bluuebunny/crossref_metadata_2025 huggingface dataset:
Microvascular permeability of skeletal muscle after eccentric contraction-induced muscle injury: in vivo imaging using two-photon laser scanning microscopy
Authors: Hotta Kazuki , Behnke Bradley Jon , Masamoto Kazuto , Shimotsu Rie , Onodera Naoya , Yamaguchi Akihiko , Poole David C. , Kano Yutaka
Published: May 2018

Via modulation of endothelial integrity and vascular permeability in response to damage, skeletal muscle microvessels play a crucial permissive role in tissue leukocyte invasion. However, direct visual evidence of altered microvascular permeability of skeletal muscle has not been technically feasible, impairing mechanistic understanding of these responses. Two-photon laser scanning microscopy (TPLSM) allows three-dimensional in vivo imaging of skeletal muscle microcirculation. We hypothesized that the regulation of microvascular permeability in vivo is temporally related to acute inflammatory and regenerative processes following muscle injury. To test our hypothesis, tibialis anterior muscles of anesthetized male Wistar rats were subjected to eccentric contractions (ECCs) via electrical stimulation. The skeletal muscle microcirculation was imaged by an intravenously infused fluorescent dye (rhodamine B isothiocyanate-dextran) to assess microvascular permeability via TPLSM 1, 3, and 7 days after ECC. Immunohistochemistry on serial muscle sections was performed to determine the proportion of VEGF-A-positive muscle fibers in the damaged muscle. Compared with control rats, the volumetrically determined interstitial leakage of fluorescent dye (5.1 ± 1.4, 5.3 ± 1.2 vs. 0.51 ± 0.14 μm3 × 106; P < 0.05, days 1 and 3, respectively, vs. control) and percentage of VEGF-A-positive fibers in the damaged muscle (10 ± 0.4%, 22 ± 1.1% vs. 0%; days 1 and 3, respectively, vs. control) were significantly higher on days 1 and 3 after ECC. The interstitial leakage volume returned to control by day 7. These results suggest that microvascular hyperpermeability assessed by in vivo TPLSM imaging is associated with ECC-induced muscle damage and increased VEGF expression.

NEW & NOTEWORTHY This investigation employed a novel in vivo imaging technique for skeletal muscle microcirculation using two-photon laser scanning microscopy that enabled microvascular permeability to be assessed by four-dimensional image analysis. By combining in vivo imaging and histological analysis, we found the temporal profile of microvascular hyperpermeability to be related to that of eccentric contraction-induced skeletal muscle injury and pronounced novel myocyte VEGF expression.
Blood flow occlusion-related O2 extraction “reserve” is present in different muscles of the quadriceps but greater in deeper regions after ramp-incremental test
Authors: Iannetta Danilo , Okushima Dai , Inglis Erin Calaine , Kondo Narihiko , Murias Juan M , Koga Shunsaku
Published: May 2018

It was recently demonstrated that an O2 extraction reserve, as assessed by the near-infrared spectroscopy (NIRS)-derived deoxygenation signal ([HHb]), exists in the superficial region of vastus lateralis (VL) muscle during an occlusion performed at the end of a ramp-incremental test. However, it is unknown whether this reserve is present and/or different in magnitude in other portions and depths of the quadriceps muscles. We tested the hypothesis that an O2 extraction reserve would exist in other regions of this muscle but is greater in deep compared with more superficial portions. Superficial (VL-s) and deep VL (VL-d) as well as superficial rectus femoris (RF-s) were monitored by a combination of low- and high-power time-resolved (TRS) NIRS. During the occlusion immediately post-ramp-incremental test there was a significant overshoot in the [HHb] signal ( P < 0.05). However, the magnitude of this increase was greater in VL-d (93.2 ± 42.9%) compared with VL-s (55.0 ± 19.6%) and RF-s (47.8 ± 14.0%) ( P < 0.05). The present study demonstrated that an O2 extraction reserve exists in different pools of active muscle fibers of the quadriceps at the end of a ramp exercise to exhaustion. The greater magnitude in the reserve observed in the deeper portion of VL, however, suggests that this portion of muscle may present a greater surplus of oxygenated blood, which is likely due to a greater population of slow-twitch fibers. These findings add to the notion that the plateau in the [HHb] signal toward the end of a ramp-incremental exercise does not indicate the upper limit of O2 extraction.

NEW & NOTEWORTHY Different portions of the quadriceps muscles exhibited an untapped O2 extraction reserve during a blood flow occlusion performed at the end of a ramp-incremental exercise. In the deeper portion of the vastus lateralis muscle, this reserve was greater compared with superficial vastus lateralis and rectus femoris. These data suggest that the O2 extraction reserve may be dependent on the vascular and/or oxidative capacities of the muscles.
Elevated extracellular potassium prior to muscle contraction reduces onset and steady-state exercise hyperemia in humans
Authors: Terwoord Janée D. , Hearon Christopher M. , Luckasen Gary J. , Richards Jennifer C. , Joyner Michael J. , Dinenno Frank A.
Published: May 2018

The increase in interstitial potassium (K+) during muscle contractions is thought to be a vasodilatory signal that contributes to exercise hyperemia. To determine the role of extracellular K+in exercise hyperemia, we perfused skeletal muscle with K+before contractions, such that the effect of any endogenously-released K+would be minimized. We tested the hypothesis that local, intra-arterial infusion of potassium chloride (KCl) at rest would impair vasodilation in response to subsequent rhythmic handgrip exercise in humans. In 11 young adults, we determined forearm blood flow (FBF) (Doppler ultrasound) and forearm vascular conductance (FVC) (FBF/mean arterial pressure) during 4 min of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions, 2) infusion of KCl before the initiation of exercise, and 3) infusion of sodium nitroprusside (SNP) as a control vasodilator. Infusion of KCl or SNP elevated resting FVC similarly before the onset of exercise (control: 39 ± 6 vs. KCl: 81 ± 12 and SNP: 82 ± 13 ml·min−1·100 mmHg−1; both P < 0.05 vs. control). Infusion of KCl at rest diminished the hyperemic (ΔFBF) and vasodilatory (ΔFVC) response to subsequent exercise by 22 ± 5% and 30 ± 5%, respectively (both P < 0.05 vs. control), whereas SNP did not affect the change in FBF ( P = 0.74 vs. control) or FVC ( P = 0.61 vs. control) from rest to steady-state exercise. These findings implicate the K+ion as an essential vasodilator substance contributing to exercise hyperemia in humans.

NEW & NOTEWORTHY Our findings support a significant and obligatory role for potassium signaling in the local vasodilatory and hyperemic response to exercise in humans.
Effect of dietary nitrate supplementation on conduit artery blood flow, muscle oxygenation, and metabolic rate during handgrip exercise
Authors: Craig Jesse C. , Broxterman Ryan M. , Smith Joshua R. , Allen Jason D. , Barstow Thomas J.
Published: May 2018

Dietary nitrate supplementation has positive effects on mitochondrial and muscle contractile efficiency during large muscle mass exercise in humans and on skeletal muscle blood flow (Q̇) in rats. However, concurrent measurement of these effects has not been performed in humans. Therefore, we assessed the influence of nitrate supplementation on Q̇ and muscle oxygenation characteristics during moderate- (40 %peak) and severe-intensity(85% peak) handgrip exercise in a randomized, double-blind, crossover design. Nine healthy men (age: 25 ± 2 yr) completed four constant-power exercise tests (2/intensity) randomly assigned to condition [nitrate-rich (nitrate) or nitrate-poor (placebo) beetroot supplementation] and intensity (40 or 85% peak). Resting mean arterial pressure was lower after nitrate compared with placebo (84 ± 4 vs. 89 ± 4 mmHg, P < 0.01). All subjects were able to sustain 10 min of exercise at 40% peak in both conditions. Nitrate had no effect on exercise tolerance during 85% peak (nitrate: 358 ± 29; placebo: 341 ± 34 s; P = 0.3). Brachial artery Q̇ was not different after nitrate at rest or any time during exercise. Deoxygenated [hemoglobin + myoglobin] was not different for 40% peak ( P > 0.05) but was elevated throughout 85% peak ( P < 0.05) after nitrate. The metabolic cost (V̇o2) was not different at the end of exercise; however, the V̇o2 primary amplitude at the onset of exercise was elevated after nitrate for the 85% peak work rate (96 ± 20 vs. 72 ± 12 ml/min, P < 0.05) and had a faster response. These findings suggest that an acute dose of nitrate reduces resting blood pressure and speeds V̇o2 kinetics in young adults but does not augment Q̇ or reduce steady-state V̇o2 during small muscle mass handgrip exercise.

NEW & NOTEWORTHY We show that acute dietary nitrate supplementation via beetroot juice increases the amplitude and speed of local muscle V̇o2 on kinetics parameters during severe- but not moderate-intensity handgrip exercise. These changes were found in the absence of an increased blood flow response, suggesting that the increased V̇o2 was attained via improvements in fractional O2 extraction and/or spatial distribution of blood flow within the exercising muscle.
Retroperitoneal Cystic Nodal Metastasis of Renal Cell Carcinoma
Authors: Yamashita Takahisa , Morozumi Makoto , Higashi Morihiro , Momose Shuji , Tamaru Jun-ichi
Published: May 2018

Cystic nodal metastasis of renal cell carcinoma is very rare. The pathogenesis of cystic nodal metastasis is thought to involve obstruction of a lymphoid vessel draining the kidney by tumor cells and retrograde metastasis from the primary site to the lymph node along the lymphatic vessels. In this study, a surgical case of small renal cell carcinoma with retroperitoneal cystic nodal metastasis is reported.
Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest‐Old Population
Authors: Kim Yeo Jin , Kim Hyun Soo , Seo Young Rok
Published: May 2018

Aged population is increasing worldwide due to the aging process that is inevitable. Accordingly, longevity and healthy aging have been spotlighted to promote social contribution of aged population. Many studies in the past few decades have reported the process of aging and longevity, emphasizing the importance of maintaining genomic stability in exceptionally long‐lived population. Underlying reason of longevity remains unclear due to its complexity involving multiple factors. With advances in sequencing technology and human genome‐associated approaches, studies based on population‐based genomic studies are increasing. In this review, we summarize recent longevity and healthy aging studies of human population focusing on DNA repair as a major factor in maintaining genome integrity. To keep pace with recent growth in genomic research, aging‐ and longevity‐associated genomic databases are also briefly introduced. To suggest novel approaches to investigate longevity‐associated genetic variants related to DNA repair using genomic databases, gene set analysis was conducted, focusing on DNA repair‐ and longevity‐associated genes. Their biological networks were additionally analyzed to grasp major factors containing genetic variants of human longevity and healthy aging in DNA repair mechanisms. In summary, this review emphasizes DNA repair activity in human longevity and suggests approach to conduct DNA repair‐associated genomic study on human healthy aging.
A Biobjective Optimization Model for Deadline Satisfaction in Line-of-Balance Scheduling with Work Interruptions Consideration
Authors: Zou Xin , Zhang Lihui , Zhang Qian
Published: May 2018

The line-of-balance (LOB) technique has demonstrated many advantages in scheduling repetitive projects, one of which is that it allows more than one crew to be hired by an activity concurrently. The deadline satisfaction problem in LOB scheduling (DSPLOB) aims to find an LOB schedule such that the project is completed within a given deadline and the total number of crews is minimized. Previous studies required a strict application of crew work continuity, which may lead to a decline in the competitiveness of solutions. This paper introduces work interruptions into the DSPLOB and presents a biobjective optimization model that can balance the two conflicting objectives of minimizing the total number of crews and maximizing work continuity. An efficient version of theϵ-constraint method is customized to find all feasible tradeoff solutions. Then, these solutions are further improved by an automated procedure to reduce the number of interruptions for each activity without deteriorating the performance in both the objectives. The effectiveness and practicability of the proposed model are verified using a considerable number of instances. The results show that introducing work interruptions provides more flexibility in reducing the total number of crews under the LOB framework, especially for serial projects with a tight deadline constraint.
Average SEP of AF Relaying in Nakagami‐m Fading Environments
Authors: Qin Dong , Wang Yuhao , Zhou Tianqing
Published: May 2018

This paper is devoted to an investigation of an exact average symbol error probability (SEP) for amplify and forward (AF) relaying in independent Nakagami‐m fading environments with a nonnegative integer plus one‐half m, which covers many actual scenarios, such as one‐side Gaussian distribution (m = 0.5). Using moment generating function approach, the closed‐form SEP is expressed in the form of Lauricella multivariate hypergeometric function. Four modulation modes are considered: rectangular quadrature amplitude modulation (QAM), M‐ary phase shift keying (MPSK), M‐ary differential phase shift keying (MDPSK), and π/4 differential quaternary phase shift keying (DQPSK). The result is very simple and general for a nonnegative integer plus one‐half m, which covers the same range as integer m. The tightness of theoretical analysis is confirmed by computer simulation results.
Synthesis and Biological Evaluation of 1,3,8-Triazaspiro[4.5]decane-2,4-dione Derivatives as Myelostimulators
Authors: Yu Valentina , Ten Assel , Baktybayeva Lyailya , Sagatbekova Indira , Praliyev Kaldybay , Zolotareva Darya , Seilkhanov Tulegen , Zazybin Alexey
Published: May 2018

Spiroconnected N-alkoxyalkylpiperidine hydantoins were obtained via the Strecker reaction of cyanohydrin with ammonium carbonate. 1,3,8-Triazaspiro[4.5]decane-2,4-diones have shown the myelostimulating activity in the artificially induced (with cyclophosphamide) myelodepressive syndrome. The compounds significantly accelerated the regeneration of lymphocyte and granulocyte cell pool of bone marrow hematopoiesis.
Evaluation of99mTc-HYNIC-VCAM-1scFvas a Potential Qualitative and Semiquantitative Probe Targeting Various Tumors
Authors: Zhang Xiao , Hu Fan , Liu Chunbao , Yin Lianglan , Zhang Yingying , Zhang Yongxue , Lan Xiaoli
Published: May 2018

Vascular cell adhesion molecule 1 (VCAM-1) is overexpressed in varieties of cancers. This study aimed to evaluate the application of a single chain variable fragment (scFv) of anti-VCAM-1 antibody labeled with99mTc as a possible imaging agent in several tumors. VCAM-1 scFv was labeled with99mTc using succinimidyl 6-hydrazinium nicotinate hydrochloride, and99mTc-HYNIC-VCAM-1scFvwas successfully synthesized with a high radiolabeling yield. VCAM-1 expression was evaluated in six cell lines by immunofluorescence staining. In vitro binding assays showed different binding affinities of99mTc-HYNIC-VCAM-1scFvin different tumor cell lines, with high uptake in B16F10 melanoma and HT1080 fibrosarcoma cells, which was consistent with immunofluorescence staining results. In vivo SPECT planar imaging demonstrated that B16F10 and HT1080 tumors could be clearly visualized. Less intense uptake was observed in human SKOV3.ip ovarian tumor, and weak uptake was observed in human A375m melanoma, MDA-MB-231 breast cancer, and 786-O renal tumors. These findings were confirmed by biodistribution and immunofluorescence studies. High uptake by B16F10 tumors was inhibited by excess unlabeled VCAM-1scFv.99mTc-HYNIC-VCAM-1scFv, which selectively binds to VCAM-1, can provide a qualitative and semiquantitative method for noninvasive evaluation of VCAM-1 expression by tumors.
The Possible Mechanisms of HSV-TK/Hyperthermia Combined with 131I-antiAFPMcAb-GCV Nanospheres to Treat Hepatoma
Authors: Lin Mei , Zhou Chenglin , Huang Junxing , Tian Weizhong , Yu Hong , Jiang Xingmao , Ye Jun , Guo Ting , Shi Yujuan , Xiao Yanhong , Bian Xuefeng , Feng Xiaoqian
Published: May 2018

Our previous findings showed a good therapeutic effect of the combination of suicide gene HSV-TK, nuclide 131I, and magnetic fluid hyperthermia (MFH) on hepatoma by using magnetic nanoparticles as linkers, far better than any monotherapy involved, with no adverse effects. This combination therapy might be an eligible strategy to treat hepatic cancer. However, it is not clear how the combination regimen took the therapeutic effects. In the current study, to explore the possible mechanisms of radionuclide-gene therapy combined with MFH to treat hepatoma at tissue, cellular, and molecular levels and to provide theoretical and experimental data for its clinical application, we examined the apoptosis induction of the combination therapy and investigated the expression of the proteins related to apoptosis such as survivin, livin, bcl-2, p53, and nucleus protein Ki67 involved in cell proliferation, detected VEGF, and MVD involved in angiogenesis of tumor tissues and analyzed the pathologic changes after treatment. The results showed that the combination therapy significantly induced the hepatoma cell apoptosis. The expression of survivin, VEGF, bcl-2, p53, livin, Ki67, and VEGF proteins and microvascular density (MVD) were all decreased after treatment. The therapeutic mechanisms may be involved in the downregulation of Ki67 expression leading to tumor cell proliferation repression and inhibition of survivin, bcl-2, p53, and livin protein expression inducing tumor cell apoptosis, negatively regulating VEGF protein expression, and reducing vascular endothelial cells, which results in tumor angiogenesis inhibition and microvascular density decrease and tumor cell necrosis. These findings offer another basic data support and theoretical foundation for the clinical application of the combination therapy.
A Dual-Type L2 11-88 Peptide from HPV Types 16/18 Formulated in Montanide ISA 720 Induced Strong and Balanced Th1/Th2 Immune Responses, Associated with High Titers of Broad Spectrum Cross-Reactive Antibodies in Vaccinated Mice
Authors: Motavalli Khiavi Farhad , Arashkia Arash , Golkar Majid , Nasimi Maryam , Roohvand Farzin , Azadmanesh Kayhan
Published: May 2018

E. coli-derived concatenated, multitype L2-conserved epitopes of human papillomavirus (HPV) L2 protein might represent a less expensive and pan-type vaccine alternative (compared to type-specific HPV L1 virus-like particles), if stable protein expression and strong immunogenicity features could be met. Herein, three dual-type- (DT-) HPV L2 fusion peptides comprising the three head-to-tail tandem repeats (multimers) of either HPV 16 epitope “17-36” or “69-81” or one copy (monomer) of 11-88 fused to the same residues of HPV 18 were constructed and expressed inE. coli. SDS-PAGE and Western blot analyses indicated the proper expression and stability of theE. coli-derived DT peptides. Mice immunized by formulation of the purified DT peptides and Freund’s adjuvant (CFA/IFA) raised neutralizing antibodies (NAbs; the highest for DT: 11-88 peptide) which showed proper cross-reactivity to HPV types: 18, 16, 31, and 45 and efficiently neutralized HPV 18/16 pseudovirusesin vitro. Immunization studies in mice by formulation of the DT: 11-88 × 1 peptide with various adjuvants (alum, MF59, and Montanides ISA 720 and 50) indicated that Montanide adjuvants elicited the highest cross-reactive titers of NAbs and similar levels of IgG1 and IgG2a (switching towards balanced Th1/Th2 responses). The results implied development of low-costE. coli-derived DT: 11-88 peptide formulated in human compatible ISA 720 adjuvant as a HPV vaccine.
A Strong Tracking SLAM Algorithm Based on the Suboptimal Fading Factor
Authors: Liang Yunpei , Dai Jiahui , Wang Kequan , Li Xiaobo , Xu Pengcheng
Published: May 2018

This paper proposes an innovative simultaneous localization and mapping (SLAM) algorithm which combines a strong tracking filter (STF), an unscented Kalman filter (UKF), and a particle filter (PF) to deal with the low accuracy of unscented FastSLAM (UFastSLAM). UFastSLAM lacks the capacity for online self-adaptive adjustment, and it is easily influenced by uncertain noise. The new algorithm updates each Sigma point in UFastSLAM by an adaptive algorithm and obtains optimized filter gain by the STF adjustment factor. It restrains the influence of uncertain noise and initial selection. Therefore, the state estimation would converge to the true value rapidly and the accuracy of system state estimation would be improved eventually. The results of simulations and practical tests show that strong tracking unscented FastSLAM (STUFastSLAM) has a significant improvement in accuracy and robustness.
SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
Authors: Sakthikumar Sharadha , Elvers Ingegerd , Kim Jaegil , Arendt Maja L. , Thomas Rachael , Turner-Maier Jason , Swofford Ross , Johnson Jeremy , Schumacher Steven E. , Alföldi Jessica , Axelsson Erik , Couto C. Guillermo , Kisseberth William C. , Pettersson Mats E. , Getz Gad , Meadows Jennifer R.S. , Modiano Jaime F. , Breen Matthew , Kierczak Marcin , Forsberg-Nilsson Karin , Marinescu Voichita D. , Lindblad-Toh Kerstin
Published: May 2018

Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.

Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. Cancer Res; 78(13); 3421–31. ©2018 AACR.
Risk Factors and Outcomes of Delirium in Older Patients Admitted to Postacute Care with and without Dementia
Authors: Gual Neus , Morandi Alessandro , Pérez Laura Monica , Brítez Laura , Burbano Pamela , Man Flor , Inzitari Marco
Published: May 2018

Background: Delirium research is poorly studied in postacute care, a growing setting due to aging populations, as well as in dementia, a critical risk factor for delirium and particularly prevalent in postacute care. We investigated risk factors for delirium and its outcomes in older adults with and without dementia admitted to a subacute care unit (SCU) after exacerbated chronic conditions. Methods: This is a prospective cohort study including patients ≥65 years old admitted to an SCU for 12 months. We collected demographics, comprehensive geriatric assessments, and presence of dementia and delirium at admission. Outcomes included discharge to previous living situation, mortality, and functional evolution. Due to the high prevalence of dementia, a subgroup analysis was performed to investigate specific risk factors for delirium and related outcomes. Results: Of 909 patients (mean age [±SD] 85.8 ± 6.7; 60% women, 47.5% with dementia), 352 (38.7%) developed delirium. The main risk factor for delirium was dementia (HR [95% CI] 5.2 [3.5–7.7]); age, functional status, and urinary tract infections were also independently associated with delirium. In dementia patients, only age (HR [95% CI] 1.0 [1.004–1.1]) and being male (HR [95% CI] 1.7 [1.04–2.6]) were associated with delirium. Delirium was associated with greater mortality (10.8 vs. 3.9%; p < 0.001) and greater functional decline in the entire sample (–12.3 vs. –6.4 Barthel index points; p < 0.001). In the dementia subgroup, patients with delirium experienced greater functional loss (p = 0.013) and less functional recovery (p = 0.025). Conclusions: In older patients admitted to postacute care, dementia is the main risk factor for delirium, and delirium carries worse clinical and functional outcomes. In patients with dementia, delirium is also relevant, since it entails a functional loss at admission and lower functional recovery.
Association of Novel ALX4 Gene Polymorphisms with Antidepressant Treatment Response: Findings from the CO-MED Trial
Authors: Gadad Bharathi S. , Raj Prithvi , Jha Manish K. , Carmody Thomas , Dozmorov Igor , Mayes Taryn L. , Wakeland Edward K. , Trivedi Madhukar H.
Published: May 2018

Genome-wide association studies (GWAS) were conducted in participants of the CO-MED (Combining Medications to Enhance Depression Outcomes) trial, a randomized, 3-treatment arm clinical trial of major depressive disorder (MDD) designed to identify markers of differential treatment outcome (response and remission). The QIDS-SR (Quick Inventory of Depressive Symptomatology, Self-Reported version) was used to measure response at week 6 (QIDS-SR ≤5) and remission at week 12 (QIDS-SR ≤6 and ≤8 at the last two study visits). Three treatment groups (escitalopram monotherapy, escitalopram + bupropion, and venlafaxine + mirtazapine) were evaluated. GWAS identified a potentially regulatory SNP rs10769025 in the ALX4 gene on chromosome 11 with a strong association (p value = 9.85925E–08) with response to escitalopram monotherapy in Caucasians. Further, haplotype analysis on 7 ALX4 variants showed that a regulatory haplotype CAAACTG was significantly associated (odds ratio = 3.4, p = 2.00E–04) with response to escitalopram monotherapy at week 6. Ingenuity pathway analyses in the present study suggest that ALX4 has an indirect connection with antidepressant gene pathways in MDD, which may account for the genetic association with treatment outcome. Functional genomics studies to investigate the role of ALX4 in antidepressant treatment outcome will be an interesting future direction.
A Multimodal Approach to the Treatment of Intraparenchymal Meningioma in a 7-Year-Old Boy: A Case Report
Authors: Vescovi Maria Caterina , Bagatto Daniele , Capo Gabriele , Maieron Marta , Marin Dario , Pegolo Enrico , Tomasino Barbara
Published: May 2018

Intraparenchymal meningiomas are very rare: only 26 cases have been diagnosed in patients younger than 20 years since 1954. They can lead to preoperative differential diagnosis mistakes due to their atypical neuroimaging appearance. A multimodal approach is thus necessary to plan a surgical procedure aiming to receive the best extent of resection while preserving the patient’s functional integrity. The authors report the case of a 7-year-old boy with a history of blurred vision, left eye deviation, and weakness on the left side of his body. Magnetic resonance imaging (MRI) revealed an intra-axial, cortical, right parietal lesion without dural attachment. MR spectroscopy and perfusion study were obtained. Since the patient was 100% left-handed, functional MRI, diffusion tensor imaging, and neuropsychological evaluation were performed before the surgical procedure. Histopathological analysis revealed the mass to be an atypical meningioma (WHO grade II). Postoperative MRI indicated complete macroscopic lesion removal. The postsurgical neuropsychological profile was not different from the profile before surgery. The boy was discharged 3 days after the surgical operation without any neurological deficits.
Epicardial Fat Thickness in Patients with Autosomal Dominant Polycystic Kidney Disease
Authors: Concistrè Antonio , Petramala Luigi , Scoccia Gianmarco , Sciomer Susanna , Bisogni Valeria , Saracino Vincenza , Iannucci Gino , Lai Silvia , Mastroluca Daniela , Iacobellis Gianluca , Letizia Claudio
Published: May 2018

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is associated with early organ damage such as left ventricular hypertrophy and higher cardiovascular risk when compared to essential hypertension (EH). Epicardial adipose tissue (EAT) is a new cardiovascular risk factor, but its role and correlation with left ventricular mass (LVM) in ADPKD is unknown. Aims: we sought to investigate whether EAT is higher and related to LVM indexed by body surface area (LVMi) in hypertensive patients with ADPKD compared to those with EH. Methods: We performed ultrasound measurement of EAT thickness, LVM, LVMi, and left atrium size (left atrial volume indexed for body surface, LAVI) in 41 consecutive hypertensive patients with ADPKD, compared to 89 EH patients. Results: EAT was significantly higher in the ADPKD group in comparison to EH subjects (9.2 ± 2.9 mm vs. 7.8 ± 1.6 mm, p < 0.001), and significantly correlated with LVM, LVMi, and LAVI in the ADPKD group (r = 0.56, p = 0.005; r = 0.424, p = 0.022; and r = 0.48, p = < 0.001, respectively). Comparing EAT against body mass index, systolic blood pressure, and age, we found that EAT was the strongest predictor of LVMi (β = 0.42, p = 0.007). Conclusion: Our data showed that EAT was higher in ADPKD patients than in EH subjects and independently correlated with LVMi. EAT measurement can be a useful marker for the cardiovascular risk stratification in ADPKD.
Unhealthy Stem Cells: When Health Conditions Upset Stem Cell Properties
Authors: Pérez Laura M. , de Lucas Beatriz , Gálvez Beatriz G.
Published: May 2018

The stem cell field has grown very rapidly during the last decade, offering the promise of innovative therapies to treat disease. Different stem cell populations have been isolated from various human adult tissues, mainly from bone marrow and adipose tissue, but many other body tissues harbor a stem cell population. Adult tissue stem cells are invariably found in discrete microenvironments termed niches, where they play key roles in tissue homeostasis by enabling lifelong optimization of organ form and function. Some diseases are known to strike at the stem cell population, through alterations in their specific microenvironments, making them non-viable. Furthermore, it has been shown that a transformed stem cell population could prompt the development of certain cancers. This review focuses on the potential negative aspects of a range of diseases on the activity of stem cells and how their potential use in cell therapies may be affected.
CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation
Authors: Park Dae-Ryoung , Nam Tae-Sik , Kim Ye-Won , Lee Seo-Ho , Kim Uh-Hyun
Published: May 2018

Background/Aims: Cyclic ADP-ribose (cADPR) is a Ca2+ -mobilization messenger that acts on ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum (SR) Ca2+ stores. Moreover, it has been proposed that cADPR serves an additional role in activating the sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA) pump. The aim of this study was to determine the exact mechanism by which cADPR regulates SR Ca2+ stores in physiologically relevant systems. Methods: We analyzed Ca2+ signals as well as the production of Ca2+ mobilizing messengers in the skeletal muscle cells of mice subjected to intensive exercise or in the SR fractions from skeletal muscle cells after β-adrenergic receptor (β-AR) stimulation. Results: We show that cADPR enhances SERCA activity in skeletal muscle cells in response to β-AR agonists, increasing SR Ca2+ uptake. We demonstrate that cADPR is generated by CD38, a cADPR-synthesizing enzyme, increasing muscle Ca2+ signals and contractile force during exercise. CD38 is upregulated by the cAMP response element–binding protein (CREB) transcription factor upon β-AR stimuli and exercise. CD38 knockout (KO) mice show defects in their exercise and cADPR synthesis capabilities, lacking a β-AR agonist-induced muscle contraction when compared to wild-type mice. The skeletal muscle of CD38 KO mice exhibits delayed cytosolic Ca2+ clearance and reduced SERCA activity upon exercise. Conclusion: These findings provide insight into the physiological adaptive mechanism by which the CD38- cADPR-SERCA signaling axis plays an essential role in muscle contraction under exercise, and define cADPR as an endogenous activator of SERCA in enhancing the SR Ca2+ load.
The Mechanism of Action of Zingerone in the Pacemaker Potentials of Interstitial Cells of Cajal Isolated from Murine Small Intestine
Authors: Kim Jung Nam , Kim Hyun Jung , Kim Iksung , Kim Yun Tai , Kim Byung Joo
Published: May 2018

Background/Aims: Zingerone, a major component found in ginger root, is clinically effective for the treatment of various diseases. Interstitial cells of Cajal (ICCs) are the pacemaker cells responsible for slow waves in the gastrointestinal (GI) tract. We investigated the effects of zingerone on the pacemaker potentials of ICCs to assess its mechanisms of action and its potential as a treatment for GI tract motility disorder. Methods: We isolated ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record the pacemaker potentials in cultured ICCs. Results: Under the current clamping mode, zingerone inhibited pacemaker potentials of ICCs concentration-dependently. These effects were blocked not by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) channel blocker, but by glibenclamide, a specific ATP-sensitive K+ channel blocker. Pretreatment with SQ-22536 (an adenylate cyclase inhibitor), LY294002 (a phosphoinositide 3-kinase inhibitor), and calphostin C (a protein kinase C (PKC) inhibitor) did not block the effects of zingerone on the pacemaker potentials relative to treatment with zingerone alone. However, zingerone-induced pacemaker potential inhibition was blocked by 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; a guanylate cyclase inhibitor), KT5823 (a protein kinase G (PKG) inhibitor), and L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor). In addition, zingerone stimulated cyclic guanosine monophosphate (cGMP) production in ICCs. Finally, pretreatment with PD98059 (a p42/44 mitogen-activated protein kinase (MAPK) inhibitor), SB203580 (a p38 MAPK inhibitor), and SP600125 (c–Jun N–terminal kinases (JNK)–specific inhibitor) blocked the zingerone-induced pacemaker potential inhibition. Conclusion: These results suggest that zingerone concentration-dependently inhibits pacemaker potentials of ICCs via NO/cGMP-dependent ATP-sensitive K+ channels through MAPK-dependent pathways. Taken together, this study shows that zingerone may have the potential for development as a GI regulation agent.
Better Renal Resistive Index Profile in Subjects with Beta Thalassemia Minor
Authors: Basut Fahrettin , Keşkek Şakir Özgür , Gülek Bozkurt
Published: May 2018

Objective: Beta thalassaemia minor is a common genetic disorder without any characteristic symptoms except mild anemia. It is found to be associated with some cardiovascular risk factors such as insulin resistance and diabetes mellitus. The renal resistive index (RRI) is a measure of renal arterial resistance to blood flow. The aim of this study was to evaluate the RRI in subjects with beta thalassemia minor (BTM). Subjects and Methods: A total of 253 subjects were included in this cross-sectional study. The study group consisted of 148 subjects with BTM and the control group consisted of 105 healthy subjects. BTM was diagnosed by a complete blood count and hemoglobin electrophoresis. Blood pressure measurement and biochemical tests were performed. The RRI of all subjects was measured using renal Doppler ultrasonography. Results: Subjects with BTM had lower renal resistive indices compared to healthy subjects (0.58 ± 0.04 vs. 0.60 ± 0.06, p = 0.0016). Additionally, the RRI levels of subjects with BTM were correlated with systolic blood pressure (p = 0.017, r = 0.194). Conclusion: In this study, lower RRI were found in subjects with BTM. This may be associated with a decreased vascular resistance and blood viscosity in these subjects.
Modulation of LIN28B/Let-7 Signaling by Propranolol Contributes to Infantile Hemangioma Involution
Authors: Mong Ezinne Francess , Akat Kemal Marc , Canfield John , Lockhart John , VanWye Jeffrey , Matar Andrew , Tsibris John C.M. , Wu June K. , Tuschl Thomas , Totary-Jain Hana
Published: May 2018

Objective—

Infantile hemangiomas (IHs) are the most common benign vascular neoplasms of infancy, characterized by a rapid growth phase followed by a spontaneous involution, or triggered by propranolol treatment by poorly understood mechanisms. LIN28/let-7 axis plays a central role in the regulation of stem cell self-renewal and tumorigenesis. However, the role of LIN28B/let-7 signaling in IH pathogenesis has not yet been elucidated.

Approach and Results—

LIN28B is highly expressed in proliferative IH and is less expressed in involuted and in propranolol-treated IH samples as measured by immunofluorescence staining and quantitative RT-PCR. Small RNA sequencing analysis of IH samples revealed a decrease in microRNAs that target LIN28B, including let-7, and an increase in microRNAs in the mir-498(46) cistron. Overexpression of LIN28B in HEK293 cells induced the expression of miR-516b in the mir-498(46) cistron. Propranolol treatment of induced pluripotent stem cells, which express mir-498(46) endogenously, reduced the expression of both LIN28B and mir-498(46) and increased the expression of let-7. Furthermore, propranolol treatment reduced the proliferation of induced pluripotent stem cells and induced epithelial–mesenchymal transition.

Conclusions—

This work uncovers the role of the LIN28B/let-7 switch in IH pathogenesis and provides a novel mechanism by which propranolol induces IH involution. Furthermore, it provides therapeutic implications for cancers in which the LIN28/let-7 pathway is imbalanced.
Progression of White Matter Hyperintensities Preceded by Heterogeneous Decline of Microstructural Integrity
Authors: van Leijsen Esther M.C. , Bergkamp Mayra I. , van Uden Ingeborg W.M. , Ghafoorian Mohsen , van der Holst Helena M. , Norris David G. , Platel Bram , Tuladhar Anil M. , de Leeuw Frank-Erik
Published: May 2018

Background and Purpose—

White matter hyperintensities (WMH) are frequently seen on neuroimaging of elderly and are associated with cognitive decline and the development of dementia. Yet, the temporal dynamics of conversion of normal-appearing white matter (NAWM) into WMH remains unknown. We examined whether and when progression of WMH was preceded by changes in fluid-attenuated inversion recovery and diffusion tensor imaging values, thereby taking into account differences between participants with mild versus severe baseline WMH.

Methods—

From 266 participants of the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort), we semiautomatically segmented WMH at 3 time points for 9 years. Images were registered to standard space through a subject template. We analyzed differences in baseline fluid-attenuated inversion recovery, fractional anisotropy, and mean diffusivity (MD) values and changes in MD values over time between 4 regions: (1) remaining NAWM, (2) NAWM converting into WMH in the second follow-up period, (3) NAWM converting into WMH in the first follow-up period, and (4) WMH.

Results—

NAWM converting into WMH in the first or second time interval showed higher fluid-attenuated inversion recovery and MD values than remaining NAWM. MD values in NAWM converting into WMH in the first time interval were similar to MD values in WMH. When stratified by baseline WMH severity, participants with severe WMH had higher fluid-attenuated inversion recovery and MD and lower fractional anisotropy values than participants with mild WMH, in all areas including the NAWM. MD values in WMH and in NAWM that converted into WMH continuously increased over time.

Conclusions—

Impaired microstructural integrity preceded conversion into WMH and continuously declined over time, suggesting a continuous disease process of white matter integrity loss that can be detected using diffusion tensor imaging even years before WMH become visible on conventional neuroimaging. Differences in microstructural integrity between participants with mild versus severe WMH suggest heterogeneity of both NAWM and WMH, which might explain the clinical variability observed in patients with similar small vessel disease severity.
the early history of weather modification
Authors: Schaefer Vincent J.
Published: May 2018

Since ancient times man has dreamed of manipulating the weather to his advantage. His efforts to this end have ranged from drawing pictographs, lighting ceremonial fires, participating in rain dances and then during the past twenty-one years in directing his attention toward utilizing certain scientific relationships to initiate physical and chemical reactions in the atmosphere.

There are certain of these reactions which can be demonstrated in both the laboratory and the field. They are spectacular to see, are fairly well understood from the scientific viewpoint and can be used to produce definite and predictable reactions.

There no longer is any question that it is quite feasible to modify supercooled clouds wherever they occur. There is still much uncertainty as to subsequent developments which may occur due to such actions especially in unstable cloud systems. Unlike supercooled fogs and stratus clouds where the seeding results may be photographed and quantitatively measured, these less stable systems involving convection, convergence and divergence of moist and dry air are difficult systems to evaluate.

This paper reviews briefly certain aspects of weather control prior to 1946 and then attempts to provide an accurate historical chronology of the significant advances which occurred during the early period of this new phase of atmospheric science.

The control of the weather within our global atmosphere has been a dream of man for many centuries. In its earliest phases this ambition was limited to the rain needed for a tiny patch of corn or some similar local and immediate need. As man's knowledge of the atmosphere increased and his needs became more urgent and widespread, his approach to such problems were increasingly directed toward a scientific consideration of the possibilities as well as limitations of changing atmospheric processes.

Prior to 1946, all of the proposals advanced toward doing something about modifying atmospheric processes failed to consider the massive nature of the atmosphere and the need to depend on triggering mechanisms to utilize the latent energy which develops from some of the physical reactions and interactions which occur in clear and cloudy skies.
the Yuba City flood: a case study of weather modification litigation*
Authors: Mann Dean E.
Published: May 2018

In December 1955 a severe tropical storm caused severe flooding throughout Northern California with damage exceeding $200,000,000. One area suffering large-scale flooding was at Yuba City, at the confluence of the Feather and Yuba Rivers. The levees broke and consequent damage was in the magnitude of $65 million. Property-owners sought recompense through suits brought in the Superior Court of Sutter County against the State of California, Pacific Gas and Electric Company (PG&E), and North American Weather Consultants (NAWC).

PG&E, through its contracting agent, NAWC, had undertaken cloud seeding operations in three places in the high Sierras, one of which was in the Lake Almanor water-shed in the Feather River system. NAWC had interrupted seeding activities in that area three days before the levees broke at Yuba City. Plaintiffs charged that PG&E and NAWC were negligent in the operation of their generators, had contributed to the total quantity of water produced by the watershed and therefore were legally liable, and that cloud seeding was ultra-hazardous activity so that those engaged in such activities were strictly liable for damages.

The suit was begun in 1958 and concluded in 1964. Trial before a judge only began in October 1963 and a decision was rendered in April 1964. The judge ruled that neither PG&E nor NAWC was liable. In accordance with an agreement among the parties no appeal was taken. Plaintiffs were successful, however, against the State, basing their claim for damages on the doctrine of inverse condemnation which holds that the State must recompense for damages incurred in the lawful exercise of its powers—in this case, the construction of levees.

The litigation raises important questions of public policy with regard to weather modification and these are considered in the light of this case.
problems and promises of deterministic extended range forecasting1
Authors: Smagorinsky Joseph
Published: May 2018

The past 20 years have encompassed remarkable scientific and technical advances in the atmospheric and oceanic sciences which herald a new era for deterministically predicting atmospheric behavior. Many of the key innovations were directly influenced, if not originated by Harry Wexler during his very productive career. This paper will deal with a critique of recent progress in modelling the atmosphere-ocean system, some of the newly exposed problems, and the needs and expectations for the future.