bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute high-fat diet upregulates glutamatergic signaling in the dorsal motor nucleus of the vagus
Authors: Clyburn Courtney , Travagli R. Alberto , Browning Kirsteen N.
Published: January 2018

Obesity is associated with dysregulation of vagal neurocircuits controlling gastric functions, including food intake and energy balance. In the short term, however, caloric intake is regulated homeostatically although the precise mechanisms responsible are unknown. The present study examined the effects of acute high-fat diet (HFD) on glutamatergic neurotransmission within central vagal neurocircuits and its effects on gastric motility. Sprague-Dawley rats were fed a control or HFD diet (14% or 60% kcal from fat, respectively) for 3–5 days. Whole cell patch-clamp recordings and brainstem application of antagonists were used to assess the effects of acute HFD on glutamatergic transmission to dorsal motor nucleus of the vagus (DMV) neurons and subsequent alterations in gastric tone and motility. After becoming hyperphagic initially, caloric balance was restored after 3 days following HFD exposure. In control rats, the non- N-methyl-d-aspartate (NMDA) receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), but not the NMDA receptor antagonist, amino-5-phosphonopentanoate (AP5), significantly decreased excitatory synaptic currents and action potential firing rate in gastric-projecting DMV neurons. In contrast, both AP5 and DNQX decreased excitatory synaptic transmission and action potential firing in acute HFD neurons. When microinjected into the brainstem, AP5, but not DNQX, decreased gastric motility and tone in acute HFD rats only. These results suggest that acute HFD upregulates NMDA receptor-mediated currents, increasing DMV neuronal excitability and activating the vagal efferent cholinergic pathway, thus increasing gastric tone and motility. Although such neuroplasticity may be a persistent adaptation to the initial exposure to HFD, it may also be an important mechanism in homeostatic regulation of energy balance.

NEW & NOTEWORTHY Vagal neurocircuits are critical to the regulation of gastric functions, including satiation and food intake. Acute high-fat diet upregulates glutamatergic signaling within central vagal neurocircuits via activation of N-methyl-d-aspartate receptors, increasing vagal efferent drive to the stomach. Although it is possible that such neuroplasticity is a persistent adaptation to initial exposure to the high-fat diet, it may also play a role in the homeostatic control of feeding.
Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier
Authors: Zhou Ting , Yu Zhihong , Jian Ming-Yuan , Ahmad Israr , Trempus Carol , Wagener Brant M. , Pittet Jean-Francois , Aggarwal Saurabh , Garantziotis Stavros , Song Weifeng , Matalon Sadis
Published: January 2018

Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO−/−) mice, and CD44 gene-deficient (CD44−/−) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44−/− resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO−/− mice. Isolated perfused lungs of HCl instilled WT but not of CD44−/− mice had elevated values of the filtration coefficient ( Kf). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( RT). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of Kf and RT, as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.
Aurothioglucose does not improve alveolarization or elicit sustained Nrf2 activation in C57BL/6 models of bronchopulmonary dysplasia
Authors: Li Qian , Li Rui , Wall Stephanie B. , Dunigan Katelyn , Ren Changchun , Jilling Tamas , Rogers Lynette K. , Tipple Trent E.
Published: January 2018

We previously showed that the thioredoxin reductase-1 (TrxR1) inhibitor aurothioglucose (ATG) improves alveolarization in hyperoxia-exposed newborn C3H/HeN mice. Our data supported a mechanism by which the protective effects of ATG are mediated via sustained nuclear factor E2-related factor 2 (Nrf2) activation in hyperoxia-exposed C3H/HeN mice 72 h after ATG administration. Given that inbred mouse strains have differential sensitivity and endogenous Nrf2 activation by hyperoxia, the present studies utilized two C57BL/6 exposure models to evaluate the effects of ATG on lung development and Nrf2 activation. The first model (0–14 days) was used in our C3H/HeN studies and the 2nd model (4–14 days) is well characterized in C57BL/6 mice. ATG significantly inhibited lung TrxR1 activity in both models; however, there was no effect on parameters of alveolarization in C57BL/6 mice. In sharp contrast to C3H/HeN mice, there was no effect of ATG on pulmonary NADPH quinone oxidoreductase-1 ( Nqo1) and heme oxygenase-1 ( Hmox1) at 72 h in either C57BL/6 model. In conclusion, although ATG inhibited TrxR1 activity in the lungs of newborn C57BL/6 mice, effects on lung development and sustained Nrf2-dependent pulmonary responses were blunted. These findings also highlight the importance of strain-dependent hyperoxic sensitivity in evaluation of potential novel therapies.
Organ-level right ventricular dysfunction with preserved Frank-Starling mechanism in a mouse model of pulmonary arterial hypertension
Authors: Wang Zhijie , Patel Jitandrakumar R. , Schreier David A. , Hacker Timothy A. , Moss Richard L. , Chesler Naomi C.
Published: January 2018

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is due to right ventricular (RV) failure. It is unclear whether RV dysfunction initiates at the organ level or the subcellular level or both. We hypothesized that chronic pressure overload-induced RV dysfunction begins at the organ level with preserved Frank-Starling mechanism in myocytes. To test this hypothesis, we induced PAH with Sugen + hypoxia (HySu) in mice and measured RV whole organ and subcellular functional changes by in vivo pressure-volume measurements and in vitro trabeculae length-tension measurements, respectively, at multiple time points for up to 56 days. We observed progressive changes in RV function at the organ level: in contrast to early PAH (14-day HySu), in late PAH (56-day HySu) ejection fraction and ventricular-vascular coupling were decreased. At the subcellular level, direct measurements of myofilament contraction showed that RV contractile force was similarly increased at any stage of PAH development. Moreover, cross-bridge kinetics were not changed and length dependence of force development (Frank-Starling relation) were not different from baseline in any PAH group. Histological examinations confirmed increased cardiomyocyte cross-sectional area and decreased von Willebrand factor expression in RVs with PAH. In summary, RV dysfunction developed at the organ level with preserved Frank-Starling mechanism in myofilaments, and these results provide novel insight into the development of RV dysfunction, which is critical to understanding the mechanisms of RV failure.

NEW & NOTEWORTHY A multiscale investigation of pulmonary artery pressure overload in mice showed time-dependent organ-level right ventricular (RV) dysfunction with preserved Frank-Starling relations in myofilaments. Our findings provide novel insight into the development of RV dysfunction, which is critical to understanding mechanisms of RV failure.
Reflex bronchoconstriction evoked by inhaled nicotine aerosol in guinea pigs: role of the nicotinic acetylcholine receptor
Authors: Lee L.-Y. , Lin R.-L. , Khosravi M. , Xu F.
Published: January 2018

Inhaled cigarette smoke stimulated vagal bronchopulmonary C fibers via an action of nicotine on neuronal nicotinic acetylcholine receptor (nAChR). Recent studies have reported that nicotine at high concentrations can also activate the transient receptor potential ankyrin 1 receptor (TRPA1) expressed in these sensory nerves. This study was performed to characterize the airway response to inhaled nicotine aerosol and to investigate the relative roles of nAChR and TRPA1 in this response. Guinea pigs were anesthetized and mechanically ventilated; one tidal volume of nicotine aerosol (2% solution) was diluted by an equal volume of air and delivered directly into the lung via a tracheal cannula in a single breath. Our results showed the following: 1) Inhalation of nicotine aerosol triggered an immediate and pronounced bronchoconstriction; the increase in total pulmonary resistance reached a peak of 588 ± 205% (mean ± SE) in 10–40 s, which gradually returned to baseline after 1–5 min. 2) Pretreatment with either atropine (iv) or mecamylamine (aerosol) almost completely abolished the nicotine-induced bronchoconstriction; the mecamylamine pretreatment did not block the bronchoconstriction and bradycardia evoked by electrical stimulation of the distal end of one sectioned vagus nerve, indicating its minimal systemic effects. 3) Pretreatment with HC-030031, a selective TRPA1 antagonist, abolished the bronchoconstriction induced by allyl isothiocyanate, a selective TRPA1 agonist, but did not attenuate the nicotine-evoked bronchoconstriction. In conclusion, inhalation of a single breath of nicotine aerosol evoked acute bronchoconstriction mediated through the cholinergic reflex pathway. This reflex response was triggered by activation of nAChR, but not TRPA1, located in airway sensory nerves.

NEW & NOTEWORTHY Recent reports revealed that nicotine at high concentration activated transient receptor potential ankyrin 1 receptor (TRPA1) expressed in vagal bronchopulmonary sensory nerves. This study showed that inhalation of a single breath of nicotine aerosol consistently evoked acute bronchoconstriction that was mediated through the cholinergic reflex pathway and triggered by activation of nicotinic acetylcholine receptor, but not TRPA1, located in these nerves. This is new and important information considering the recent rapid and alarming rise in the prevalence of e-cigarette use for nicotine inhalation.
The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells
Authors: Man Y. K. Stella , Davies James A. , Coughlan Lynda , Pantelidou Constantia , Blázquez-Moreno Alfonso , Marshall John F. , Parker Alan L. , Halldén Gunnel
Published: January 2018

Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the αvβ6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, AdΔΔ, to selectively target αvβ6 integrins to facilitate systemic delivery. Structural modifications to AdΔΔ include the expression of the small but potent αvβ6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3Δ-A20T, infected and killed αvβ6 integrin–expressing cells more effectively than the parental wild-type (Ad5wt) virus and AdΔΔ. Viral uptake through αvβ6 integrins rather than native viral receptors (CAR, αvβ3 and αvβ5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3Δ-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3Δ-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3Δ-A20T is highly selective for αvβ6 integrin–expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients. Mol Cancer Ther; 17(2); 575–87. ©2018 AACR.
Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer
Authors: Annala Matti , Vandekerkhove Gillian , Khalaf Daniel , Taavitsainen Sinja , Beja Kevin , Warner Evan W. , Sunderland Katherine , Kollmannsberger Christian , Eigl Bernhard J. , Finch Daygen , Oja Conrad D. , Vergidis Joanna , Zulfiqar Muhammad , Azad Arun A. , Nykter Matti , Gleave Martin E. , Wyatt Alexander W. , Chi Kim N.
Published: January 2018

Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.

Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444–57. ©2018 AACR.

See related commentary by Jayaram et al., p. 392.

This article is highlighted in the In This Issue feature, p. 371
Hidradenitis Suppurativa: An Asian Perspective from a Singaporean Institute
Authors: Choi Ellie , Cook Alex R. , Chandran Nisha Suyien
Published: January 2018

Background: Demographic studies of hidradenitis suppurativa (HS) in Western countries have found an association with the female gender and with co-morbidities, such as the metabolic syndrome. There are few studies in an Asian context. Objective: This study examines the characteristics of HS at a Singaporean institute and compares them to those of existing studies in the West. Methods: We report a series of 58 patients with HS seen at the University Dermatological Clinic, National University Hospital, Singapore, over a 13-year period between January 2004 and December 2016. Results: Of 58 patients, 34 were male (58.6%). The axilla was the most common site affected, followed by the groin and buttocks. We did not find significant differences in disease characteristics between males and females, such as disease severity or location of disease. Metabolic co-morbidities were common, although paediatric-onset HS patients were less likely to be overweight, obese or smokers. Conclusion: The higher proportion of male HS patients in our cohort compared to the West may reflect differences in the prevalence of obesity and smoking in the 2 populations. Metabolic co-morbidities were similarly prevalent in both adult and paediatric HS patients. These findings offer insight into the factors influencing the development of HS.
Integrated 68Gallium Labelled Prostate-Specific Membrane Antigen-11 Positron Emission Tomography/Magnetic Resonance Imaging Enhances Discriminatory Power of Multi-Parametric Prostate Magnetic Resonance Imaging
Authors: Al-Bayati Mohammad , Grueneisen Johannes , Lütje Susanne , Sawicki Lino M. , Suntharalingam Saravanabavaan , Tschirdewahn Stephan , Forsting Michael , Rübben Herbert , Herrmann Ken , Umutlu Lale , Wetter Axel
Published: January 2018

Purpose: To evaluate diagnostic accuracy of integrated 68Gallium labelled prostate-specific membrane antigen (68Ga-PSMA)-11 positron emission tomography (PET)/MRI in patients with primary prostate cancer (PCa) as compared to multi-parametric MRI. Material and Methods: A total of 22 patients with recently diagnosed primary PCa underwent clinically indicated 68Ga-PSMA-11 PET/CT for initial staging followed by integrated 68Ga-PSMA-11 PET/MRI. Images of multi-parametric magnetic resonance imaging (mpMRI), PET and PET/MRI were evaluated separately by applying Prostate Imaging Reporting and Data System (PIRADSv2) for mpMRI and a 5-point Likert scale for PET and PET/MRI. Results were compared with pathology reports of biopsy or resection. Statistical analyses including receiver operating characteristics analysis were performed to compare the diagnostic performance of mpMRI, PET and PET/MRI. Results: PET and integrated PET/MRI demonstrated a higher diagnostic accuracy than mpMRI (area under the curve: mpMRI: 0.679, PET and PET/MRI: 0.951). The proportion of equivocal results (PIRADS 3 and Likert 3) was considerably higher in mpMRI than in PET and PET/MRI. In a notable proportion of equivocal PIRADS results, PET led to a correct shift towards higher suspicion of malignancy and enabled correct lesion classification. Conclusion: Integrated 68Ga-PSMA-11 PET/MRI demonstrates higher diagnostic accuracy than mpMRI and is particularly valuable in tumours with equivocal results from PIRADS classification.
Congenital Malalignment of the Great Toenails: A Review
Authors: Catalfo Piera , Musumeci Maria Letizia , Lacarrubba Francesco , Dinotta Franco , Micali Giuseppe
Published: January 2018

Congenital malalignment of the great toenail is an under­estimated dystrophic disorder of unknown origin characterized by lateral deviation of the nail plates, which are not parallel to the major axis of the distal phalanx. It usually presents in infancy or childhood, while late onset is uncommon. Treatment depends on the degree of deviation. If minimal, a conservative and expectant attitude, based on prevention and treatment of possible complications, is recommended because of the possibility of spontaneous regression of the nail deviation. Surgical therapy may be considered in patients with severe or complicated forms.
Resveratrol Promotes Recovery of Hearing following Intense Noise Exposure by Enhancing Cochlear SIRT1 Activity
Authors: Xiong Hao , Ou Yongkang , Xu Yaodong , Huang Qiuhong , Pang Jiaqi , Lai Lan , Zheng Yiqing
Published: January 2018

The sirtuin SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase known to have protective effects against a wide range of neurological disorders. In the present study, we discovered that C57BL/6 mice fed a long-term diet supplemented with high-dose resveratrol exhibited increased cochlear SIRT1 activity and presented a better recovery of hearing and less loss of hair cells after intense noise exposure compared with those fed a standard chew. Moreover, resveratrol attenuated cochlear SIRT1 decrease and reduced oxidative stress in the cochlea after noise exposure. These results suggest a considerable therapeutic potential of resveratrol for the treatment of noise-induced hearing loss.
Direct Aspiration Catheter Fracture and Retrieval during Neurothrombectomy
Authors: Moshayedi Pouria , Jadhav Ashutosh P.
Published: January 2018

Background: Application of direct aspiration catheters has revolutionized acute stroke care and has led to significant improvement in clinical outcome with a good safety profile. Catheter fracture and retention is a rare but potentially devastating complication. Case Description: Here we present two cases of acute stroke complicated by aspiration catheter fracture and retention. Successful catheter retrieval and revascularization was achieved in both cases. The stenosis or tortuosity of vascular anatomy appears to be the probable contributor to catheter breakage by anchoring the catheter with resultant fracture at the constraint point from catheter withdrawal tensile stress. Conclusion: This report describes application of snare devices in retrieving a broken catheter during thrombectomy in the anterior and posterior circulation, and therefore presents a technique that can be safely utilized to address catheter breakage complicating thrombectomy in different vascular anatomic locations.
Artificial Intelligence for the Artificial Kidney: Pointers to the Future of a Personalized Hemodialysis Therapy
Authors: Hueso Miguel , Vellido Alfredo , Montero Nuria , Barbieri Carlo , Ramos Rosa , Angoso Manuel , Cruzado Josep Maria , Jonsson Anders
Published: January 2018

Background: Current dialysis devices are not able to react when unexpected changes occur during dialysis treatment or to learn about experience for therapy personalization. Furthermore, great efforts are dedicated to develop miniaturized artificial kidneys to achieve a continuous and personalized dialysis therapy, in order to improve the patient’s quality of life. These innovative dialysis devices will require a real-time monitoring of equipment alarms, dialysis parameters, and patient-related data to ensure patient safety and to allow instantaneous changes of the dialysis prescription for the assessment of their adequacy. The analysis and evaluation of the resulting large-scale data sets enters the realm of “big data” and will require real-time predictive models. These may come from the fields of machine learning and computational intelligence, both included in artificial intelligence, a branch of engineering involved with the creation of devices that simulate intelligent behavior. The incorporation of artificial intelligence should provide a fully new approach to data analysis, enabling future advances in personalized dialysis therapies. With the purpose to learn about the present and potential future impact on medicine from experts in artificial intelligence and machine learning, a scientific meeting was organized in the Hospital Universitari Bellvitge (L’Hospitalet, Barcelona). As an outcome of that meeting, the aim of this review is to investigate artificial intel ligence experiences on dialysis, with a focus on potential barriers, challenges, and prospects for future applications of these technologies. Summary and Key Messages: Artificial intelligence research on dialysis is still in an early stage, and the main challenge relies on interpretability and/or comprehensibility of data models when applied to decision making. Artificial neural networks and medical decision support systems have been used to make predictions about anemia, total body water, or intradialysis hypotension and are promising approaches for the prescription and monitoring of hemodialysis therapy. Current dialysis machines are continuously improving due to innovative technological developments, but patient safety is still a key challenge. Real-time monitoring systems, coupled with automatic instantaneous biofeedback, will allow changing dialysis prescriptions continuously. The integration of vital sign monitoring with dialysis parameters will produce large data sets that will require the use of data analysis techniques, possibly from the area of machine learning, in order to make better decisions and increase the safety of patients.
Prevention of Doxorubicin-Induced Renal Toxicity by Theanine in Rats
Authors: Nagai Katsuhito , Fukuno Shuhei , Otani Keisuke , Nagamine Yoshiki , Omotani Sachiko , Hatsuda Yasutoshi , Myotoku Michiaki , Konishi Hiroki
Published: January 2018

Doxorubicin (DOX) is a highly potent anti-neoplastic agent widely used in clinical practice, but its dosage and duration of administration are strictly limited due to dose-related organ damage. In the present study, we examined whether theanine, an amino acid derivative found in green tea leaves, can protect against DOX-induced acute nephrotoxicity in rats. Decreases in the creatinine clearance by DOX administration were attenuated by concurrent treatment with theanine, which was consistent with the change in histological renal images assessed by microscopic examination. Theanine had no effect on the distribution of DOX to the kidney. The production of lipid peroxide in the kidney after DOX administration was suppressed by concurrent treatment with theanine. Reduced glutathione content, but not superoxide dismutase activity, was decreased following DOX administration, whereas this change was suppressed when theanine was given in combination with DOX. These results suggest that theanine prevents DOX-induced acute nephrotoxicity through its antioxidant properties.
Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia–Reperfusion
Authors: Praetner Marc , Zuchtriegel Gabriele , Holzer Martin , Uhl Bernd , Schaubächer Johanna , Mittmann Laura , Fabritius Matthias , Fürst Robert , Zahler Stefan , Funken Dominik , Lerchenberger Maximilian , Khandoga Andrej , Kanse Sandip , Lauber Kirsten , Krombach Fritz , Reichel Christoph A.
Published: January 2018

Objective—

Ischemia–reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, and transplantation. In addition to its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated in the pathogenesis of I/R injury. The underlying mechanisms remain largely obscure.

Approach and Results—

Using different in vivo microscopy techniques as well as ex vivo analyses and in vitro assays, we identified that plasminogen activator inhibitor-1 rapidly accumulates on microvascular endothelial cells on I/R enabling this protease inhibitor to exhibit previously unrecognized functional properties by inducing an increase in the affinity of β2 integrins in intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor–related protein-1 and mitogen-activated protein kinase–dependent signaling pathways that initiate intravascular adherence of these immune cells to the microvascular endothelium. Subsequent to this process, extravasating neutrophils disrupt endothelial junctions and promote the postischemic microvascular leakage. Conversely, deficiency of plasminogen activator inhibitor-1 effectively reversed leukocyte infiltration, microvascular dysfunction, and tissue injury on experimental I/R without exhibiting side effects on microvascular hemostasis.

Conclusions—

Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury.
MTHFR
Gene and Serum Folate Interaction on Serum Homocysteine Lowering
Authors: Huang Xiao , Qin Xianhui , Yang Wenbin , Liu Lishun , Jiang Chongfei , Zhang Xianglin , Jiang Shanqun , Bao Huihui , Su Hai , Li Ping , He Mingli , Song Yun , Zhao Min , Yin Delu , Wang Yu , Zhang Yan , Li Jianping , Yang Renqang , Wu Yanqing , Hong Kui , Wu Qinhua , Chen Yundai , Sun Ningling , Li Xiaoying , Tang Genfu , Wang Binyan , Cai Yefeng , Hou Fan Fan , Huo Yong , Wang Hong , Wang Xiaobin , Cheng Xiaoshu
Published: January 2018

Objective—

This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)–lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (
MTHFR
) C677T genotypes and serum folate levels.

Approach and Results—

This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and
MTHFR
C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L;
P
=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by
MTHFR
genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes.

Conclusions—

Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual
MTHFR
C677T genotype and folate status.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00794885.
Hyporesponsiveness to Darbepoetin Alfa in Patients With Heart Failure and Anemia in the RED-HF Study (Reduction of Events by Darbepoetin Alfa in Heart Failure)
Authors: van der Meer Peter , Grote Beverborg Niels , Pfeffer Marc A. , Olson Kurt , Anand Inder S. , Westenbrink B. Daan , McMurray John J.V. , Swedberg Karl , Young James B. , Solomon Scott D. , van Veldhuisen Dirk J.
Published: January 2018

Background:

A poor response to erythropoiesis-stimulating agents such as darbepoetin alfa has been associated with adverse outcomes in patients with diabetes mellitus, chronic kidney disease, and anemia; whether this is also true in heart failure is unclear.

Methods and Results:

We performed a post hoc analysis of the RED-HF trial (Reduction of Events by Darbepoetin Alfa in Heart Failure), in which 1008 patients with systolic heart failure and anemia (hemoglobin level, 9.0–12.0 g/dL) were randomized to darbepoetin alfa. We examined the relationship between the hematopoietic response to darbepoetin alfa and the incidence of all-cause death or first heart failure hospitalization during a follow-up of 28 months. For the purposes of the present study, patients in the lowest quartile of hemoglobin change after 4 weeks were considered nonresponders. The median initial hemoglobin change in nonresponders (n=252) was −0.25 g/dL and +1.00 g/dL in the remainder of patients (n=756). Worse renal function, lower sodium levels, and less use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were independently associated with nonresponse. Although a low endogenous erythropoietin level helped to differentiate responders from nonresponders, its predictive value in a multivariable model was poor (C statistic=0.69). Nonresponders had a higher rate of all-cause death or first heart failure hospitalization (hazard ratio, 1.25; 95% confidence interval, 1.02–1.54) and a higher risk of all-cause mortality (hazard ratio, 1.30; 95% confidence interval, 1.04–1.63) than responders.

Conclusions:

A poor response to darbepoetin alfa was associated with worse outcomes in heart failure patients with anemia. Patients with a poor response were difficult to identify using clinical and biochemical biomarkers.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00358215.
Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling
Authors: Zhao Rong-Rong , Ackers-Johnson Matthew , Stenzig Justus , Chen Chen , Ding Tao , Zhou Yue , Wang Peipei , Ng Shi Ling , Li Peter Y. , Teo Gavin , Rudd Pauline M. , Fawcett James W. , Foo Roger S.Y.
Published: January 2018

Background:

Heart failure is a leading cause of mortality and morbidity, and the search for novel therapeutic approaches continues. In the monogenic disease mucopolysaccharidosis VI, loss-of-function mutations in arylsulfatase B lead to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans, manifesting as myriad cardiac symptoms. Here, we studied changes in myocardial CS in nonmucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling.

Methods:

Healthy and diseased human and rat left ventricles were subjected to histological and immunostaining methods to analyze glycosaminoglycan distribution. Glycosaminoglycans were extracted and analyzed for quantitative and compositional changes with Alcian blue assay and liquid chromatography–mass spectrometry. Expression changes in 20 CS-related genes were studied in 3 primary human cardiac cell types and THP-1–derived macrophages under each of 9 in vitro stimulatory conditions. In 2 rat models of pathological remodeling induced by transverse aortic constriction or isoprenaline infusion, recombinant human arylsulfatase B (rhASB), clinically used as enzyme replacement therapy in mucopolysaccharidosis VI, was administered intravenously for 7 or 5 weeks, respectively. Cardiac function, myocardial fibrosis, and inflammation were assessed by echocardiography and histology. CS-interacting molecules were assessed with surface plasmon resonance, and a mechanism of action was verified in vitro.

Results:

Failing human hearts displayed significant perivascular and interstitial CS accumulation, particularly in regions of intense fibrosis. Relative composition of CS disaccharides remained unchanged. Transforming growth factor–β induced CS upregulation in cardiac fibroblasts. CS accumulation was also observed in both the pressure-overload and the isoprenaline models of pathological remodeling in rats. Early treatment with rhASB in the transverse aortic constriction model and delayed treatment in the isoprenaline model proved rhASB to be effective at preventing cardiac deterioration and augmenting functional recovery. Functional improvement was accompanied by reduced myocardial inflammation and overall fibrosis. Tumor necrosis factor–α was identified as a direct binding partner of CS glycosaminoglycan chains, and rhASB reduced tumor necrosis factor–α—induced inflammatory gene activation in vitro in endothelial cells and macrophages.

Conclusions:

CS glycosaminoglycans accumulate during cardiac pathological remodeling and mediate myocardial inflammation and fibrosis. rhASB targets CS effectively as a novel therapeutic approach for the treatment of heart failure.
Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality After Pressure Overload Injury in Mice
Authors: Witsch Thilo , Martinod Kimberly , Sorvillo Nicoletta , Portier Irina , De Meyer Simon F. , Wagner Denisa D.
Published: January 2018

Background

A disintegrin‐like metalloproteinase with thrombospondin motif type 1 member 13 (ADAMTS13), the von Willebrand factor–cleaving enzyme, decreases leukocyte and platelet recruitment and, thus, reduces thrombosis and inflammation. Recombinant human ADAMTS13 (rhADAMTS13) is a novel drug candidate for ischemia/reperfusion injury and has shown short‐term benefits in mouse models of myocardial injury, but long‐term outcome has not been investigated.

Methods and Results

We evaluated the impact of rhADAMTS13 on cardiac remodeling, scarring, and contractile function, under chronic left ventricular pressure overload. The role of von Willebrand factor and the effect of rhADAMTS13 treatment were studied. This model of heart failure, based on ascending aortic constriction, produces a coronary inflammatory response and microvascular dysfunction, resulting in fibrotic remodeling and cardiac failure. Mice were treated with either rhADAMTS13 or vehicle and assessed for coronary vascular inflammation and ventricular function at several postsurgical time points, as well as for cardiac fibrosis after 4 weeks. Early upon induction of pressure overload under rhADAMTS13 treatment, we detected less endothelial‐lumen–associated von Willebrand factor, fewer platelet aggregates, and decreased activated transforming growth factor‐β1 levels than in vehicle‐treated mice. We observed significant preservation of cardiac function and decrease in fibrotic remodeling as a result of rhADAMTS13 administration.

Conclusions

Herein, we show that rhADAMTS13 decreases coronary vascular dysfunction and improves cardiac remodeling after left ventricular pressure overload in mice. We propose that this effect may, at least in part, be the result of decreased von Willebrand factor–mediated recruitment of platelets, a major source of the activated profibrotic cytokine transforming growth factor‐β1. Our study further supports the therapeutic potential of rhADAMTS13 for conditions characterized by inflammatory cardiac damage that results in fibrosis.
Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery
Authors: Meyers Eric C. , Solorzano Bleyda R. , James Justin , Ganzer Patrick D. , Lai Elaine S. , Rennaker Robert L. , Kilgard Michael P. , Hays Seth A.
Published: January 2018

Background and Purpose—

Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks.

Methods—

Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks.

Results—

VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery.

Conclusions—

This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.
Size of Ruptured Intracranial Aneurysms Is Decreasing
Authors: Korja Miikka , Kivisaari Riku , Rezai Jahromi Behnam , Lehto Hanna
Published: January 2018

Background and Purpose—

Decrease in the incidence of subarachnoid hemorrhage over the past decades has been related to decreased smoking rates, especially among <50-year-old people. We studied whether these epidemiological changes are reflected in changes in the size and location of ruptured intracranial aneurysms (RIAs).

Methods—

We identified consecutive patients admitted to a nonprofit academic hospital with saccular RIAs between 1989 and 2008. We averaged and analyzed mean sizes of RIAs in 4-year admission groups. In statistical analysis, we used the χ
2
test for categorical variables and the Kruskal–Wallis test to assess differences between continuous and categorical variables. For linear trend assessments, we used the linear-by-linear association and ANOVA tests.

Results—

Of 2660 consecutive patients (59% women) with RIAs, 1176 (44%) were <50 years on admission. In people <50 years, the averaged annual mean size of RIAs decreased 16% from 9.2 mm in 1989 to 1992 to 7.7 mm in 2005 to 2008 in women and 13% (from 9.3 to 8.1 mm) in men (decreasing linear trend;
P
=0.001). RIA sizes did not change in 50-year-old or older patients, whereas the proportion of posterior circulation RIAs almost tripled to 13%, also with a linear relationship (
P
<0.001).

Conclusions—

The size of RIAs seems to be decreasing among younger generations of hospital-admitted subarachnoid hemorrhage patients, whereas 50-year-old and older subarachnoid hemorrhage patients have an increasing proportion of posterior circulation RIAs. These epidemiological changes are noteworthy, especially if they are universal and ongoing.
The Institutional Approach for Modeling the Evolution of Human Societies
Authors: Powers Simon T.
Published: January 2018

Artificial life is concerned with understanding the dynamics of human societies. A defining feature of any society is its institutions. However, defining exactly what an institution is has proven difficult, with authors often talking past each other. This article presents a dynamic model of institutions, which views them as political game forms that generate the rules of a group's economic interactions. Unlike most prior work, the framework presented here allows for the construction of explicit models of the evolution of institutional rules. It takes account of the fact that group members are likely to try to create rules that benefit themselves. Following from this, it allows us to determine the conditions under which self-interested individuals will create institutional rules that support cooperation—for example, that prevent a tragedy of the commons. The article finishes with an example of how a model of the evolution of institutional rewards and punishments for promoting cooperation can be created. It is intended that this framework will allow artificial life researchers to examine how human groups can themselves create conditions for cooperation. This will help provide a better understanding of historical human social evolution, and facilitate the resolution of pressing societal social dilemmas.
A taxonomic revision of the genus Bacopa (Gratioleae, Plantaginaceae) in Argentina
Authors: SOSA MARÍA DE LAS MERCEDES , MORONI PABLO , O’LEARY NATALY
Published: January 2018

In the present work a revision of Bacopa for Argentina is presented. In this country the genus is integrated by twelve native taxa: eleven species and one variety. Full descriptions, along with distribution information, nomenclatural and taxonomical remarks and illustrations are provided. Two new synonyms are proposed, lectotypes are designated for the species and variety names: Bacopa congesta (second-step lectotype), B. congesta var. hirsuta, B. dubia, B. hassleriana, B. pedersenii, B. ranaria var. guaranitica, B. simulans, Bramia indica, Gratiola repens, Herpestis salzmannii, Herpestis tweedii (second-step lectotype), and a neotype is designated for Monniera rotundifolia.
Description of two new and two known species of the Genus Tylencholaimellus Cobb in M. V. Cobb, 1915 (Nematoda: Dorylaimida: Tylencholaimoidea)
Authors: AHMAD WASIM , AHAD SUMAYA
Published: January 2018

Two new and two known species of the dorylaimid nematode genus Tylencholaimellus Cobb in M.V. Cobb, 1915 are described and illustrated. Tylencholaimellus arabicus sp. n. collected from Saudi Arabia is characterized by having small sized body (L= 0.66–0.83 mm); outer cuticle with distinct transverse striations; inner layer thick with fine transverse striations; lip region offset by a deep constriction, inner liplets slightly raised; odontostyle 15–17 µm, odontophore 8–10 µm, combined length 25–26 μm; female genital system mono-opisthodelphic; anterior uterine sac 0.5–1.3 times midbody diameter in length; transverse vulva and short conoid tail Tylencholaimellus masakii sp. n. collected from Japan is characterized by having small sized body (L= 0.77–0.81 mm); lip region offset by a slight constriction; labial disc present; odontostyle 11–12 µm, odontophore 6–7 µm, combined length 18–18.5 μm; female genital system mono-opisthodelphic; anterior uterine sac 1.1–1.8 midbody diameter long; transverse vulva and rounded-conoid tail. Tylencholaimellus striatus Thorne, 1939 and T. projectus Siddiqi, 1964 are redescribed based on material collected from India. A diagnostic compendium of the genus Tylencholaimellus is also provided.
Molecular delineation of the Agave Red Worm Comadia redtenbacheri (Lepidoptera: Cossidae)
Authors: CÁRDENAS-AQUINO MARÍA DEL ROSARIO , ALARCÓN-RODRÍGUEZ NORMA MARINA , RIVAS-MEDRANO MARIO , GONZÁLEZ-HERNÁNDEZ HÉCTOR , VARGAS-HERNÁNDEZ MATEO , SÁNCHEZ-ARROYO HUSSEIN , LLANDERAL-CÁZARES CELINA
Published: January 2018

Comadia redtenbacheri (Hammerschmidt) (Agave Red Worm) is the only member of the family Cossidae that has been described as a phytophagous specialist of the plant genus Agave, which is mainly distributed in México. A new extraction protocol adapted from Stewart & Via (1993) has been implemented for sequencing the COI gene from samples collected in five states of the North Central (Querétaro and Zacatecas), South Central (Estado de México) and East Central (Hidalgo and Tlaxcala) regions of México with the purpose of contributing to delineation of the species. A Maximum Likelihood (ML) tree based on these COI sequences as well as COI sequences from other Cossinae species was developed to complement the existing morphological and taxonomic approaches to delineation of this species. As expected, our Comadia samples cluster together within a monophyletic clade that includes four C. redtenbacheri sequences previously reported. This group seems to be consistent with our reconstruction, which is supported by a bootstrap value of over 99%. The closely related branches associated with the latter group include organisms known to be the plant and tree borers of the Cossinae subfamily. The COI sequences from our samples were analyzed to determine the percentage of identity among the C. redtenbacheri in a first attempt to detect differences in the sequence that matches a particular region of México.
Redescription of Vieja hartwegi (Taylor & Miller 1980) (Teleostei: Cichlidae) from the Grijalva River basin, Mexico and Guatemala, with description of a rheophilic morph
Authors: GÓMEZ-GONZÁLEZ ADÁN E. , ÁLVAREZ FERNANDO , MATAMOROS WILFREDO A. , VELÁZQUEZ-VELÁZQUEZ ERNESTO , SCHMITTER-SOTO JUAN J. , GONZÁLEZ-DÍAZ ALFONSO A. , MCMAHAN CALEB D.
Published: January 2018

Vieja hartwegi was described by Taylor and Miller in 1980 based on 45 juvenile and sub-adult specimens, but this species shows an enormous variation in coloration patterns during ontogenic development and between individuals. Additionally, morphological data have demonstrated the existence of two forms in V. hartwegi: the typical morph of a moderately deep to slightly elongated body shape with midlateral band, and a rheophilic morph with an elongated to slightly deep body shape and lack of midlateral band. Herein we redescribe V. hartwegi adding adults and individuals from broad geographic ranges, as well as a rheophilic morph recently discovered in the upper reaches of the Grijalva River basin in Mexico. The set of characters include coloration, meristic, morphometric and osteological features. Vieja hartwegi is a polymorphic species whose forms may be segregating because of habitat preferences and food habits.