bluuebunny/crossref_metadata_2025 huggingface dataset:
10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly
Authors: Oliveira Danyllo , Leal Gabriela Ferraz , Sertié Andréa L , Caires Jr Luiz Carlos , Goulart Ernesto , Musso Camila Manso , Oliveira João Ricardo Mendes de , Krepischi Ana Cristina Victorino , Vianna-Morgante Angela Maria , Zatz Mayana
Published: October 2018

Background

Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the ALFY, DPP6, KIF11 and DYRK1A genes.

Objective

This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members.

Methods

Following clinical evaluation of two sibs and their mother presenting with autosomal dominant MCPH, array comparative genome hybridisation was performed using genomic DNA from peripheral blood of the family members. Gene and protein expression studies were carried out in cultured skin fibroblasts.

Results

A 382 kb microduplication at 10q23.31 was detected, encompassing the entire PTEN, KLLN and ATAD1 genes. PTEN haploinsufficiency has been causally associated with macrocephaly and autism spectrum disorder and, therefore, was considered the most likely candidate gene to be involved in this autosomal dominant form of MCPH. In the patients’ fibroblasts, PTEN mRNA and protein were found to be overexpressed, and the phosphorylation patterns of upstream and downstream components of the mammalian target of rapamycin (mTOR) signalling pathway were dysregulated.

Conclusions

Taken together, our results demonstrate that the identified submicroscopic 10q23.31 duplication in a family with MCPH leads to markedly increased expression of PTEN and reduced activity of the mTOR signalling pathway. These results suggest that the most probable pathomechanism underlying the microcephaly phenotype in this family involves downregulation of the mTOR pathway through overexpression of PTEN.
The Most Commonly Treated Acupuncture Indications in the United States: A Cross-Sectional Study
Authors: Wang Haiyi , Yang Guanhu , Wang Shaobai , Zheng Xin , Zhang Wei , Li Yongming
Published: October 2018

Acupuncture has been a popular alternative medicine in the United States for several decades. Its therapeutic effects on pain have been validated by both basic and clinical researches, and it is currently emerging as a unique non-pharmaceutical choice for pain against opioid crisis. However, the full spectrum of acupuncture indications remains unexplored. In this study, we conducted a cross-sectional survey among 419 acupuncturists nation-wide to investigate the top 10 and top 99 acupuncture indications in private clinics in the United States. We found the top 10 indications to be: lower back pain, depression, anxiety, headache, arthritis, allergies, general pain, female infertility, insomnia, neck pain and frozen shoulder. Among the top 99 indications, pain represents the largest category; and mental health management, especially for mood disorders, is in greatest demand. The following popular groups are: immune system dysfunctions, gastrointestinal diseases, gynecology and neurology. In addition, specialty index, commonality index, and the potential to become medical specialties were estimated for each indication. Demographic analysis suggests that China trained acupuncturists tend to have broader indication spectrums, but the top conditions treated are primarily decided by local needs. Also, gender, resident states, age and clinical experience all affect indication distributions. Our data for the first time outlines the profile of acupuncture treatable conditions in the US and is valuable for strategic planning in acupuncture training, healthcare administration and public education.
Design and Analysis of a Broadband Current-Mode CMOS Direct-Conversion Receiver Frond-End Circuit
Authors: Chen Xin Han , Song Shuxiang , Cen Mingcan
Published: October 2018

A broadband (0.8–5[Formula: see text]GHz) CMOS current-mode direct-conversion receiver has been integrated in a 0.18-[Formula: see text]m CMOS process. The proposed receiver front-end features a broadband active-balun low-noise transconductance amplifier (LNTA) driving a current-mode passive mixer terminated by a low-input-impedance transimpedance amplifier (TIA). The receiver chain has improved robustness to out-of-band interference, conversion gain and outstanding linearity. With the technique of noise and distortion cancellation which performs a better input impedance matching, we employ a broadband common-gate–common-source (CG–CS) LNTA and a current mirror to improve both gain and noise figure (NF) performance. Compared to the 50% duty-cycle switching stage, the 25% duty-cycle I–Q switching stage is implemented by using serial switches driven by 50% quadrature local oscillator (LO) signals separately, which improves the down-conversion gain by 3[Formula: see text]dB and lowers the noise figure. The transimpedance amplifier employs the [Formula: see text]-boosting technique to realize low input impedance and high transimpedance gain. The core circuit (RF and baseband signal path) consumes 26[Formula: see text]mW, and the prototype receiver achieves approximately 33–34.5-dB conversion gain, 8.1–9.35-dB NF and 7.5–9.8-dBm IIP3 from 0.8[Formula: see text]GHz to 5[Formula: see text]GHz.
Ternary universal sums of generalized polygonal numbers
Authors: Ju Jangwon , Oh Byeong-Kweon , Seo Bangnam
Published: October 2018

An integer of the form [Formula: see text], for some integer [Formula: see text], is called a generalized polygonal number of order [Formula: see text]. A ternary sum [Formula: see text] of generalized polygonal numbers, for some positive integers [Formula: see text] and some integers [Formula: see text], is said to be universal over [Formula: see text] if for any nonnegative integer [Formula: see text], the equation [Formula: see text] has an integer solution [Formula: see text]. In this paper, we prove the universalities of [Formula: see text] ternary sums of generalized polygonal numbers, which was conjectured by Sun.
Engineering geological considerations for the ‘Old’ Beacon Hill Railway Tunnel, Hong Kong Special Administrative Region
Authors: Mackay Alexander D.
Published: October 2018

The ‘Old’ Beacon Hill Tunnel was constructed through granite from 1906 to 1910 as part of the Kowloon Canton Railway in the then British colony of Hong Kong. It was the first railway tunnel to be constructed in this region and, at 2.2 km long, longer than any Chinese railway tunnel. Prior to Japanese occupation in December 1941, the British detonated charges to collapse the tunnel to deny its use as an invasion route. Following Japanese defeat in 1945 and return to British government, the tunnel was re-excavated and the damaged sections were supported using steel arches based on Terzaghi's rock mass classification system, which uses geological descriptions to classify loading onto arched tunnel supports. The railway was subsequently realigned during the 1980s and placed in a new tunnel running alongside and west of the ‘Old’ Beacon Hill Tunnel, which was converted to accommodate a pipeline connecting gas supplies. Ground investigations implemented after return of the territory to Chinese sovereignty in July 1997 established that groundwater flow and tunnel stability were influenced by a dyke within the granite, joint set orientation, faulting and weathering as well as the wartime detonations.
Crime and Safety in Suburbia
Authors: Singer Simon I. , Drakulich Kevin
Published: October 2018

Criminologists have long focused their attention on the inner-city street corner and neglected the suburban cul-de-sac. Crime in the suburbs should be of greater criminological concern. Cities are no longer centrally located. Suburbanization has impacted not only where most Americans live but also the types and reasons for crime. We begin this review with an overview of the unique structures of the suburb and the rise of the suburban city. We complicate the image of the dangerous city and the safe suburb and examine broad trends in crime and safety within each. The reasons and types of suburban crimes are further related to the decentered, diffused, and less public places of suburbia. Types of crime are described and prospects for future research into the structure and culture of suburbanization as they relate to comparative criminological research are discussed.
Prevalence of Gastrointestinal Parasitic Infections and Assessment of Deworming Program among Cattle and Buffaloes in Gampaha District, Sri Lanka
Authors: Gunathilaka Nayana , Niroshana Dimuthu , Amarasinghe Deepika , Udayanga Lahiru
Published: October 2018

Gastrointestinal (GI) parasitic infection is a serious issue in cattle management. The effects of GI parasites may vary with age, sex of cattle, nutritional condition, and severity of infection. Prevalence of GI parasites among cattle population in Gampaha District has not been studied and there is no published study available. A total of 45 farms rearing cattle were selected randomly in three areas, namely, Kelaniya, Ganemulla, and Welisara, under three Veterinary Surgeon Divisions (VSD) in Gampaha District (Mahara, Gampaha, and Welisara). Freshly voided cattle fecal samples were collected randomly from the selected farms during March 2017–December 2017. Out of 163 cattle and buffaloes examined, 13.39% (n=22) were positive for eggs of one or more species of GI parasites. The prevalence of parasitic infection was higher in buffaloes (31.25%, 5/16) as compared to that of cows (11.56%, 21/147), but the difference was not significant (P >0.05). Hookworms (Bunostomum spp.), whipworms (Trichuris spp.), digenetic trematodes (Paramphistomum spp.), cestodes (Moniezia spp.), and oocysts of protozoans (coccidians) were found during the study. The nontreated animals indicated the highest percentage of parasitic infections accounting for 46.67% (n= 14), followed by partially treated individuals (15.15%, n= 5). GI parasite prevalence in males was higher when compared to that of females, but the difference was nonsignificant (P >0.05). General Linear Modelling (GLM) revealed that the effect of treatment status was significantly associated with the prevalence of GI parasites. The calves and yearlings had the highest rate of GI parasitic infections. The highest infection rate was observed at Kelaniya, followed by Welisara. Future investigations are necessary to evaluate the economic impact of GI parasites in the study areas.
Impact of Radiofrequency Ablation and Antiarrhythmic Medications on the Quality of Life of Patients with Supraventricular Tachycardias: Preliminary Validation of the Greek Version of the Umea22 (U22) Questionnaire
Authors: Domeyer Philippe-Richard , Giannakidou Smaragda Ch. , Kyriakou Panagiota , Katsari Vasiliki , Antoniadis Antonios P. , Lagos Ioannis K. , Fragakis Nikolaos , Varaklioti Agoritsa , Vassilikos Vassilios P.
Published: October 2018

Objective. This study aims to (i) translate, culturally adapt, and preliminarily validate the arrhythmia-specific Umea22 (U22) questionnaire and (ii) assess the impact of radiofrequency (RF) ablation and medical treatment on the quality of life of patients with supraventricular tachycardias (SVTs). Methods. A total of 140 patients with atrioventricular nodal re-entry tachycardia (AVNRT) and atrioventricular re-entry tachycardia (AVRT) were enrolled in the study. Of these, 100 patients underwent RF ablation (group A) and 40 patients were managed with antiarrhythmic medications (group B). Health-related quality of life (HRQoL) was assessed for both groups using the Short Form-36 Health Survey (SF-36) and the arrhythmia-specific Umea22 (U22) questionnaire at baseline and 3-month follow-up. Exploratory and confirmatory factor analyses were performed to assess the validity of the U22 questionnaire. Univariate comparisons of HRQoL scores between study timepoints and multivariate regression analyses adjusting for baseline confounders were conducted. Results. The factor analysis of the U22 questionnaire yielded a six-factor model (“burden of spells”; “heart contractility”; “character of spells”; “general/non-specific feeling”; “other specific somatic symptoms”; “fear”) with acceptable fit results. Patients of group A showed significant improvement in all SF-36 and U22 scores at 3 months’ follow-up compared to baseline (all p<0.05). Patients of group B presented deterioration of the total SF-36 score (p=0.001) and improvement of certain U22 measures, namely, well-being (p=0.004), heartbeat speed, and intensity during arrhythmia spells (p<0.0001 for both measures) at 3 months’ follow-up, compared to baseline. Employment status, male sex, and urban residence emerged as important predictors. Conclusion. The Greek version of the U22 questionnaire is a valid tool to assess SVT-related symptoms. RF ablation appears to exert more pronounced beneficial outcomes on HRQoL of patients with SVTs compared to medical treatment. Prompt referral of patients with SVTs to specialist centers may favorably affect their quality of life and should be encouraged.
The Dynamic Properties of Historic Timber‐Framed Masonry Structures in Bursa, Turkey
Authors: Bağbancı M. Bilal , Bağbancı Özlem Köprülü
Published: October 2018

Timber‐framed masonry structures are known as an effective earthquake load resisting system in high seismicity regions such as Bursa, Turkey. Intense earthquakes have occurred throughout history; however, many of the traditional timber structures have been able to survive without significant damage until the present day. In this study, six historic two‐storied timber‐framed masonry structures dating from the nineteenth century in Bursa City are investigated by using laboratory and in situ structural health monitoring tests. Although the houses have the same construction techniques, different masonry infill materials are used inside the timber frames. Stone, adobe, and brick are used as infill materials. Mud and lime mortars are used as binding materials. Mud mortar is used with stone and adobe materials. Lime mortar is used with brick material. The physical, mechanical, and dynamic parameters such as density, specific gravity, porosity, elastic modulus, frequencies, mode shapes, and damping ratios of the studied structures were investigated and the results were comparatively discussed. It is understood that the use of different infill materials affects the dynamic behaviors of these structures.
Existence of Generalized Nash Equilibrium in n-Person Noncooperative Games under Incomplete Preference
Authors: Li Xingchang
Published: October 2018

To prove the existence of Nash equilibrium by traditional ways, a common condition that the preference of players must be complete has to be considered. This paper presents a new method to improve it. Based on the incomplete preference corresponding to equivalence class set being a partial order set, we translate the incomplete preference problems into the partial order problems. Using the famous Zorn lemma, we get the existence theorems of fixed point for noncontinuous operators in incomplete preference sets. These new fixed point theorems provide a new way to break through the limitation. Finally, the existence of generalized Nash equilibrium is strictly proved in the n-person noncooperative games under incomplete preference.
Existence Results for Impulsive Fractional q-Difference Equation with Antiperiodic Boundary Conditions
Authors: Zuo Mingyue , Hao Xinan
Published: October 2018

In this paper, we investigate the impulsive fractional q-difference equation with antiperiodic conditions. The existence and uniqueness results of solutions are established via the theorem of nonlinear alternative of Leray-Schauder type and the Banach contraction mapping principle. Two examples are given to illustrate our results.
Sevoflurane Exacerbates Cognitive Impairment Induced by Aβ1–40 in Rats through Initiating Neurotoxicity, Neuroinflammation, and Neuronal Apoptosis in Rat Hippocampus
Authors: Tian Yue , Chen Ke-yan , Liu Li-dan , Dong Yun-xia , Zhao Ping , Guo Shan-bin
Published: October 2018

Objective. This study was aimed at investigating whether sevoflurane inhalation induced cognitive impairment in rats with a possible mechanism involved in the event. Methods. Thirty-two rats were randomly divided into four groups of normal saline (NS) + O2, NS + sevoflurane (sevo), amyloid-β peptide (Aβ) + O2, and Aβ + sevo. The rats in the four groups received bilateral intrahippocampus injections of NS or Aβ. The treated hippocampus was harvested after inhaling 30% O2 or 2.5% sevoflurane. Evaluation of cognitive function was performed by Morris water maze (MWZ) and an Aβ1–42 level was determined by ELISA. Protein and mRNA expressions were executed by immunohistochemical (IHC) staining, Western blotting, and qRT-PCR. Results. Compared with the NS-treated group, sevoflurane only caused cognitive impairment and increased the level of Aβ1–42 of the brain in the Aβ-treated group. Sevoflurane inhalation but not O2 significantly increased glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule (IBA)1 expression in Aβ-treated hippocampus of rats. Expression levels for Bcl-xL, caspase-9, receptor for advanced glycation end products (RAGE) and brain-derived neurotrophic factor (BDNF) were significantly different in quantification of band intensity between the rats that inhaled O2 and sevoflurane in Aβ-treated groups (all P<0.05). Interleukin- (IL-) 1β, nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) mRNA expression increased after the rats inhaled sevoflurane in the Aβ-treated group (both P<0.01). There were no significant differences in the change of GFAP, IBA1, Bcl-xL, caspase-9, RAGE, BDNF, IL-1β, NF-κB, and iNOS in the NS + O2 and NS + sevo group (all P>0.05). Conclusion. Sevoflurane exacerbates cognitive impairment induced by Aβ1–40 in rats through initiating neurotoxicity, neuroinflammation, and neuronal apoptosis in rat hippocampus.
Use of Noninvasive Ventilation with Volume-Assured Pressure Support to Avoid Tracheostomy in Severe Obstructive Sleep Apnea
Authors: Diaz-Abad Montserrat , Isaiah Amal , Rogers Valerie E , Pereira Kevin D. , Lasso-Pirot Anayansi
Published: October 2018

Obstructive sleep apnea (OSA) is a common disorder in children but can occasionally present with life-threatening hypoxemia. Obesity is a significant risk factor for poor outcomes of OSA treatment. Continuous positive airway pressure (CPAP) is indicated in children who are not candidates for or have an unsatisfactory response to adenotonsillectomy. Children acutely at risk for significant morbidity with other therapies are candidates for a tracheostomy. An eight-year-old patient with morbid obesity and severe OSA refractory to CPAP therapy was treated successfully with a novel noninvasive ventilation (NIV) mode with volume-assured pressure support (VAPS) and avoided tracheostomy.
Management of Congenital Clinical Anophthalmos with Orbital Cyst: A Kinshasa Case Report
Authors: Stahnke Thomas , Erbersdobler Andreas , Knappe Steffi , Guthoff Rudolf F. , Kilangalanga Ngoy J.
Published: October 2018

An early developmental lack of the optic vesicle can result in congenital anophthalmia, defined as a complete absence of the eye, which can be distinguished from congenital microphthalmos, where ocular rudiments are present. Here, a rare pediatric case of congenital clinical anophthalmos with orbital cyst in the left orbit is reported. The patient was a 14-month-old girl with no other congenital defects who underwent surgical and prothetic management in St. Joseph’s Hospital Kinshasa, Democratic Republic of the Congo (DRC). Surgery was carried out under general anesthesia. The cyst was punctured and its wall fully excised. Near the orbital apex pigmented elements representing iris, ciliary body, and choroidal or retinal remnants were found. The specimens were fixed in formalin for histological examination. Surgical cyst removal including socket deepening for an artificial eye was performed. Postoperative wound healing was uneventful and a satisfactory cosmetic outcome was achieved in all follow-up examinations. Histological examination revealed rudimentary ocular structures similar to degenerated lens tissue with a typical, PAS-positive capsule. Additionally, pigmented epithelial structures, which seem to be of ciliary body, iris, and choroidal or retinal-type epithelium origin, could be detected, prompting the final diagnosis, microphthalmia with dominant cyst formation.
Genotoxicity Evaluation of an Ethanol Extract Mixture of Astragali Radix and Salviae miltiorrhizae Radix
Authors: Lee Jin-Seok , Cho Jung-Hyo , Lee Dong-Soo , Son Chang-Gue
Published: October 2018

Myelophil, a combination of Astragali Radix and Salviae Radix, is one of the most commonly used remedies for disorders of Qi and blood in traditional Chinese medicine. Based on the clinical applications of these plants, in particular to pregnant woman, this study aimed to evaluate the genotoxic potential of an ethanol extract mixture of the above two herbs, called Myelophil. Following the Organization for Economic Cooperation and Development (OECD) Guideline methods, a genotoxicity test was conducted using a bacterial reverse mutation test with Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and Escherichia coli (WP2μvrA), an in vitro mammalian chromosome aberration test using a Chinese hamster ovary cell line (CHO‐K1), and an in vivo mammalian erythrocyte micronucleus test using ICR mouse bone marrow. In the Ames test, for both types of mutations (base substitution and frameshift) under conditions with/without an S9 mix up to 5,000 μg/plate, Myelophil did not increase the number of revertant colonies of all S. typhimurium strains as well as E. coli strain. For both short (6 h) and long tests with/without S9 mix, the chromosome aberration test did not show any significant increase in the number of structural or numerical chromosome aberrations by Myelophil. In addition, no significant change in the number of micronucleated polychromatic erythrocytes or polychromatic erythrocytes was observed in the bone marrow of an ICR mouse administered Myelophil orally at 2,000 mg/kg/day for 2 days, respectively. These results are the first to provide experimental evidence that Myelophil, an ethanol extract mixture of Astragali Radix and Salviae Radix, has no risk of genotoxicity.
New Approach of the Oxidant Peroxo Method (OPM) Route to Obtain Ti(OH)4 Nanoparticles with High Photocatalytic Activity under Visible Radiation
Authors: Nogueira André E. , Ribeiro Lucas S. , Gorup Luiz F. , Silva Gelson T. S. T. , Silva Fernando F. B. , Ribeiro Caue , Camargo Emerson R.
Published: October 2018

Environmental problems related to the generation of wastewater contaminated with organic compounds and the emissions of pollutants from fuel burning have become major global problems. Thus, there is a need for the development of alternative and economically viable technologies for the remediation of the affected ecosystems. Therefore, this work describes the preparation and characterization of a Ti(OH)4 catalyst with the modified surface for application in the photodegradation of organic compounds (methylene blue (MB) dye and the drug amiloride (AML)) and in the artificial photosynthesis process. Characterization results reveal that peroxo groups on the surface of the catalyst had a great influence on the optical properties of the Ti(OH)4 and consequently in its photocatalytic property. This catalyst showed a high photocatalytic activity for the degradation of organic pollutants under visible radiation, reaching approximately 98% removal of both the dye and the drug in 150 min of reaction. In addition, the catalyst presented a great potential for the reduction of CO2 under ultraviolet (UV) radiation when compared to P25, which is a classic catalyst used in photocatalytic processes. The highest photocatalytic activity can be attributed to the strong visible light absorption, due to the narrow band gap, and the effective separation of photogenerated electron-hole pairs caused by the peroxo groups on the Ti(OH)4 surface.
Insecticide Resistance and Fitness: The Case of Four Aedes aegypti Populations from Different Brazilian Regions
Authors: David Mariana Rocha , Garcia Gabriela Azambuja , Valle Denise , Maciel-de-Freitas Rafael
Published: October 2018

Background. Chemical control is still a major strategy to constrain vector density and mitigate pathogen transmission. However, insecticide overuse poses a high selective pressure, favouring the spread of resistance alleles in natural populations. In an insecticide-free environment, a fitness cost is expected in resistant insects when compared to susceptible counterparts. This study investigates whether insecticide resistance to an organophosphate (temephos) and a pyrethroid (deltamethrin) is associated with fitness traits in four Aedes aegypti wild populations sampled every three months over one year. Findings. We measured development time from larvae to adult, female survival, wing length, fecundity, and adult resistance to starvation in field insecticide resistant Ae. aegypti populations four times over a year. These results were confronted with resistance levels to temephos and deltamethrin and with potentially related mechanisms, including a kdr mutation in the pyrethroid target site. No differences in fitness cost were found after contrasting mosquitoes from the same population collected throughout a year, irrespective of differences in insecticide resistance levels. Additionally, significant differences were not observed among field populations. However, compared to the reference strain Rockefeller, field females survived significantly less. Moreover, larval development was equal or slower in three out of four field populations. In no case differences were evidenced in starvation tolerance, wing length, and fecundity. Conclusions. Overall, field resistant mosquitoes seemed to have a slight fitness disadvantage when compared with the Rockefeller susceptible strain which might represent a potential fitness cost of insecticide resistance. However, after comparing Ae. aegypti from the same population but sampled at different moments, or from different field populations, mosquito life-history traits varied independently of resistance ratios. The metabolic deviations necessary to overcome the adverse effects of insecticides may cause an energy trade-off that affects energy allocation and ultimately basic demands of insect biology. The extent of fitness cost due to insecticide resistance is critical information to delay the evolution of resistance in wild vector populations.
On the Effect of Labour Productivity on Growth: Endogenous Fluctuations and Complex Dynamics
Authors: Grassetti F. , Mammana C. , Michetti E.
Published: October 2018

This paper introduces a sigmoidal production function that considers production possible even when the only input is labour. The long-run behaviour of an economy described by the neoclassical Solow-type growth model with differential savings is investigated considering the technology presented. It is found that labour productivity influences the existence of boom and bust periods as well as the level of capital per capita in equilibrium.
Pure Red Cell Aplasia Associated with Thymolipoma: Complete Anaemia Resolution following Thymectomy
Authors: Ferreira David , Ponraj Royston , Yeung Adrian , de Malmanche Jillian
Published: October 2018

Pure red cell aplasia is an uncommon cause of anaemia rarely associated with thymoma. A combination of immunosuppressive therapy and thymectomy offers a potential cure. Thymectomy alone rarely results in anaemia resolution. A seventy-three-year-old male with Klinefelter syndrome presented with progressively increasing shortness of breath and anaemia. Serological testing supported primary bone marrow pathology, and a bone marrow biopsy was performed. A pure red cell aplasia was seen on bone marrow examination, and computed tomography of the chest demonstrated a thymoma. Thymectomy was performed, and histology revealed a thymolipoma. Complete anaemia resolution was achieved following thymectomy alone. This suggests that thymomas may directly mediate immune dysregulation resulting in erythroid precursor destruction.
Neostigmine Attenuates Proinflammatory Cytokine Expression in Preoptic Area but Not Choroid Plexus during Lipopolysaccharide-Induced Systemic Inflammation
Authors: Herman Andrzej P. , Tomaszewska-Zaremba Dorota , Kowalewska Marta , Szczepkowska Aleksandra , Oleszkiewicz Małgorzata , Krawczyńska Agata , Wójcik Maciej , Antushevich Hanna , Skipor Janina
Published: October 2018

The study was designed to examine whether the administration of neostigmine (0.5 mg/animal), a peripheral inhibitor of acetylcholinesterase (AChE), during an immune/inflammatory challenge provoked by intravenous injection of bacterial endotoxin—lipopolysaccharide (LPS; 400 ng/kg)—attenuates the synthesis of proinflammatory cytokines in the ovine preoptic area (POA), the hypothalamic structure playing an essential role in the control of the reproduction process, and in the choroid plexus (CP), a multifunctional organ sited at the interface between the blood and cerebrospinal fluid in the ewe. Neostigmine suppressed (p<0.05) LPS-stimulated synthesis of cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF)αin the POA, and this effect was similar to that induced by the treatment with systemic AChE inhibitor—donepezil (2.5 mg/animal). On the other hand, both AChE inhibitors did not influence the gene expression of these cytokines and their corresponding receptors in the CP. It was found that this structure seems to not express the neuronal acetylcholine (ACh) receptor subunit alpha-7, required for anti-inflammatory action of ACh. The mechanism of action involves inhibition of the proinflammatory cytokine synthesis on the periphery as well as inhibition of their de novo synthesis rather in brain microvessels and not in the CP. In conclusion, it is suggested that the AChE inhibitors incapable of reaching brain parenchyma might be used in the treatment of neuroinflammatory processes induced by peripheral inflammation.
Possible Monitoring and Removal of As(III) by an Integrated System of Electrochemical Sensor and Nanocomposite Materials
Authors: Chu Xuan T. , Trieu Quan V. V. , Tran Thinh Q. , Pham Thanh D. , Vu Trung Q. , Tran Thuy H. , Mai Tuan A.
Published: October 2018

In this study, nanocomposites composed of magnetite nanoparticles (MNPs) coated with polyaniline fabricated by in situ polymerization were prepared for arsenic adsorption. Properties of particular MNPs and their nanocomposites were characterized with scanning electron microscopy, X-ray diffraction spectroscopy, and Fourier transform infrared spectroscopy. The As(III) concentration before and after adsorption on nanocomposites was detected by atomic absorption spectroscopy method and then compared with the results measured by a self-developed potentiostat system with anodic stripping voltammetry method. The polyaniline coating resulted in an improvement for As(III) adsorption ability of magnetite nanoparticles, and among the three compositions of PAni/MNP nanocomposites, the 5 wt% PAni showed the highest capability of As(III) adsorption (or removal) of 50 mg/g. Performing pH investigation, the concentration of remaining As decreased when pH increased from 2 to 5 and reached saturation value at higher pH. Above all, the electronic device can be integrated with As(III) removal system using PAni/MNP nanocomposites, proving to act as an independent monitoring system, and even more the adsorbent on the composites could be removed and the recyclability of the material was also investigated.
An Analysis of the Association between Epilepsy-Related Genes and Vertigo in the Polish Population
Authors: Pawlak-Osińska Katarzyna , Linkowska Katarzyna , Hołub Karolina , Winiarska Katarzyna , Stankiewicz Bartosz , Kaźmierczak Henryk , Osiński Stanisław , Marzec Maria , Grzybowski Tomasz
Published: October 2018

Considering the possibility of a common genetic background of vertigo and epilepsy, we genotyped an affected group of individuals with vertigo and an unaffected group, by studying 26 single-nucleotide polymorphisms (SNPs) in 14 genes which were previously reported to be of particular importance for epilepsy. Significant differences were found between the patients and the control group (χ2 = 38.3, df = 3, p = 1.6 × 10–7) for the frequencies of haplotypes consist ing of 2 SNPs located in chromosome 11 (rs1939012 and rs1783901 within genes MMP8 and SCN3B, respectively). The haplotype rs1939012:C-rs1783901:A, consisting of the minor-frequency alleles was found to be associated with a higher risk of vertigo (OR = 5.0143, 95% CI = 1.6991–14.7980, p = 0.0035). In contrast, the haplotype rs1939012:T-rs1783901:A showed a significant association with a decreased risk of the disease (OR = 0.0597, 95% CI = 0.0136–0.2620, p = 0.0002). Our results suggest that the SNPs rs1939012 and rs1783901 may play a potential role of gene regulation and/or epistasis in a complex etiology of vertigo.
Cardiac Dysfunction in Duchenne Muscular Dystrophy Is Less Frequent in Patients With Mutations in the Dystrophin Dp116 Coding Region Than in Other Regions
Authors: Yamamoto Tetsushi , Awano Hiroyuki , Zhang Zhujun , Sakuma Mio , Kitaaki Shoko , Matsumoto Masaaki , Nagai Masashi , Sato Itsuko , Imanishi Takamitsu , Hayashi Nobuhide , Matsuo Masafumi , Iijima Kazumoto , Saegusa Jun
Published: October 2018

Background

Duchenne muscular dystrophy (DMD), the most common inherited muscular disease in childhood, is caused by dystrophin deficiency because of mutations in the
DMD
gene. Although DMD is characterized by fatal progressive muscle wasting, cardiomyopathy is the most important nonmuscle symptom threatening the life of patients with DMD. The relationship between cardiac involvement and dystrophin isoforms has not been analyzed.

Methods and Results

The results of 1109 echocardiograms obtained from 181 Japanese DMD patients with confirmed mutations in the
DMD
gene were retrospectively analyzed. Patients showed an age-related decline in left ventricular ejection fraction. Patients were divided by patterns of dystrophin isoform deficiency into 5 groups. The cardiac dysfunction-free survival was significantly higher in the group with mutations in the Dp116 coding region than the others, whereas no significant differences in the other 3 groups. At age 25 years, the cardiac dysfunction-free rate was 0.6 in the Dp116 group, but only 0.1 in others. PCR amplification of Dp116 transcript in human cardiac muscle indicated promoter activation.

Conclusions

Left ventricular ejection fraction in DMD declined stepwise with age. Cardiac dysfunction was less frequent in Dp116-deficient than other patients with DMD. Dp116 transcript was identified in human cardiac muscle for the first time. These results indicate that Dp116 is associated with cardiac involvement in DMD.
Genome-Wide Association Study Identifies a Novel Genetic Risk Factor for Recurrent Venous Thrombosis
Authors: de Haan Hugoline G. , van Hylckama Vlieg Astrid , Germain Marine , Baglin Trevor P. , Deleuze Jean-François , Trégouët David-Alexandre , Rosendaal Frits R.
Published: October 2018

Background:

Genetic risk factors for a first venous thrombosis (VT) seem to have little effect on recurrence risk. Therefore, we aimed specifically to identify novel genetic determinants of recurrent VT. To date, genome-wide association studies are lacking.

Methods and Results:

We performed a genome-wide association scan in 1279 patients from the MEGA (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) follow-up study; 832 patients who remained recurrence free during a median follow-up time of 6.1 years and 447 recurrent VT patients with a median time-to-recurrence of 2.6 years. We analyzed genotype probabilities of ≈8.6 million variants, imputed to the Genome of the Netherlands project reference panel, with a minor allele frequency ≥1% for an association with recurrent VT. One region exceeded genome-wide significance (
P
≤5×10
−
8
), mapping to the well-known factor V Leiden locus. Conditional association analyses on factor V Leiden did not yield any secondary association signals. We also identified 52 suggestive association signals (
P
<1×10
−5
) at 17 additional loci. None of these loci were previously implicated in VT risk. Replication analyses for 17 lead variants were performed in 350 patients with recurrent VT and 1866 patients with a single VT event from the MEGA follow-up study, THE-VTE (Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism) study, and LETS (Leiden Thrombophilia Study). We observed an association with recurrence for an intergenic variant at 18q22.1 with an odds ratio of 1.7 (95% confidence interval, 1.2–2.6) per copy of the minor allele.

Conclusions:

We confirmed the association of factor V Leiden and identified a novel risk locus at 18q22.1 in the first large genetic study on recurrent VT.
Genetic Reduction in Left Ventricular Protein Kinase C-α and Adverse Ventricular Remodeling in Human Subjects
Authors: Hu Ray , Morley Michael P. , Brandimarto Jeffrey , Tucker Nathan R. , Parsons Victoria A. , Zhao Sihai D. , Meder Benjamin , Katus Hugo A. , Rühle Frank , Stoll Monika , Villard Eric , Cambien François , Lin Honghuang , Smith Nicholas L. , Felix Janine F. , Vasan Ramachandran S. , van der Harst Pim , Newton-Cheh Christopher , Li Jin , Kim Cecilia E. , Hakonarson Hakon , Hannenhalli Sridhar , Ashley Euan A. , Moravec Christine S. , Tang W.H. Wilson , Maillet Marjorie , Molkentin Jeffery D. , Ellinor Patrick T. , Margulies Kenneth B. , Cappola Thomas P
Published: October 2018

Background:

Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with
PRKCA
expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations.

Methods and Results:

We analyzed the
cis
expression quantitative trait locus for
PRKCA
marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes,
P
=1×10
−41
). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (
R
2
=1.0) linkage disequilibrium with rs9912468 within intron 2 of
PRKCA.
We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The
PRKCA
enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α–lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α–lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations.

Conclusions:

These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.
Prospective Study of Epigenetic Age Acceleration and Incidence of Cardiovascular Disease Outcomes in the ARIC Study (Atherosclerosis Risk in Communities)
Authors: Roetker Nicholas S. , Pankow James S. , Bressler Jan , Morrison Alanna C. , Boerwinkle Eric
Published: October 2018

Background:

DNA methylation-based patterns of biological aging, known as epigenetic age acceleration, are predictive of all-cause mortality, but little is known about their association with cardiovascular disease (CVD).

Methods:

We estimated 2 versions of epigenetic age acceleration (Horvath and Hannum) using whole-blood samples from 2543 blacks. Linear and Cox proportional hazards regression, respectively, were used to assess the association of age acceleration with carotid intima–media thickness (cross-sectionally) and incident cardiovascular events, including CVD mortality, myocardial infarction, fatal coronary heart disease, peripheral arterial disease, and heart failure, during a median 21-year follow-up. All models were adjusted for chronological age and traditional CVD risk factors.

Results:

In comparison to chronological age, the 2 measures of epigenetic age acceleration were weaker, but independent, potential risk markers for subclinical atherosclerosis and most incident cardiovascular outcomes, including fatal coronary heart disease, peripheral arterial disease, and heart failure. For example, each 5-year increment of epigenetic age acceleration was associated with an average of 0.01 mm greater carotid intima–media thickness (each
P
≤0.01), and the hazard ratios (95% confidence intervals) of fatal coronary heart disease per 5-year increment in Horvath and Hannum age acceleration were 1.17 (1.02–1.33) and 1.22 (1.04–1.44), respectively.

Conclusions:

In this sample of blacks, increased epigenetic age acceleration in whole blood was a potential risk marker for incident fatal coronary heart disease, peripheral arterial disease, and heart failure independently of chronological age and traditional CVD risk factors. DNA methylation–based measures of biological aging may help to identify new pathophysiological mechanisms contributing to the development of CVD.
Association of Genetic Instrumental Variables for Lung Function on Coronary Artery Disease Risk
Authors: Au Yeung Shiu Lun , Borges Maria-Carolina , Lawlor Debbie A.
Published: October 2018

Background:

Lung function, assessed by forced expiratory volume in 1 second (FEV
1
) and forced vital capacity (FVC), is inversely associated with coronary artery disease (CAD), but these associations could be because of confounding or reversed causality. We conducted a 2-sample Mendelian randomization study, using publicly available data from relevant genome-wide association studies, to examine the role of FEV
1
or FVC on CAD.

Methods:

We used the most recent genome-wide association studies on lung function to extract genetic instruments related to FEV
1
and FVC (n=92 749). Data on the association between genetic instruments and CAD were obtained from Coronary Artery Disease Genome wide Replication and Meta-analysis plus The Coronary Artery Disease Genetics 1000 Genomes-based genome-wide association studies (60 801 CAD cases and 123 504 controls). We used inverse-variance weighting with a multiplicative random effect to estimate the genetic instrumented association of FEV
1
and FVC on CAD. Sensitivity analyses included weighted median and MR-Egger methods.

Results:

Each SD greater FEV
1
was associated with a lower risk of CAD (odds ratio, 0.78 per SD; 95% confidence interval, 0.62–0.98) with a similar magnitude for FVC on CAD risk (odds ratio, 0.82 per SD; 95% confidence interval, 0.64–1.06). Estimates for FEV
1
were similar when using MR-Egger method (odds ratio, 0.80 per SD; 95% confidence interval, 0.33–1.94) although the magnitude was smaller for weighted median method (odds ratio, 0.93 per SD; 95% confidence interval, 0.75–1.17). Estimates for FVC in the sensitivity analyses were attenuated (median) or changed direction (MR-Egger).

Conclusions:

Our study suggested an inverse relation between FEV
1
and CAD, but for FVC, evidence is less clear.
Partitioning the Pleiotropy Between Coronary Artery Disease and Body Mass Index Reveals the Importance of Low Frequency Variants and Central Nervous System–Specific Functional Elements
Authors: Nikpay Majid , Turner Adam W , McPherson Ruth
Published: October 2018

Background:

The objective of this study is to investigate the extent and nature of pleiotropy between coronary artery disease (CAD) and body mass index (BMI).

Methods:

We examined the contribution of genome-wide single-nucleotide polymorphisms (minor allele frequency ≥0.01) to co-occurrence of CAD and BMI in a sample of genetically unrelated 8041 subjects (genetic resemblance ≤0.025) of European ancestry using mixed-linear-models. We further partitioned the estimated pleiotropy according to biological features to gain insight into the nature of pleiotropy between CAD and BMI.

Results:

We found significant (
P
<0.0001) positive genetic correlation between CAD and BMI (
r

g

=0.60). The estimated pleiotropy explained 68% of phenotypic correlation, and it was not proportionally distributed across the chromosomes; notably, chromosome 10 contributed more; whereas, chromosomes 11 and 14 contributed less to pleiotropy than expected given their chromosomal length. We noted that a large proportion (63%;
P
=0.002) of the pleiotropy is attributed to single-nucleotide polymorphisms with low allele frequency (minor allele frequency <0.05). Of note, pleiotropy was enriched among central nervous system genes and genes of metabolic pathways. Further analyses revealed that these effects are more pronounced in the proopiomelanocortin pathway and genes involved in carbohydrate metabolism. After genome-wide association study meta-analysis, only single-nucleotide polymorphisms downstream of the
MC4R
gene were found concordantly associated with (
P
<5×10
–8
) BMI and CAD with lead single-nucleotide polymorphism being rs663129 (combined
P
=2.7×10
–65
). Finally, partitioning the pleiotropy according to functional elements pointed to the importance of superenhancers and notably brain-specific superenhancers.

Conclusions:

Genome-wide pleiotropy substantially contributes to co-occurrence of CAD and obesity, and it is highly enriched among low frequency variants and central nervous system–specific functional elements.