyclic adenosine monophosphate and calcium/calmodulin‐dependent kinase II (CaMKII) were measured in the cortex, thalamus, and hippocampus of naive Wistar rats and GAERSs, administered with artificial cerebrospinal fluid (aCSF) as a vehicle, or either acute or chronic atipamezole (12 μg), the latter being administered for 5 consecutive days.

Results

Atipamezole significantly suppressed SWDs dose‐dependently, without affecting the relative power values of EEG frequency spectrum. The stereotypic activity was significantly lower in both naive Wistar rats and GAERSs receiving the highest dose (31 μg) of atipamezole compared to GAERSs receiving aCSF. In GAERSs, CaMKII levels were found to be higher in the thalamus after the acute and chronic application of SWD‐suppressing doses of atipamezole (12 and 31 μg) compared to aCSF.

Significance

This study emphasizes the α2AR‐related modulation of absence epilepsy and particularly the significance of α2AR antagonism in suppressing SWDs. Atipamezole's SWD‐suppressive actions may be through CaMKII‐mediated second messenger systems in the thalamus.
Neonatal genetic epilepsies display convergent white matter microstructural abnormalities
Authors: Sandoval Karamian Amanda G. , Wusthoff Courtney J. , Boothroyd Derek , Yeom Kristen W. , Knowles Juliet K.
Published: October 2020

White matter undergoes rapid development in the neonatal period. Its structure during and after development is influenced by neuronal activity. Pathological neuronal activity, as in seizures, might alter white matter, which in turn may contribute to network dysfunction. Neonatal epilepsy presents an opportunity to investigate seizures and early white matter development. Our objective was to determine whether neonatal seizures in the absence of brain injury or congenital anomalies are associated with altered white matter microstructure. In this retrospective case‐control study of term neonates, cases had confirmed or suspected genetic epilepsy and normal brain magnetic resonance imaging (MRI) and no other conditions independently impacting white matter. Controls were healthy neonates with normal MRI results. White matter microstructure was assessed via quantitative mean diffusivity (MD). In 22 cases, MD was significantly lower in the genu of the corpus callosum, compared to 22 controls, controlling for gestational age and postmenstrual age at MRI. This finding suggests convergent abnormal corpus callosum microstructure in neonatal epilepsies with diverse suspected genetic causes. Further study is needed to determine the specific nature, causes, and functional impact of seizure‐associated abnormal white matter in neonates, a potential pathogenic mechanism.
Insecticide exposure affects intergenerational patterns of DNA methylation in the Colorado potato beetle, Leptinotarsa decemlineata
Authors: Brevik Kristian , Bueno Erika M. , McKay Stephanie , Schoville Sean D. , Chen Yolanda H.
Published: October 2020

Insecticide use is pervasive as a selective force in modern agroecosystems. Insect herbivores exposed to these insecticides have been able to rapidly evolve resistance to them, but how they are able to do so is poorly understood. One possible but largely unexplored explanation is that exposure to sublethal doses of insecticides may alter epigenetic patterns that are heritable. For instance, epigenetic mechanisms, such as DNA methylation that modifies gene expression without changing the underlying genetic code, may facilitate the emergence of resistant phenotypes in complex ways. We assessed the effects of sublethal insecticide exposure, with the neonicotinoid imidacloprid, on DNA methylation in the Colorado potato beetle, Leptinotarsa decemlineata, examining both global changes in DNA methylation and specific changes found within genes and transposable elements. We found that exposure to insecticide led to decreases in global DNA methylation for parent and F2 generations and that many of the sites of changes in methylation are found within genes associated with insecticide resistance, such as cytochrome P450s, or within transposable elements. Exposure to sublethal doses of insecticide caused heritable changes in DNA methylation in an agricultural insect herbivore. Therefore, epigenetics may play a role in insecticide resistance, highlighting a fundamental mechanism of evolution while informing how we might better coexist with insect species in agroecosystems.
Genetic mixing for population management: From genetic rescue to provenancing
Authors: Hoffmann Ary A. , Miller Adam D. , Weeks Andrew R.
Published: October 2020

Animal and plant species around the world are being challenged by the deleterious effects of inbreeding, loss of genetic diversity, and maladaptation due to widespread habitat destruction and rapid climate change. In many cases, interventions will likely be needed to safeguard populations and species and to maintain functioning ecosystems. Strategies aimed at initiating, reinstating, or enhancing patterns of gene flow via the deliberate movement of genotypes around the environment are generating growing interest with broad applications in conservation and environmental management. These diverse strategies go by various names ranging from genetic or evolutionary rescue to provenancing and genetic resurrection. Our aim here is to provide some clarification around terminology and to how these strategies are connected and linked to underlying genetic processes. We draw on case studies from the literature and outline mechanisms that underlie how the various strategies aim to increase species fitness and impact the wider community. We argue that understanding mechanisms leading to species decline and community impact is a key to successful implementation of these strategies. We emphasize the need to consider the nature of source and recipient populations, as well as associated risks and trade‐offs for the various strategies. This overview highlights where strategies are likely to have potential at population, species, and ecosystem scales, but also where they should probably not be attempted depending on the overall aims of the intervention. We advocate an approach where short‐ and long‐term strategies are integrated into a decision framework that also considers nongenetic aspects of management.
The vitamin A ester retinyl propionate has a unique metabolic profile and higher retinoid‐related bioactivity over retinol and retinyl palmitate in human skin models
Authors: Bjerke Donald L. , Li Rui , Price Jason M. , Dobson Roy L. M. , Rodrigues MyriamRubecca , Tey ChingSiang , Vires Laura , Adams Rachel L. , Sherrill Joseph D. , Styczynski Peter B. , Goncalves Kirsty , Maltman Victoria , Przyborski Stefan , Oblong John E.
Published: October 2020

Human skin is exposed daily to environmental stressors, which cause acute damage and inflammation. Over time, this leads to morphological and visual appearance changes associated with premature ageing. Topical vitamin A derivatives such as retinol (ROL), retinyl palmitate (RPalm) and retinyl propionate (RP) have been used to reverse these changes and improve the appearance of skin. This study investigated a stoichiometric comparison of these retinoids using in vitro and ex vivo skin models. Skin biopsies were treated topically to compare skin penetration and metabolism. Treated keratinocytes were evaluated for transcriptomics profiling and hyaluronic acid (HA) synthesis and treated 3D epidermal skin equivalents were stained for epidermal thickness, Ki67 and filaggrin. A retinoic acid receptor‐alpha (RARα) reporter cell line was used to compare retinoid activation levels. Results from ex vivo skin found that RP and ROL have higher penetration levels compared with RPalm. RP is metabolized primarily into ROL in the viable epidermis and dermis whereas ROL is esterified into RPalm and metabolized into the inactive retinoid 14‐hydroxy‐4,14‐retro‐retinol (14‐HRR). RP treatment yielded higher RARα activation and HA synthesis levels than ROL whereas RPalm had a null effect. In keratinocytes, RP and ROL stimulated similar gene expression patterns and pathway theme profiles. In conclusion, RP and ROL show a similar response directionality whereas RPalm response was inconsistent. Additionally, RP has a consistently higher magnitude of response compared with ROL or RPalm.
Absence of ethnic difference on single‐dose pharmacokinetics of rivoceranib between healthy male Caucasian, Japanese, and Chinese subjects
Authors: Sachar Madhav , Park Cheol Hee , Pesco‐Koplowitz Luana , Koplowitz Barry , McGinn Arlo
Published: October 2020

Rivoceranib (known in China as apatinib) is a selective vascular endothelial growth factor receptor‐2 (VEGFR‐2) tyrosine kinase inhibitor which inhibits angiogenesis in solid tumors. The aim of study was to evaluate potential pharmacokinetic (PK) differences between the Caucasian, Japanese, and Chinese populations. An open‐label, single‐dose, parallel‐design PK study of rivoceranib was conducted in Caucasian, Japanese, and Chinese subjects. A total of 18 healthy males were recruited to each group (54 total), and 201 mg rivoceranib tablets (as 250 mg rivoceranib mesylate) were administered orally to subjects. Plasma samples were collected, and rivoceranib plasma concentration was determined using LC‐MS/MS. For PK analysis, non‐compartmental and compartmental analyses were performed. Intrinsic factors (CYP2C19 and CYP3A4 genotype) were also examined. Non‐compartmental analysis showed no significant difference in AUC0–t, AUC0–∞, Cmax, tmax, and t1⁄2. Apparent clearance and volume of distribution were different across the three populations; however, the extent of this difference does not require dose modification. For compartmental modeling, a two‐compartment model was used to fit the plasma concentrations. No significant difference was observed in absorption, elimination, and intercompartmental transfer rate constants among the three groups. The present study shows no major ethnic PK differences between Caucasian, Japanese, and Chinese populations.
Marginal lands for bioenergy in China; an outlook in status, potential and management
Authors: Qaseem Mirza Faisal , Wu Ai-Min
Published: October 2020

Energy consumption and CO2 emissions have been increasing continuously over the past few decades in China and there is a pressing need to replace the fossil fuel‐based economy with an efficient low‐carbon system, tailor‐made to future requirements. China is starting an energy transition with the aim of building an energy system for the future. China has made tremendous progress in increasing the amount of renewable energy and reducing the cost of renewable energy over the last 20 years. According to the 14th 5 year plan, China aims to incorporate 20% of renewable energy to the primary energy mix and attain 27% reduction in CO2 emissions. Bioenergy crops constitute a significant proportion of biomass‐based bioenergy and have recently been promoted by the Chinese Government to help overcome food and fuel conflict. Steps are being taken to promote bioenergy crops on marginal lands in China, and various regions across the country with soil marginality have been evaluated for bioenergy crop cultivation. The present paper reviews the status of bioenergy in China and the potential status of marginal lands from different regions of China. It also elaborates on some of the policies, subsidies and incentives allocated by the Chinese Government for the promotion of biomass‐based energy. Land management and plant improvement strategies were discussed, which are effective in making marginal lands suitable for bioenergy crop cultivation. Managing planting strategies, intercropping and crop rotation are effective management practices used in China for the utilization of marginal lands. A national investigation is desirable for creating an inventory of technical and economic potential of biomass feedstocks that could be planted on marginal lands. This would assist with highlighting the pros and cons of using marginal lands for bioenergy production and effective policy making.
Clinical significance of a positive Clostridioides difficile glutamate dehydrogenase test on the outcomes of hospitalized older patients
Authors: Nagayoshi Yohsuke , Yamamoto Kazuko , Sato Shuntaro , Suyama Naofumi , Izumikawa Takuya , Izumikawa Kinichi , Miyazaki Taiga , Izumikawa Koichi , Yanagihara Katsunori , Mukae Hiroshi
Published: October 2020

Aim

Clostridioides difficile infection worsens the outcome of older hospitalized patients; thus, its diagnosis is necessary for the nosocomial infection control. The standard diagnostic test's limited sensitivity for Clostridioides difficile infection, an enzyme immunoassay for Clostridioides difficile toxins, is of clinical concern. Glutamate dehydrogenase detection is usually tested combined with Clostridioides difficile toxins. However, the clinical significance of a positive glutamate dehydrogenase result is unclear. We evaluated the association between positive glutamate dehydrogenase results, in‐hospital mortality and hospital stay length among older patients with suspected Clostridioides difficile infection.

Methods

In this retrospective cohort study, we examined the data of patients who received antibiotics (except for Clostridioides difficile infection treatment) after admission and tested for Clostridioides difficile infection using an enzyme immunoassay for Clostridioides difficile toxins and glutamate dehydrogenase in a secondary care hospital located in a rural region with high aging rate, between 2015 and 2018.

Results

In total, 188 patients were included (83.5% of them aged >75 years). Glutamate dehydrogenase positivity was independently associated with in‐hospital mortality (adjusted odds ratio 2.19, 95% confidence interval 1.14–4.21) and hospital stay length (regression coefficient 16.0, 95% confidence interval 5.15–26.9). Clostridioides difficile toxin positivity was independently associated with hospital stay duration (regression coefficient 14.5, 95% confidence interval 0.04–29.1), unlike in‐hospital mortality.

Conclusions

Glutamate dehydrogenase was closely related to in‐hospital mortality and prolonged hospitalization compared with Clostridioides difficile toxin. Clinicians should not neglect glutamate dehydrogenase‐positive patients, even when they are Clostridioides difficile toxin‐negative, and consider them as having poor prognostic potential. Geriatr Gerontol Int 2020; 20: 1138–1144.