bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal Optical Imaging to Investigate Spatiotemporal Changes in Cerebrovascular Function in AUDA Treatment of Acute Ischemic Stroke
Authors: Wang Han-Lin , Chen Jia-Wei , Yang Shih-Hung , Lo Yu-Chun , Pan Han-Chi , Liang Yao-Wen , Wang Ching-Fu , Yang Yi , Kuo Yun-Ting , Lin Yi-Chen , Chou Chin-Yu , Lin Sheng-Huang , Chen You-Yin
Published: June 2021

Administration of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) has been demonstrated to alleviate infarction following ischemic stroke. Reportedly, the main effect of AUDA is exerting anti-inflammation and neovascularization via the inhibition of soluble epoxide hydrolase. However, the major contribution of this anti-inflammation and neovascularization effect in the acute phase of stroke is not completely elucidated. To investigate the neuroprotective effects of AUDA in acute ischemic stroke, we combined laser speckle contrast imaging and optical intrinsic signal imaging techniques with the implantation of a lab-designed cranial window. Forepaw stimulation was applied to assess the functional changes via measuring cerebral metabolic rate of oxygen (CMRO2) that accompany neural activity. The rats that received AUDA in the acute phase of photothrombotic ischemia stroke showed a 30.5 ± 8.1% reduction in the ischemic core, 42.3 ± 15.1% reduction in the ischemic penumbra (p < 0.05), and 42.1 ± 4.6% increase of CMRO2 in response to forepaw stimulation at post-stroke day 1 (p < 0.05) compared with the control group (N = 10 for each group). Moreover, at post-stroke day 3, increased functional vascular density was observed in AUDA-treated rats (35.9 ± 1.9% higher than that in the control group, p < 0.05). At post-stroke day 7, a 105.4% ± 16.4% increase of astrocytes (p < 0.01), 30.0 ± 10.9% increase of neurons (p < 0.01), and 65.5 ± 15.0% decrease of microglia (p < 0.01) were observed in the penumbra region in AUDA-treated rats (N = 5 for each group). These results suggested that AUDA affects the anti-inflammation at the beginning of ischemic injury and restores neuronal metabolic rate of O2 and tissue viability. The neovascularization triggered by AUDA restored CBF and may contribute to ischemic infarction reduction at post-stroke day 3. Moreover, for long-term neuroprotection, astrocytes in the penumbra region may play an important role in protecting neurons from apoptotic injury.
Misregulation of Drosophila Sidestep Leads to Uncontrolled Wiring of the Adult Neuromuscular System and Severe Locomotion Defects
Authors: Kinold Jaqueline C. , Brenner Marcel , Aberle Hermann
Published: June 2021

Holometabolic organisms undergo extensive remodelling of their neuromuscular system during metamorphosis. Relatively, little is known whether or not the embryonic guidance of molecules and axonal growth mechanisms are re-activated for the innervation of a very different set of adult muscles. Here, we show that the axonal attractant Sidestep (Side) is re-expressed during Drosophila metamorphosis and is indispensable for neuromuscular wiring. Mutations in side cause severe innervation defects in all legs. Neuromuscular junctions (NMJs) show a reduced density or are completely absent at multi-fibre muscles. Misinnervation strongly impedes, but does not completely abolish motor behaviours, including walking, flying, or grooming. Overexpression of Side in developing muscles induces similar innervation defects; for example, at indirect flight muscles, it causes flightlessness. Since muscle-specific overexpression of Side is unlikely to affect the central circuits, the resulting phenotypes seem to correlate with faulty muscle wiring. We further show that mutations in beaten path Ia (beat), a receptor for Side, results in similar weaker adult innervation and locomotion phenotypes, indicating that embryonic guidance pathways seem to be reactivated during metamorphosis.
Perceptions of Modulatory Factors in Migraine and Epilepsy: A Multicenter Study
Authors: Ur Özçelik Emel , Lin Katia , Mameniškienè Ruta , Sauter Dalbem Juiane , Siqueira Heloise Helena , Samaitienė Rūta , Vega Zeissig Luz Eleonora , Fonseca Armando Ferreira , Mazini Alves Juliana , dos Santos Lunardi Mariana , de Queiroz Luiz Paulo , Zubavičiūtė Erika , Wolf Peter , Baykan Betül
Published: June 2021

Background: Migraine and epilepsy are both common episodic disorders, typically precipitated or inhibited by some modulatory factors (MFs).

Objective: To assess the self-perception of MFs in patients with migraine (PWM) compared to patients with epilepsy (PWE) with a standardized protocol in different countries.

Methods: Transcultural multicenter comparative cross-sectional study. All consecutive patients who fulfilled the ICHD-3 criteria for migraine and ILAE's criteria for epilepsy, with at least 1 year of follow-up were interviewed with a semi-structured questionnaire on clinical and epidemiological data and were asked to identify all experienced MFs from a provided list.

Results: A total of 608 individuals were surveyed at five university referral centers in Brazil, Guatemala, Lithuania and Turkey. Two hundred and nineteen (91.6%) PWM and 305 (82.7%) PWE identified attack precipitating factors (PFs; p < 0.001). The most frequent three PFs reported by epilepsy patients were: “lack of sleep” (56.6%), “emotional stress” (55.3%), “negative feelings” (53.9%), while among migraine patients “emotional stress” (81.6%), “lack of sleep” (77.8%), “negative feelings” (75.7%) were cited. Inhibitory factors (IFs) for the episodes were reported by 68 (28.5%) PWM and 116 (31.4%) PWE. “Darkness” was the most common one, described by 35.6% of PWM whereas “positive feelings” reported by 10.6% of PWE. Most MFs are concordant across the countries but some transcultural differences were noted.

Conclusion: The MFs of migraine and epilepsy attacks and their varying frequencies according to different countries were investigated with the same standardized questionnaire, for the first time. MFs were recognized very often in both migraine and epilepsy cohorts, but in distinct disease-specific prevalence, being more frequent in migraine. Recognition of self-perceived MFs may be helpful for the management of both illnesses.
Early Development of Locomotor Patterns and Motor Control in Very Young Children at High Risk of Cerebral Palsy, a Longitudinal Case Series
Authors: Bekius Annike , Bach Margit M. , van de Pol Laura A. , Harlaar Jaap , Daffertshofer Andreas , Dominici Nadia , Buizer Annemieke I.
Published: June 2021

The first years of life might be critical for encouraging independent walking in children with cerebral palsy (CP). We sought to identify mechanisms that may underlie the impaired development of walking in three young children with early brain lesions, at high risk of CP, via comprehensive instrumented longitudinal assessments of locomotor patterns and muscle activation during walking. We followed three children (P1–P3) with early brain lesions, at high risk of CP, during five consecutive gait analysis sessions covering a period of 1 to 2 years, starting before the onset of independent walking, and including the session during the first independent steps. In the course of the study, P1 did not develop CP, P2 was diagnosed with unilateral and P3 with bilateral CP. We monitored the early development of locomotor patterns over time via spatiotemporal gait parameters, intersegmental coordination (estimated via principal component analysis), electromyography activity, and muscle synergies (determined from 11 bilateral muscles via nonnegative matrix factorization). P1 and P2 started to walk independently at the corrected age of 14 and 22 months, respectively. In both of them, spatiotemporal gait parameters, intersegmental coordination, muscle activation patterns, and muscle synergy structure changed from supported to independent walking, although to a lesser extent when unilateral CP was diagnosed (P2), especially for the most affected leg. The child with bilateral CP (P3) did not develop independent walking, and all the parameters did not change over time. Our exploratory longitudinal study revealed differences in maturation of locomotor patterns between children with divergent developmental trajectories. We succeeded in identifying mechanisms that may underlie impaired walking development in very young children at high risk of CP. When verified in larger sample sizes, our approach may be considered a means to improve prognosis and to pinpoint possible targets for early intervention.
Acoustic Analysis of Phonation in Children With Smith–Magenis Syndrome
Authors: Hidalgo-De la Guía Irene , Garayzábal-Heinze Elena , Gómez-Vilda Pedro , Martínez-Olalla Rafael , Palacios-Alonso Daniel
Published: June 2021

Complex simultaneous neuropsychophysiological mechanisms are responsible for the processing of the information to be transmitted and for the neuromotor planning of the articulatory organs involved in speech. The nature of this set of mechanisms is closely linked to the clinical state of the subject. Thus, for example, in populations with neurodevelopmental deficits, these underlying neuropsychophysiological procedures are deficient and determine their phonation. Most of these cases with neurodevelopmental deficits are due to a genetic abnormality, as is the case in the population with Smith–Magenis syndrome (SMS). SMS is associated with neurodevelopmental deficits, intellectual disability, and a cohort of characteristic phenotypic features, including voice quality, which does not seem to be in line with the gender, age, and complexion of the diagnosed subject. The phonatory profile and speech features in this syndrome are dysphonia, high f0, excess vocal muscle stiffness, fluency alterations, numerous syllabic simplifications, phoneme omissions, and unintelligibility of speech. This exploratory study investigates whether the neuromotor deficits in children with SMS adversely affect phonation as compared to typically developing children without neuromotor deficits, which has not been previously determined. The authors compare the phonatory performance of a group of children with SMS (N = 12) with a healthy control group of children (N = 12) matched in age, gender, and grouped into two age ranges. The first group ranges from 5 to 7 years old, and the second group goes from 8 to 12 years old. Group differences were determined for two forms of acoustic analysis performed on repeated recordings of the sustained vowel /a/ F1 and F2 extraction and cepstral peak prominence (CPP). It is expected that the results will enlighten the question of the underlying neuromotor aspects of phonation in SMS population. These findings could provide evidence of the susceptibility of phonation of speech to neuromotor disturbances, regardless of their origin.
White Matter Changes With Rehabilitation in Children With Developmental Coordination Disorder: A Randomized Controlled Trial
Authors: Izadi-Najafabadi Sara , Zwicker Jill G.
Published: June 2021

Background and Objectives: Children with developmental coordination disorder (DCD) have difficulty learning motor skills, which can affect their participation in activities of daily living and psychosocial well-being. Over 50% of children with DCD also have attention deficit hyperactivity disorder (ADHD), which further exacerbates their motor problems and impact on quality of life. A rehabilitation approach known as Cognitive Orientation to Occupational Performance uses problem-solving strategies to help children learn motor skills they wish to achieve. While this cognitive approach has been effective for children with DCD, few studies have examined the effectiveness of this approach for children with co-occurring ADHD. Further, the underlying mechanism and neural basis of this intervention are largely unknown.

Methods: In this randomized waitlist-controlled trial, we used MRI to examine white matter microstructure after intervention in 8–12-year-old children with DCD (n= 28) and with DCD and co-occurring ADHD (n= 25). Children in both groups were randomized to either a treatment group or waitlist group at their first MRI. The treatment group began the intervention after their MRI scan and returned for a post-treatment scan at 3 months, and follow-up scan at 6 months; the waitlist group waited 3 months before their second MRI, received the intervention, and then had a post-treatment scan. Each child received intervention once weekly for 10 weeks. Diffusion tensor imaging was used to acquire white matter diffusion parameters and was analyzed using tract-based spatial statistics (TBSS).

Results and Conclusion: Children with DCD showed significant improvement in white matter microstructure in the bilateral anterior thalamic radiation, bilateral sensorimotor tract, bilateral cingulum, fornix, splenium and body of corpus callosum, right inferior fronto-occipital fasciculus, and white matter pathways to bilateral inferior gyri, right middle frontal gyrus, frontal medial cortex, and left cuneus. We suggest that these rehabilitation-induced neural changes in children with DCD occurred in regions associated with attention, self-regulation, motor planning, and inter-hemispheric communication, which positively affected brain connectivity and motor function. In contrast, children with DCD and co-occurring ADHD did not show any brain changes following the intervention. Modifications to the treatment protocol might help address the attentional and self-regulatory needs of children with a dual diagnosis.

Clinical Trial Registration:ClinicalTrials.govID: NCT02597751.
Prediction of Neural Diameter From Morphology to Enable Accurate Simulation
Authors: Reed Jonathan D. , Blackwell Kim T.
Published: June 2021

Accurate neuron morphologies are paramount for computational model simulations of realistic neural responses. Over the last decade, the online repository NeuroMorpho.Org has collected over 140,000 available neuron morphologies to understand brain function and promote interaction between experimental and computational research. Neuron morphologies describe spatial aspects of neural structure; however, many of the available morphologies do not contain accurate diameters that are essential for computational simulations of electrical activity. To best utilize available neuron morphologies, we present a set of equations that predict dendritic diameter from other morphological features. To derive the equations, we used a set of NeuroMorpho.org archives with realistic neuron diameters, representing hippocampal pyramidal, cerebellar Purkinje, and striatal spiny projection neurons. Each morphology is separated into initial, branching children, and continuing nodes. Our analysis reveals that the diameter of preceding nodes, Parent Diameter, is correlated to diameter of subsequent nodes for all cell types. Branching children and initial nodes each required additional morphological features to predict diameter, such as path length to soma, total dendritic length, and longest path to terminal end. Model simulations reveal that membrane potential response with predicted diameters is similar to the original response for several tested morphologies. We provide our open source software to extend the utility of available NeuroMorpho.org morphologies, and suggest predictive equations may supplement morphologies that lack dendritic diameter and improve model simulations with realistic dendritic diameter.
Classification of Schizophrenia by Combination of Brain Effective and Functional Connectivity
Authors: Zhao Zongya , Li Jun , Niu Yanxiang , Wang Chang , Zhao Junqiang , Yuan Qingli , Ren Qiongqiong , Xu Yongtao , Yu Yi
Published: June 2021

At present, lots of studies have tried to apply machine learning to different electroencephalography (EEG) measures for diagnosing schizophrenia (SZ) patients. However, most EEG measures previously used are either a univariate measure or a single type of brain connectivity, which may not fully capture the abnormal brain changes of SZ patients. In this paper, event-related potentials were collected from 45 SZ patients and 30 healthy controls (HCs) during a learning task, and then a combination of partial directed coherence (PDC) effective and phase lag index (PLI) functional connectivity were used as features to train a support vector machine classifier with leave-one-out cross-validation for classification of SZ from HCs. Our results indicated that an excellent classification performance (accuracy = 95.16%, specificity = 94.44%, and sensitivity = 96.15%) was obtained when the combination of functional and effective connectivity features was used, and the corresponding optimal feature number was 15, which included 12 PDC and three PLI connectivity features. The selected effective connectivity features were mainly located between the frontal/temporal/central and visual/parietal lobes, and the selected functional connectivity features were mainly located between the frontal/temporal and visual cortexes of the right hemisphere. In addition, most of the selected effective connectivity abnormally enhanced in SZ patients compared with HCs, whereas all the selected functional connectivity features decreased in SZ patients. The above results showed that our proposed method has great potential to become a tool for the auxiliary diagnosis of SZ.
Prefrontal Inter-brain Synchronization Reflects Convergence and Divergence of Flow Dynamics in Collaborative Learning: A Pilot Study
Authors: Nozawa Takayuki , Kondo Mutsumi , Yamamoto Reiko , Jeong Hyeonjeong , Ikeda Shigeyuki , Sakaki Kohei , Miyake Yoshihiro , Ishikawa Yasushige , Kawashima Ryuta
Published: June 2021

Flow is a highly motivated and affectively positive state in which a person is deeply engaged in an activity and feeling enjoyment from it. In collaborative activities, it would be optimal if all participants were in a state of flow. However, flow states fluctuate amongst individuals due to differences in the dynamics of motivation and cognition. To explore the possibility that inter-brain synchronization can provide a quantitative measure of the convergence and divergence of collective motivational dynamics, we conducted a pilot study to investigate the relationship between inter-brain synchronization and the interpersonal similarity of flow state dynamics during the collaborative learning process. In two English as a Foreign Language (EFL) classes, students were divided into groups of three-four and seated at desks facing each other while conducting a 60-min group work. In both classes, two groups with four members were randomly selected, and their medial prefrontal neural activities were measured simultaneously using wireless functional near-infrared spectroscopy (fNIRS) devices. Later the participants observed their own activities on recorded videos and retrospectively rated their subjective degree of flow state on a seven-point scale for each 2-min period. For the pairs of students whose neural activities were measured, the similarity of their flow experience dynamics was evaluated by the temporal correlation between their flow ratings. Prefrontal inter-brain synchronization of the same student pairs during group work was evaluated using wavelet transform coherence. Statistical analyses revealed that: (1) flow dynamics were significantly more similar for the student pairs within the same group compared to the pairs of students assigned across different groups; (2) prefrontal inter-brain synchronization in the relatively short time scale (9.3–13.9 s) was significantly higher for the within-group pairs than for the cross-group pairs; and (3) the prefrontal inter-brain synchronization at the same short time scale was significantly and positively correlated with the similarity of flow dynamics, even after controlling for the effects of within- vs. cross-group pair types from the two variables. These suggest that inter-brain synchronization can indeed provide a quantitative measure for converging and diverging collective motivational dynamics during collaborative learning, with higher inter-brain synchronization corresponding to a more convergent flow experience.
A Comparison of the Distortion in the Same Field MRI and MR-Linac System With a 3D Printed Phantom
Authors: Liu Xuechun , Li Zhenjiang , Rong Yi , Cao Minsong , Li Hongyu , Jia Chuntao , Shi Liting , Lu Weizhao , Gong Guanzhong , Yin Yong , Qiu Jianfeng
Published: June 2021

Purpose

A 3D printed geometric phantom was developed that can be scanned with computed tomography (CT) and magnetic resonance imaging (MRI) to measure the geometric distortion and determine the relevant dose changes.

Materials and Methods

A self-designed 3D printed photosensitive resin phantom was used, which adopts grid-like structures and has 822 1 cm2 squares. The scanning plan was delivered by three MRI scanners: the Elekta Unity MR-Linac 1.5T, GE Signa HDe 1.5T, and GE Discovery-sim 750 3.0T. The geometric distortion comparison was concentrated on two 1.5T MRI systems, whereas the 3.0T MRI was used as a supplemental experiment. The most central transverse images in each dataset were selected to demonstrate the plane distortion. Some mark points were selected to analyze the distortion in the 3D direction based on the plane geometric distortion. A treatment plan was created with the off-line Monaco system.

Results

The distortion increases gradually from the center to the outside. The distortion range is 0.79 ± 0.40 mm for the Unity, 1.31 ± 0.56 mm for the GE Signa HDe, and 2.82 ± 1.48 mm for the GE Discovery-sim 750. Additionally, the geometric distortion slightly affects the actual planning dose of the radiotherapy.

Conclusion

Geometric distortion increases gradually from the center to the outside. The distortion values of the Unity were smaller than those of the GE Signa HDe, and the Unity has the smallest geometric distortion. Finally, the Unity’s dose variation best matched with the standard treatment plan.
Progression-Free Survival, Prognostic Factors, and Surgical Outcome of Spheno-Orbital Meningiomas
Authors: Masalha Waseem , Heiland Dieter Henrik , Steiert Christine , Krüger Marie T. , Schnell Daniel , Scheiwe Christian , Schnell Oliver , Grosu Anca-L. , Beck Jürgen , Grauvogel Jürgen
Published: June 2021

Objective

Spheno-orbital meningiomas (SOM) are rare intracranial tumors that arise at the sphenoid wing. These tumors can invade important neurovascular structures making radical resection difficult, while residual tumors often lead to recurrence. The purpose of this study was to evaluate prognostic factors influencing the recurrence and progression-free survival (PFS) rates of spheno-orbital meningiomas, with a particular focus on the role of surgery and postoperative radiotherapy.

Methods

Between 2000 and March 2020, 65 cases of spheno-orbital meningioma were included, of which 50 cases underwent surgical treatment alone, and 15 cases underwent resection and radiotherapy. A Kaplan-Meier analysis was performed to provide median point estimates and PFS rates; further, Cox regression analysis was used to identify significant factors associated with treatment.

Results

Gross total resection significantly reduced the risk of recurrence (p-value = 0.0062). There was no significant benefit for progression-free survival after postoperative radiotherapy (p-value = 0.42). Additionally, spheno-orbital meningiomas with an invasion of the cavernous sinus and intraconal invasion showed significantly worse PFS compared to other locations (p-value = 0.017).

Conclusion

The maximal safe resection remains the most important prognostic factor associated with lower recurrence rates and longer PFS in patients with spheno-orbital meningioma. The invasion of the cavernous sinus and intraconal invasion was an independent factor associated with worse PFS. Patients with postoperative high-precision radiotherapy did not show significantly better PFS due to the small number of patients.
An Integrated Analysis of the Response of Colorectal Adenocarcinoma Caco-2 Cells to X-Ray Exposure
Authors: Guardamagna Isabella , Lonati Leonardo , Savio Monica , Stivala Lucia A. , Ottolenghi Andrea , Baiocco Giorgio
Published: June 2021

Colorectal cancer is among the three top cancer types for incidence and the second in terms of mortality, usually managed with surgery, chemotherapy and radiotherapy. In particular, radiotherapeutic concepts are crucial for the management of advanced rectal cancer, but patients’ survival remains poor, despite advances in treatment modalities. The use of well-characterized in vitro cell culture systems offers an important preclinical strategy to study mechanisms at the basis of cell response to therapeutic agents, including ionizing radiation, possibly leading to a better understanding of the in vivo response to the treatment. In this context, we present an integrated analysis of results obtained in an extensive measurement campaign of radiation effects on Caco-2 cells, derived from human colorectal adenocarcinoma. Cells were exposed to X-rays with doses up to 10 Gy from a radiotherapy accelerator. We measured a variety of endpoints at different post-irradiation times: clonogenic survival after ~ 2 weeks; cell cycle distribution, cell death, frequency of micronucleated cells and atypical mitoses, activation of matrix metalloproteases (MMPs) and of different proteins involved in DNA damage response and cell cycle regulation at earlier time points, up to 48 h post-exposure. Combined techniques of flow cytometry, immunofluorescence microscopy, gelatin zymography and western blotting were used. For selected endpoints, we also addressed the impact of the irradiation protocol, comparing results obtained when cells are plated before irradiation or first-irradiated and then re-plated. Caco-2 resistance to radiation, previously assessed up to 72 h post exposure in terms of cell viability, does not translate into a high clonogenic survival. Survival is not affected by the irradiation protocol, while endpoints measured on a shorter time frame are. Radiation mainly induces a G2-phase arrest, confirmed by associated molecular markers. The activation of death pathways is dose- and time-dependent, and correlates with a dose-dependent inhibition of MMPs. Genomic aberrations are also found to be dose-dependent. The phosphorylated forms of several proteins involved in cell cycle regulation increase following exposure; the key regulator FoxM1 appears to be downregulated, also leading to inhibition of MMP-2. A unified molecular model of the chain of events initiated by radiation is proposed to interpret all experimental results.
A Critical Review and Scientific Prospective on Contraceptive Therapeutics from Ayurveda and Allied Ancient Knowledge
Authors: Bhatt Narendra , Deshpande Manasi
Published: June 2021

Commonly used synthetic or prescribed hormonal drugs are known to interfere with the endocrine system and may have adverse reproductive, neurological, developmental, and metabolic effects in the body. These may also produce adverse effects such as polycystic ovarian disorder, endometriosis, early puberty, infertility or toxicity to gonads, testicular germ cell cancer, breast or prostate cancer, brain developmental problems, and even birth defects. Globally, the emergence of renewed interest in natural products for reproductive health is on the rise, which offers opportunities for new contraceptive developments. The search for alternate, safer contraceptive products or agents of natural origin is of scientific interest. Ayurvedic classical texts offer knowledge and information about the reproductive function and therapeutics including those for enhancement and limiting male and female fertility. Review of ancient, medieval, and recent—including texts on erotica that provide information on approaches and large numbers of formulations and drugs of plant, mineral or animal origin—claimed to have sterilizing, contraceptive, abortifacient, and related properties is presented. Few among these are known to be toxic and few are not so common. However, most of the formulations, ingredients, or modes of administration have remained unattended to, due to issues related to consumer compliance and limitations of standardization and lack of appropriate validation modalities. Several of these ingredients have been studied for their phytoconstituents and for the variety of pharmacological activities. Efforts to standardize several classical dosage forms and attempts to adapt to modern technologies have been made. List of formulations, ingredients, and their properties linked with known constituents, pharmacological, biological, and toxicity studies have been provided in a series of tables. The possible effectiveness and safety of selected formulations and ingredients have been examined. Suggestions based on new drug delivery systems integrated with advances in biotechnology, to provide prospects for new therapeutics for contraception, have been considered. Ayurveda is built on a holistic paradigm of biological entity rather than limited gonadal functions. Graphic presentation of a few carefully chosen possibilities has been depicted. New approaches to standardization and ethnopharmacological validation of natural contraceptive therapeutics may offer novel mechanisms and modalities and therapeutic opportunities to satisfy unmet needs of contraception.
Theragnosis for Duchenne Muscular Dystrophy
Authors: Luce Leonela , Carcione Micaela , Mazzanti Chiara , Buonfiglio Paula I. , Dalamón Viviana , Mesa Lilia , Dubrovsky Alberto , Corderí José , Giliberto Florencia
Published: June 2021

Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA’s metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.
Bawei Chenxiang Wan Ameliorates Cardiac Hypertrophy by Activating AMPK/PPAR-α Signaling Pathway Improving Energy Metabolism
Authors: Zhang Xiaoying , Zhang Zhiying , Wang Pengxiang , Han Yiwei , Liu Lijun , Li Jie , Chen Yichun , Liu Duxia , Wang Jinying , Tian Xiaoying , Zhao Qin , Yan Fengxia
Published: June 2021

Bawei Chenxiang Wan (BCW), a well-known traditional Chinese Tibetan medicine formula, is effective for the treatment of acute and chronic cardiovascular diseases. In the present study, we investigated the effect of BCW in cardiac hypertrophy and underlying mechanisms. The dose of 0.2, 0.4, and 0.8 g/kg BCW treated cardiac hypertrophy in SD rat model induced by isoprenaline (ISO). Our results showed that BCW (0.4 g/kg) could repress cardiac hypertrophy, indicated by macro morphology, heart weight to body weight ratio (HW/BW), left ventricle heart weight to body weight ratio (LVW/BW), hypertrophy markers, heart function, pathological structure, cross-sectional area (CSA) of myocardial cells, and the myocardial enzymes. Furthermore, we declared the mechanism of BCW anti-hypertrophy effect was associated with activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator–activated receptor-α (PPAR-α) signals, which regulate carnitine palmitoyltransferase1β (CPT-1β) and glucose transport-4 (GLUT-4) to ameliorate glycolipid metabolism. Moreover, BCW also elevated mitochondrial DNA-encoded genes of NADH dehydrogenase subunit 1(ND1), cytochrome b (Cytb), and mitochondrially encoded cytochrome coxidase I (mt-co1) expression, which was associated with mitochondria function and oxidative phosphorylation. Subsequently, knocking down AMPK by siRNA significantly can reverse the anti-hypertrophy effect of BCW indicated by hypertrophy markers and cell surface of cardiomyocytes. In conclusion, BCW prevents ISO-induced cardiomyocyte hypertrophy by activating AMPK/PPAR-α to alleviate the disturbance in energy metabolism. Therefore, BCW can be used as an alternative drug for the treatment of cardiac hypertrophy.
Triphala Churna—A Traditional Formulation in Ayurveda Mitigates Diabetic Neuropathy in Rats
Authors: Suryavanshi Sachin V. , Barve Kalyani , Addepalli Veeranjaneyulu , Utpat Sachin V. , Kulkarni Yogesh A.
Published: June 2021

Neuropathy is a common complication of diabetes affecting a large number of people worldwide. Triphala churna is a formulation mentioned in Ayurveda-a traditional system of medicine. It is a simple powder formulation consisting of powders of three fruits, Emblica officinalis L., Terminalia bellirica (Gaertn.) Roxb. and Terminalia chebula Retz. Individual components of Triphala churna have anti-diabetic and antioxidant activities. Hence, this study was designed to evaluate the effect of Triphala churna on diabetic neuropathy. Diabetes was induced with streptozotocin (STZ, 55 mg/kg, i. p.) in rats. Animals were grouped and treated orally with Triphala churna at a dose of 250, 500, and 1,000 mg/kg after 6 weeks of diabetes induction for the next 4 weeks. At the end of study, parameters such as body weight, plasma glucose level, motor nerve conduction velocity were determined. The effect of Triphala churna on thermal hyperalgesia, mechanical hyperalgesia, and mechanical allodynia was also determined at the end of study. The plasma cytokine levels like TGF-β1, TNF-α, and IL-1β were determined by ELISA assay. Histopathology study of the sciatic nerve was studied. Western blotting was performed to study the expression of neuronal growth factor.Treatment with Triphala churna showed a significant reduction in plasma glucose and a significant rise in body weight. Triphala treatment significantly increased the motor nerve conduction velocity and decreased the thermal and mechanical hyperalgesia, as well as mechanical allodynia. The treatment significantly inhibited levels of circulatory cytokines like TGF-β1, TNF-α, and IL-1β. Histopathology study confirmed the neuroprotective effect of Triphala churna. The expression of NGF was significantly increased in sciatic nerves after treatment with Triphala churna. From the results, it can be concluded that Triphala churna delays the progression of neuropathy in diabetic rats.
miR-199a Overexpression Enhances the Potency of Human Induced-Pluripotent Stem-Cell–Derived Cardiomyocytes for Myocardial Repair
Authors: Bian Weihua , Chen Wangping , Nguyen Thanh , Zhou Yang , Zhang Jianyi
Published: June 2021

Mammalian cardiomyocytes exit the cell cycle during the perinatal period, and although cardiomyocytes differentiated from human induced-pluripotent stem cells (hiPSC-CMs) are phenotypically immature, their intrinsic cell-cycle activity remains limited. Thus, neither endogenous cardiomyocytes nor the small number of transplanted hiPSC-CMs that are engrafted by infarcted hearts can remuscularize the myocardial scar. microRNAs are key regulators of cardiomyocyte proliferation, and when adeno-associated viruses coding for microRNA-199a (miR-199a) expression were injected directly into infarcted pig hearts, measures of cardiac function and fibrosis significantly improved, but the treatment was also associated with lethal arrhythmia. For the studies reported here, the same vector (AAV6-miR-199a) was transduced into hiPSC-CMs, and the cells were subsequently evaluated in a mouse model of myocardial infarction. AAV6-mediated miR-199a overexpression increased proliferation in both cultured and transplanted hiPSC-CMs, and measures of left ventricular ejection fraction, fractional shortening, and scar size were significantly better in mice treated with miR-199a–overexpressing hiPSC-CMs than with hiPSC-CMs that had been transduced with a control vector. Furthermore, although this investigation was not designed to characterize the safety of transplanted AAV6-miR-199a–transduced hiPSC-CMs, there was no evidence of sudden death. Collectively, these results support future investigations of miR-199a–overexpressing hiPSC-CMs in large animals.
Celastrol Attenuates RANKL-Induced Osteoclastogenesis in vitro and Reduces Titanium Particle-Induced Osteolysis and Ovariectomy-Induced Bone Loss in vivo
Authors: Xu Qiang , Chen Guiping , Xu Huaen , Xia Guoming , Zhu Meisong , Zhan Haibo , Zhang Bin , Dai Min , Fan Hongxian , Liu Xuqiang
Published: June 2021

Excessive bone resorption by osteoclasts contributes significantly to osteoclast-related diseases such as periprosthetic osteolysis and osteoporosis. Osteolysis in a titanium particle-induced calvarial model and bone loss in an ovariectomized mice model occurred similarly to those in humans; thus, these models can be used to evaluate potential therapies for aseptic prosthetic loosening and osteoporosis. Celastrol, which is extracted from the seeds of the genus Tripterygium, has been thoroughly investigated for its anti-inflammatory and anti-cancer pharmacological effects. However, the mechanisms involving bone metabolism by which celastrol inhibits osteoclastogenesis are not yet fully understood. We demonstrated that celastrol inhibited the receptor activator of nuclear factor κB ligand-induced osteoclastogenesis and the bone resorptive function of osteoclasts in vitro by inhibiting the activation of transforming growth factor β-activated kinase 1-mediated NF-κB and mitogen-activated protein kinase signaling pathways and downregulating osteoclastogenesis marker-related genes. Furthermore, celastrol was also shown to be beneficial in both the titanium particle-induced osteolysis calvarial and the murine ovariectomy-induced bone loss. Collectively, our results suggested that celastrol is promising for the prevention of aseptic prosthetic loosening and osteoporosis in the treatment of osteolytic diseases induced by disrupted osteoclast formation and function.
PPARγ Mediates the Anti-Epithelial-Mesenchymal Transition Effects of FGF1ΔHBS in Chronic Kidney Diseases via Inhibition of TGF-β1/SMAD3 Signaling
Authors: Wang Dezhong , Zhao Tianyang , Zhao Yushuo , Yin Yuan , Huang Yuli , Cheng Zizhao , Wang Beibei , Liu Sidan , Pan Minling , Sun Difei , Wang Zengshou , Zhu Guanghui
Published: June 2021

Podocytes are essential components of the glomerular basement membrane. Epithelial-mesenchymal-transition (EMT) in podocytes results in proteinuria. Fibroblast growth factor 1 (FGF1) protects renal function against diabetic nephropathy (DN). In the present study, we showed that treatment with an FGF1 variant with decreased mitogenic potency (FGF1ΔHBS) inhibited podocyte EMT, depletion, renal fibrosis, and preserved renal function in two nephropathy models. Mechanistic studies revealed that the inhibitory effects of FGF1ΔHBS podocyte EMT were mediated by decreased expression of transforming growth factor β1 via upregulation of PPARγ. FGF1ΔHBS enhanced the interaction between PPARγ and SMAD3 and suppressed SMAD3 nuclei translocation. We found that the anti-EMT activities of FGF1ΔHBS were independent of glucose-lowering effects. These findings expand the potential uses of FGF1ΔHBS in the treatment of diseases associated with EMT.
Influence of Fibrosis Amount and Patterns on Ventricular Arrhythmogenesis and Pumping Efficacy: Computational Study
Authors: Heikhmakhtiar Aulia Khamas , Tekle Abrha Abebe , Lim Ki Moo
Published: June 2021

Myocardial fibrosis is an integral component of most forms of heart failure. Clinical and computational studies have reported that spatial fibrosis pattern and fibrosis amount play a significant role in ventricular arrhythmogenicity. This study investigated the effect of the spatial distribution of fibrosis and fibrosis amount on the electrophysiology and mechanical performance of the human ventricles. Seventy-five fibrosis distributions comprising diffuse, patchy, and compact fibrosis types that contain 10–50% fibrosis amount were generated. The spatial fibrosis distribution was quantified using the fibrosis entropy (FE) metric. Electrical simulations under reentry conditions induced using the S1–S2 protocol were conducted to investigate the fibrosis arrhythmogenicity. We also performed mechanical simulations to examine the influence of the fibrosis amount and the spatial distribution of fibrosis on the pumping efficacy of the LV. We observed that the mean FE of the compact type is the largest among the three types. The electrical simulation results revealed that the ventricular arrhythmogenicity of diffuse fibrosis depends on the fibrosis amount and marginally on the spatial distribution of fibrosis. Meanwhile, the ventricular arrhythmogenicity of the compact and patchy fibrosis pattern is more reliant on the spatial distribution of fibrosis than on the fibrosis amount. The average number of phase singularities (PSs) in the compact fibrosis pattern was the highest among the three patterns of fibrosis. The diffuse type of fibrosis has the lowest average number of PSs than that in the patchy and compact fibrosis. The reduction in the stroke volume (SV) showed high influence from the electrical instabilities induced by the fibrosis amount and pattern. The compact fibrosis exhibited the lowest SV among the three patterns except in the 40% fibrosis amount. In conclusion, the fibrosis pattern is as crucial as the fibrosis amount for sustaining and aggravating ventricular arrhythmogenesis.
Dysregulation of the Excitatory Renal Reflex in the Sympathetic Activation of Spontaneously Hypertensive Rat
Authors: Ye Chao , Zheng Fen , Wang Jing-Xiao , Wang Xiao-Li , Chen Qi , Li Yue-Hua , Kang Yu-Ming , Zhu Guo-Qing
Published: June 2021

Excessive sympathetic activation plays crucial roles in the pathogenesis of hypertension. Chemical stimulation of renal afferents increases the sympathetic activity and blood pressure in normal rats. This study investigated the excitatory renal reflex (ERR) in the development of hypertension in the spontaneously hypertensive rat (SHR). Experiments were performed in the Wistar-Kyoto rat (WKY) and SHR aged at 4, 12, and 24 weeks under anesthesia. Renal infusion of capsaicin was used to stimulate renal afferents, and thus, to induce ERR. The ERR was evaluated by the changes in the contralateral renal sympathetic nerve activity and mean arterial pressure. At the age of 4 weeks, the early stage with a slight or moderate hypertension, the ERR was more enhanced in SHR compared with WKY. The pressor response was greater than the sympathetic activation response in the SHR. At the age of 12 weeks, the development stage with severe hypertension, there was no significant difference in the ERR between the WKY and SHR. At the age of 24 weeks, the later stage of hypertension with long-term several hypertensions, the ERR was more attenuated in the SHR compared with the WKY. On the other hand, the pressor response to sympathetic activation due to the ERR was smaller at the age of 12 and 24 weeks than those at the age of 4 weeks. These results indicate that ERR is enhanced in the early stage of hypertension, and attenuated in the later stage of hypertension in the SHR. Abnormal ERR is involved in the sympathetic activation and the development of hypertension.
Airway Pressure Release Ventilation Mode Improves Circulatory and Respiratory Function in Patients After Cardiopulmonary Bypass, a Randomized Trial
Authors: Ge Huiqing , Lin Ling , Xu Ying , Xu Peifeng , Duan Kailiang , Pan Qing , Ying Kejing
Published: June 2021

Importance

Postoperative pulmonary complications and cardiovascular complications are major causes of morbidity, mortality, and resource utilization in cardiac surgery patients.

Objectives

To investigate the effects of airway pressure release ventilation (APRV) on respiration and hemodynamics in post cardiac surgery patients.

Main Outcomes and Measures

A single-center randomized control trial was performed. In total, 138 patients undergoing cardiopulmonary bypass were prospectively screened. Ultimately 39 patients met the inclusion criteria and were randomized into two groups: 19 patients were managed with pressure control ventilation (PCV) and 20 patients were managed with APRV. Respiratory mechanics after 4 h, hemodynamics within the first day, and Chest radiograph score (CRS) and blood gasses within the first three days were recorded and compared.

Results

A higher cardiac index (3.1 ± 0.7 vs. 2.8 ± 0.8 L⋅min–1⋅m2; p < 0.05), and shock volume index (35.4 ± 9.2 vs. 33.1 ± 9.7 ml m–2; p < 0.05) were also observed in the APRV group after 4 h as well as within the first day (p < 0.05). Compared to the PCV group, the PaO2/FiO2 was significantly higher after 4 h in patients of APRV group (340 ± 97 vs. 301 ± 82, p < 0.05) and within the first three days (p < 0.05) in the APRV group. CRS revealed less overall lung injury in the APRV group (p < 0.001). The duration of mechanical ventilation and ICU length of stay were not significantly (p = 0.248 and 0.424, respectively).

Conclusions and Relevance

Compared to PCV, APRV may be associated with increased cardiac output improved oxygenation, and decreased lung injury in postoperative cardiac surgery patients.
The Decomposition of Between and Within Effects in Contextual Models
Authors: Guo Siwen , Houang Richard T. , Schmidt William H.
Published: June 2021

In contextual studies, group compositions are often extracted from individual data in the sample, in order to estimate the group compositional effects [e.g., school socioeconomic status (SES) effect] controlling for interindividual differences in multilevel models. As the same variable is used at both group level and individual level, an appropriate decomposition of between and within effects is a key to providing a clearer picture of these organizational and individual processes. The current study developed a new approach with within-group finite population correction (fpc). Its performances were compared with the manifest and latent aggregation approaches in the decomposition of between and within effects. Under a moderate within-group sampling ratio, the between effect estimates from the new approach had a lesser degree of bias and higher observed coverage rates compared with those from the manifest and latent aggregation approaches. A real data application was also used to illustrate the three analysis approaches.