bluuebunny/crossref_metadata_2025 huggingface dataset:
Detrital zircons and sediment dispersal from the Coahuila terrane of northern Mexico into the Marathon foreland of the southern Midcontinent
Authors: Thomas William A. , Gehrels George E. , Lawton Timothy F. , Satterfield Joseph I. , Romero Mariah C. , Sundell Kurt E.
Published: June 2019

New analyses of U-Pb ages along with previously published analyses of detrital zircons from sandstones in the foreland of the Marathon orogen in west Texas have significant implications regarding provenance. The most prominent concentrations of U-Pb ages are at 1200–1000, 700–500, and 500–290 Ma. The accreted Coahuila terrane in the Marathon hinterland and nearby terranes with Gondwanan (Amazonia) affinity include Paleozoic volcanic and plutonic rocks, as well as Precambrian basement rocks. Late Paleozoic Las Delicias arc rocks have ages of 331–270 Ma. Detrital zircons from Upper Jurassic and Lower Cretaceous sandstones, which were deposited in local basins around the Coahuila terrane, provide a record of detritus available from proximal sources within Coahuila, including important peaks at 1040, 562, 422, 414, 373, and 282 Ma. Components of the detrital-zircon populations in the Marathon foreland have unique matches with primary and/or detrital sources in the Coahuila terrane. Although some components of the Marathon populations also have age matches in Laurentia (Appalachians), others do not; however, all components of the Marathon populations have potential sources in Coahuila. Analyses of εHft show generally more negative values in Amazonia than in Laurentia, and εHft values for Marathon sandstones have distributions similar to those in Amazonia. Therefore, the Coahuila terrane provides a provenance for all of the detrital-zircon ages in the Marathon foreland, requiring no mixing from other sources.
Unusual cause of airway obstruction: subglottic oncocytic cyst
Authors: Protts Faith Louise Mary Sibthorp , Goh Samantha
Published: June 2019

Oncocytic cysts are rare benign cystic lesions, which are usually seen in the supraglottic region. They usually present with symptoms of hoarse voice or the sensation of a lump in the throat. Management is with complete excision and follow-up to monitor for recurrence. In this unusual case, an elderly woman presenting with shortness of breath following recent treatment for pneumonia developed rapidly worsening stridor during admission. Flexible nasal endoscopy revealed a large pedunculated cystic lesion arising from the subglottic laryngeal mucosa. A tracheostomy was performed as an emergency and the lesion was then excised. Histology confirmed the diagnosis of a benign oncocytic cyst. Although oncocytic cysts are a recognised benign pathology of the supraglottic larynx, they should remain in the differential diagnosis for the subglottic larynx. Management is based on cases of supraglottic pathology, and we advise careful monitoring for this previously unreported pathology.
Open-label placebo clinical trials: is it the rationale, the interaction or the pill?
Authors: Blease Charlotte R , Bernstein Michael H. , Locher Cosima
Published: June 2019

National surveys of primary care physicians demonstrate that placebo use is prevalent. Against their widespread use, until recently, it was assumed among researchers that placebos must be deceptively prescribed for beneficial effects to be elicited. However, a new programme of research in placebo studies indicates that it may be possible to harness placebo effects in clinical practice via ethical, non-deceptively prescribed ‘open label placebos’ (‘OLPs’). To date, there have been 14 small scale clinical and experimental trials into OLPs. Results suggest therapeutic potential of these treatments for a range of conditions and symptoms. In this evidence-based Analysis we identify conceptual issues that, if not given due consideration, risk undermining research methodologies in OLP trials. Counterintuitively, owing to the nuances posed by placebo terminology, and the difficulties of designing placebos controls in OLP trials, we suggest that experimentalists reflect more deeply when formulating adequate comparison groups. Further research is needed to disentangle which specific components of OLPs are effective, such as: the rationale provided to participants; the quality of provider interaction; and/or the action of taking the pills. We conclude with recommendations for how researchers might take up the significant challenge of devising optimal placebo controls for OLP clinical trials. Although these issues are intricate, they are not merely academic: without due diligence to conceptual, and as a consequence, methodological considerations, OLP effect sizes may be over- or underestimated. We conclude that there may yet be potential to use OLPs in medical practice but clinical translation depends on rigorously controlled research.
Impact of mobile health applications on self-management in patients with type 2 diabetes mellitus: protocol of a systematic review
Authors: Bene Benard Ayaka , O’Connor Siobhan , Mastellos Nikolaos , Majeed Azeem , Fadahunsi Kayode Philip , O’Donoghue John
Published: June 2019

Introduction

The emergence of mobile health (mHealth) solutions, particularly mHealth applications (apps), has shown promise in self-management of chronic diseases including type 2 diabetes mellitus (T2DM). While majority of the previous systematic reviews have focused on the effectiveness of mHealth apps in improving treatment outcomes in patients with T2DM, there is a need to also understand how mHealth apps influence self-management of T2DM. This is crucial to ensure improvement in the design and use of mHealth apps for T2DM. This protocol describes how a systematic review will be conducted to determine in which way(s) mHealth apps might impact on self-management of T2DM.

Methods

The following electronic databases will be searched from inception to April 2019: PubMed, MEDLINE, EMBASE, Global Health, PsycINFO, CINAHL, The Cochrane Central Register of Controlled Trials, Scopus, Web of Science, ProQuest Dissertations & Theses Global, Health Management Information Consortium database, Google Scholar and ClinicalTrials.gov. The Cochrane risk of bias tool will be used to assess methodological quality. The primary outcome measures to be assessed will be ‘change in blood glucose’. The secondary outcomes measures will be ‘changes in cardiovascular risk markers’ (including blood pressure, body mass index and blood lipids), and self-management practices. Others will include: health-related quality of life, economic data, social support, harms (eg, death or complications leading to hospital admissions or emergency unit attendances), death from any cause, anxiety or depression and adverse events (eg, hypoglycaemic episodes).

Ethics and dissemination

This study will not involve the collection of primary data and will not require ethical approval. The review will be published in a peer-reviewed journal and a one-page summary of the findings will be shared with relevant organisations. Presentation of findings will be made at appropriate conferences.

Trial registration number

CRD42017071106.
Assessing the relationship between near-infrared spectroscopy-derived regional cerebral oxygenation and neurological dysfunction in critically ill adults: a prospective observational multicentre protocol, on behalf of the Canadian Critical Care Trials Group
Authors: Wood Michael D , Khan Jasmine , Lee Kevin F H , Maslove David M , Muscedere John , Hunt Miranda , Scott Stephen H , Day Andrew , Jacobson Jill A , Ball Ian , Slessarev Marat , O’Regan Niamh , English Shane W , McCredie Victoria , Chasse Michaël , Griesdale Donald , Boyd J Gordon
Published: June 2019

Introduction

Survivors of critical illness frequently exhibit acute and chronic neurological complications. The underlying aetiology of this dysfunction remains unknown but may be associated with cerebral ischaemia. This study will use near-infrared spectroscopy to non-invasively quantify regional cerebral oxygenation (rSO2) to assess the association between poor rSO2during the first 72 hours of critical illness with delirium severity, as well as long-term sensorimotor and cognitive impairment among intensive care unit (ICU) survivors. Further, the physiological determinants of rSO2will be examined.

Methods and analysis

This multicentre prospective observational study will consider adult patients (≥18 years old) eligible for enrolment if within 24 hours of ICU admission, they require mechanical ventilation and/or vasopressor support. For 72 hours, rSO2will be continuously recorded, while vital signs (eg, heart rate) and peripheral oxygenation saturation will be concurrently captured with data monitoring software. Arterial and central venous gases will be sampled every 12 hours for the 72 hours recording period and will include: pH, PaO2, PaCO2, and haemoglobin concentration. Participants will be screened daily for delirium with the confusion assessment method (CAM)-ICU, whereas the brief-CAM will be used on the ward. At 3 and 12 months post-ICU discharge, neurological function will be assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and KINARM sensorimotor and cognitive robot-based behavioural tasks.

Ethics and dissemination

The study protocol has been approved in Ontario by a central research ethics board (Clinical Trials Ontario); non-Ontario sites will obtain local ethics approval. The study will be conducted under the guidance of the Canadian Critical Care Trials Group (CCCTG) and the results of this study will be presented at national meetings of the CCCTG for internal peer review. Results will also be presented at national/international scientific conferences. On completion, the study findings will be submitted for publication in peer-reviewed journals.

Trial registration number

NCT03141619
Quality of life after interventions for malignant pleural effusions: a systematic review
Authors: Sivakumar Parthipan , Saigal Anita , Ahmed Liju
Published: June 2019

Background

Malignant pleural effusion (MPE) results in breathlessness and impairment of health-related quality of life (HRQOL). This study reviews the existing literature on HRQOL following invasive interventions in MPE.

Methods

Five electronic databases were systematically searched and assessed three times during the review process and last completed on 15 June 2018. We included all studies evaluating HRQOL outcomes for the following interventions: therapeutic thoracocentesis, talc slurry (TS) pleurodesis, indwelling pleural catheter (IPC) insertion and thoracoscopic talc poudrage (TTP) pleurodesis. Meta-analysis was not performed due to substantial heterogeneity in the published data.

Results

17 studies were included in the review reporting HRQOL outcomes in 2515 patients. TTP, TS and IPC were associated with modest but inconsistent improvements in HRQOL up to 12 weeks. No intervention was significantly different from another in HRQOL outcomes at any time point. The attrition to follow-up was 48.3% (664/1374) at 3 months. The overall quality of studies was inadequate.

Conclusion

TTP, TS and IPC seem to improve HRQOL in MPE over 4–12 weeks, but there are insufficient longer term data due to high attrition rates. Evidence on the most effective treatment strategy is limited by the small number of randomised or comparative studies.

Trial registration number

CRD42016051003.
A comparative analysis of 3MAX aspiration versus 3 mm Trevo Retriever for distal occlusion thrombectomy in acute stroke
Authors: Haussen Diogo C , Eby Brendan , Al-Bayati Alhamza R , Grossberg Jonathan A , Rodrigues Gabriel Martins , Frankel Michael R , Nogueira Raul G
Published: June 2019

Background

Although aspiration and stent retriever thrombectomy perform similarly in proximal occlusions, no comparative series are available in distal occlusions. We aimed to compare the 3 mm Trevo Retriever against the 3MAX thromboaspiration catheter in distal arterial occlusions.

Methods

A single-center retrospective review of a prospectively maintained databank for patients treated with the 3 mm Trevo stent retriever or 3MAX thromboaspiration as the upfront approach for distal occlusions (middle cerebral artery mid/distal M2/M3, anterior cerebral artery A1/A2/A3 or posterior cerebral artery P1/P2) from January 2014 to July 2018 was performed. The primary outcome was the rate of distal occlusion first-pass reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) 2b–3).

Results

Of 1100 patients treated within the study period, 137 patients/144 different arteries were treated with the 3 mm Trevo (n=92) or 3MAX device (n=52). The groups had comparable demographics and baseline characteristics. There was a higher rate of first-pass mTICI 2b–3 reperfusion (62% vs 44%; p=0.03), a trend towards a higher rate of final mTICI 2b–3 reperfusion (84% vs 69%; p=0.05), and lower use of adjuvant therapy (15% vs 31%; p=0.03) with the 3 mm Trevo compared with the 3MAX. The median number of passes (p=0.46), frequency of arterial spasm (p=1.00), rates of parenchymal hematomas (p=0.22)/subarachnoid hemorrhage (p=0.37) in the territory of the approached vessel were similar across the two groups. The 90-day rate of good outcomes (45% vs 46% in the 3 mm Trevo and 3MAX groups, respectively; p=0.84) was comparable. Multivariable regression identified baseline NIH Stroke Scale (NIHSS) score (OR 0.9; 95% CI 0.8 to 0.97; p<0.01) and use of 3 mm Trevo (OR 2.2; 95% CI 1.1 to 4.6; p=0.02) independently associated with first-pass mTICI 2b–3 reperfusion.

Conclusions

In the setting of distal arterial occlusions, the 3 mm Trevo may lead to higher rates of first-pass reperfusion than direct 3MAX thromboaspiration. Lower NIHSS was found to be associated with improved reperfusion rates as observed in more proximal lesions. Further studies are warranted.
Increased baseline ECG R-R dispersion predicts improvement in systolic function after atrial fibrillation ablation
Authors: Koene Ryan J , Buch Eric , Seo Young-Ji , Li Jian-Ming , Mbai Mackenzi , Chandrashekhar Y , Shivkumar Kalyanam , Tholakanahalli Venkatakrishna N
Published: June 2019

Background

Atrial fibrillation (AF) is associated with left ventricular (LV) systolic dysfunction which may improve after AF ablation. We hypothesised that increased ventricular irregularity, as measured by R-R dispersion on the baseline ECG, would predict improvement in the left ventricular ejection fraction (LVEF) after AF ablation.

Methods

Patients with LVEF <50% at two US centres (2007–2016), having both a preablation and postablation echocardiogram or cardiac MRI, were included. LVEF improvement was defined as absolute increase in LVEF by >7.5%. Multivariable logistic regression (restricted to echocardiographic/ECG variables) was performed to evaluate predictors of LVEF improvement.

Results

Fifty-two patients were included in this study. LVEF improved in 30 patients (58%) and was unchanged/worsened in 22 patients (42%). Those with versus without LVEF improvement had an increased baseline R-R dispersion (645±155 ms vs 537±154 ms, p=0.02, respectively). The average baseline heart rate in all patients was 93 beats per minute. After multivariable logistic regression, increased R-R dispersion (OR 1.59, 95% CI 1.00 to 2.55, p=0.03) predicted LVEF improvement.

Conclusions

Increased R-R dispersion on ECG was independently associated with improved systolic function after AF ablation. This broadens the existing knowledge of arrhythmia-induced cardiomyopathy, demonstrating that irregular electrical activation (as measured by increased R-R dispersion on ECG) is associated with a cardiomyopathy capable of improving after AF ablation.
Learning from history: Lord Brain and Hashimoto’s encephalopathy
Authors: Crotty Grace F , Doherty Colin , Solomon Isaac H , Berry James D , Samuels Martin A
Published: June 2019

We present two historic cases of severe encephalopathy associated with antithyroid antibodies. The first was published by Lord Brain of Eynsham, and the second was from our department’s archives. Although both cases are from archival sources, they continue to inform current clinical care. We briefly review the poorly defined entity, Hashimoto’s encephalopathy, and discuss diagnostic advances for autoimmune encephalopathy and for Creutzfeldt-Jakob disease. We advocate for giving a trial of corticosteroids to patients with ‘encephalopathy, not otherwise specified’ while awaiting antibody results or more definitive testing. Our case, initially diagnosed as having Creutzfeldt-Jakob disease, responded remarkably (with video evidence) to a trial of corticosteroids.
Continuing surveillance of invasive Haemophilus influenzae disease in northwestern Ontario emphasizes the importance of serotype a and non-typeable strains as causes of serious disease: a Canadian Immunization Research Network (CIRN) Study
Authors: Cerqueira Ashley , Byce Sarah , Tsang Raymond S.W. , Jamieson Frances B. , Kus Julianne V. , Ulanova Marina
Published: June 2019

In the post-Haemophilus influenzae serotype b (Hib) vaccine era, invasive H. influenzae serotype a (Hia) disease emerged in Canadian First Nation, Inuit, and Alaskan Indigenous populations. Previous studies by our group found a high incidence of invasive Hia disease in northwestern Ontario. We retrospectively reviewed 24 cases (4 pediatric and 20 adult) of invasive H. influenzae disease hospitalized at the northwestern Ontario regional hospital between August 2011 and June 2018. The objectives were to further document the changing epidemiology of invasive H. influenzae disease in the region and to discuss potential control measures. Twenty-two H. influenzae isolates were serotyped and characterized using molecular-biological methods. Of the serotyped cases, there were 2 Hib, 9 Hia, and 11 non-typeable (NTHi). All Hia isolates belonged to the most common sequence types (ST) found in Canada (ST-23 and ST-929); 8 out of 9 were pan susceptible to antibiotics. One (11%) of 9 Hia and 5 (45%) of 11 NTHi cases were fatal. Our data on the consistent presence of serious invasive H. influenzae disease, with 41% prevalence of Hia (9 out of 22 serotyped isolates) and 50% prevalence of NTHi strains (11 out of 22), emphasize the importance of continued surveillance of H. influenzae in the post-Hib vaccine era and are critical information to inform potential vaccine development.
Trophic interactions between the Kelp Gull (Larus dominicanus) and Royal and Cayenne terns (Thalasseus maximus maximusandThalasseus sandvicensis eurygnathus, respectively) in a human-modified environment
Authors: Marinao Cristian , Suárez Nicolás , Yorio Pablo
Published: June 2019

Many closely related seabirds nest in mixed colonies, and this association may result in interspecific interactions such as competition for common resources and kleptoparasitism. Trophic interactions were evaluated between the Kelp Gull (Larus dominicanus Lichtenstein, 1823) and Royal and Cayenne terns (Thalasseus maximus maximus (Boddaert, 1783) and Thalasseus sandvicensis eurygnathus (Saunders, 1876), respectively) nesting at a mixed-species colony in an area with high availability of recreational fishery waste for the opportunistic Kelp Gull. Diet analyses were based on gull chick stomach content samples and direct observations of food delivered to tern chicks in 2013 and 2014, complemented in 2014 with carbon and nitrogen stable isotope analysis of chick whole-blood samples. Main prey species of Kelp Gull chicks were Cynoscion guatucupa (Cuvier, 1830), a demersal species obtained from recreational fishery waste, Argentine anchovies (Engraulis anchoita Hubbs and Marini, 1935), and insects. Engraulis anchoita and Odontesthes spp. were the main prey of both tern species. Trophic niche and isotopic niche overlap between the Kelp Gull and Royal and Cayenne terns was low. Kelp Gull kleptoparasitism on Royal and Cayenne terns was ≤2.5% and <0.6%, respectively. The use of anthropogenic food subsidies by Kelp Gulls may be mediating the trophic relationships among species, favouring their use of predictable and abundant fishery waste over a more unpredictable pelagic schooling fish such as E. anchoita.
Existence of almost periodic solutions for fractional impulsive neutral stochastic differential equations with infinite delay
Authors: Ma Xiao , Shu Xiao-Bao , Mao Jianzhong
Published: June 2019

In this paper, we investigate the existence of almost periodic solutions for fractional impulsive neutral stochastic differential equations with infinite delay in Hilbert space. The main conclusion is obtained by using fractional calculus, operator semigroup and fixed point theorem. In the end, we give an example to illustrate our main results.
CORES
Authors: Wen Weidong , Li Yang , Li Wenhai , Deng Lingfeng , He Yanxiang
Published: June 2019

The relatively high cost of record deserialization is increasingly becoming the bottleneck of column-based storage systems in tree-structured applications [58]. Due to record transformation in the storage layer, unnecessary processing costs derived from fields and rows irrelevant to queries may be very heavy in nested schemas, significantly wasting the computational resources in large-scale analytical workloads. This leads to the question of how to reduce both the deserialization and IO costs of queries with highly selective filters following arbitrary paths in a nested schema.

We present CORES (Column-Oriented Regeneration Embedding Scheme) to push highly selective filters down into column-based storage engines, where each filter consists of several filtering conditions on a field. By applying highly selective filters in the storage layer, we demonstrate that both the deserialization and IO costs could be significantly reduced. We show how to introduce fine-grained composition on filtering results. We generalize this technique by two pair-wise operations, rollup and drilldown, such that a series of conjunctive filters can effectively deliver their payloads in nested schema. The proposed methods are implemented on an open-source platform. For practical purposes, we highlight how to build a column storage engine and how to drive a query efficiently based on a cost model. We apply this design to the nested relational model especially when hierarchical entities are frequently required by ad hoc queries. The experiments, including a real workload and the modified TPCH benchmark, demonstrate that CORES improves the performance by 0.7×--26.9× compared to state-of-the-art platforms in scan-intensive workloads.
Volume-regulated Cl− current: contributions of distinct Cl− channels and localized Ca2+ signals
Authors: Liu Yani , Zhang Huiran , Men Hongchao , Du Yuwei , Xiao Ziqian , Zhang Fan , Huang Dongyang , Du Xiaona , Gamper Nikita , Zhang Hailin
Published: June 2019

The swelling-activated chloride current ( ICl,swell) is induced when a cell swells and plays a central role in maintaining cell volume in response to osmotic stress. The major contributor of ICl,swell is the volume-regulated anion channel (VRAC). Leucine-rich repeat containing 8A (LRRC8A; SWELL1) was recently identified as an essential component of VRAC, but the mechanisms of VRAC activation are still largely unknown; moreover, other Cl− channels, such as anoctamin 1 (ANO1), were also suggested to contribute to ICl,swell. In this present study, we investigated the roles of LRRC8A and ANO1 in activation of ICl,swell; we also explored the role of intracellular Ca2+ in ICl,swell activation. We used a CRISPR/Cas9 gene editing approach, electrophysiology, live fluorescent imaging, selective pharmacology, and other approaches to show that both LRRC8A and ANO1 can be activated by cell swelling in HEK293 cells. Yet, both channels contribute biophysically and pharmacologically distinct components to ICl,swell, with LRRC8A being the major component. Cell swelling induced oscillatory Ca2+ transients, and these Ca2+ signals were required to activate both the LRRC8A- and ANO1-dependent components of ICl,swell. Both ICl,swell components required localized rather than global Ca2+ for activation. Interestingly, while intracellular Ca2+ was necessary and sufficient to activate ANO1, it was necessary but not sufficient to activate LRRC8A-mediated currents. Finally, Ca2+ transients linked to the ICl,swell activation were mediated by the G protein-coupled receptor-independent PLC isoforms.
Use of adult mesenchymal stromal cells in tissue repair: impact of physical exercise
Authors: Bourzac Celine , Bensidhoum Morad , Pallu Stephane , Portier Hugues
Published: June 2019

Physical exercise (PE) has unquestionable beneficial effects on health, which likely extend into several organ-to-cell physiological processes. At the cell scale, endogenous mesenchymal stromal cells (MSCs) contribute to tissue repair, although their repair capacities may be insufficient in paucicellular or severely damaged tissues. For this reason, MSC transplantation holds great promise for tissue repair. With the goals of understanding if PE has beneficial effects on MSC biology and if PE potentiates their role in tissue repair, we reviewed literature reports regarding the effects of PE on MSC properties (specifically, proliferation, differentiation, and homing) and of a combination of PE and MSC transplantation on tissue repair (specifically neural, cartilage, and muscular tissues). Contradictory results have been reported; interpretation is complicated because various and different species, cell sources, and experimental protocols, specifically exercise programs, have been used. On the basis of these data, the effects of exercise on MSC proliferation and differentiation depend on exercise characteristics (type, intensity, duration, etc.) and on the characteristics of the tissue from which the MSCs were collected. For the in vitro studies, the level of strain (and other details of the mechanical stimulus), the time elapsed between the end of exposure to strain and MSC collection, the age of the donors, as well as the passage number at which the MSCs are evaluated also play a role. The combination of PE and MSC engraftment improves neural, cartilage, and muscular tissue recovery, but it is not clear whether the effects of MSCs and exercise are additive or synergistic.
Temporal induction of intestinal epithelial hypoxia-inducible factor-2α is sufficient to drive colitis
Authors: Solanki Sumeet , Devenport Samantha N. , Ramakrishnan Sadeesh K. , Shah Yatrik M.
Published: June 2019

Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α is sufficient to exacerbate colitis.

NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.
Pulmonary capillary surface area in supine exercising humans: demonstration of vascular recruitment
Authors: Langleben David , Orfanos Stylianos E. , Giovinazzo Michele , Schlesinger Robert D. , Naeije Robert , Fox Benjamin D. , Abualsaud Ali O. , Blenkhorn Fay , Rudski Lawrence G. , Catravas John D.
Published: June 2019

In exercising humans, cardiac output (CO) increases, with minor increases in pulmonary artery pressure (PAP). It is unknown if the CO is accommodated via distention of already perfused capillaries or via recruitment of nonconcomitantly perfused pulmonary capillaries. Ten subjects (9 female) performed symptom-limited exercise. Six had resting mean PAP (PAPm) <20 mmHg, and four had PAPm between 21 and 24 mmHg. The first-pass pulmonary circulatory metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) was measured at rest and at peak exercise, and functional capillary surface area (FCSA) was calculated. Data are means ± SD. Mean pulmonary arterial pressure rose from 18.8 ± 3.3 SD mmHg to 28.5 ± 4.6 SD mmHg, CO from 6.4 ± 1.6 to 13.4 ± 2.9 L/min, and pulmonary artery wedge pressure from 14 ± 3.3 to 19.5 ± 5 mmHg (all P ≤ 0.001). Percent BPAP metabolism fell from 74.7 ± 0.1% to 67.1 ± 0.1%, and FCSA/body surface area (BSA) rose from 2,939 ± 640 to 5,018 ± 1,032 mL·min−1·m−2 (all P < 0.001). In nine subjects, the FCSA/BSA-to-CO relationship suggested principally capillary recruitment and not distention. In subject 10, a marathon runner, resting CO and FCSA/BSA were high, and increases with exercise suggested distention. Exercising humans demonstrate pulmonary capillary recruitment and distention. At moderate resting CO, increasing blood flow causes principally recruitment while, based on one subject, when exercise begins at high CO, further increases appear to cause distention. Our findings clarify an important physiologic question. The technique may provide a means for further understanding exercise physiology, its limitation in pulmonary hypertension, and responses to therapy.
Regulation of catecholamine release from the adrenal medulla is altered in deer mice (Peromyscus maniculatus) native to high altitudes
Authors: Scott Angela L. , Pranckevicius Nicole A. , Nurse Colin A. , Scott Graham R.
Published: June 2019

High-altitude natives have evolved to overcome environmental hypoxia and provide a compelling system to understand physiological function during reductions in oxygen availability. The sympathoadrenal system plays a key role in responses to acute hypoxia, but prolonged activation of this system in chronic hypoxia may be maladaptive. Here, we examined how chronic hypoxia exposure alters adrenal catecholamine secretion and how adrenal function is altered further in high-altitude natives. Populations of deer mice ( Peromyscus maniculatus) native to low and high altitudes were each born and raised in captivity at sea level, and adults from each population were exposed to normoxia or hypobaric hypoxia for 5 mo. Using carbon fiber amperometry on adrenal slices, catecholamine secretion evoked by low doses of nicotine (10 µM) or acute hypoxia (Po2∼15–20 mmHg) was reduced in lowlanders exposed to hypobaric hypoxia, which was attributable mainly to a decrease in quantal charge rather than event frequency. However, secretion evoked by high doses of nicotine (50 µM) was unaffected. Hypobaric hypoxia also reduced plasma epinephrine and protein expression of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase in the adrenal medulla of lowlanders. In contrast, highlanders were unresponsive to hypobaric hypoxia, exhibiting typically low adrenal catecholamine secretion, plasma epinephrine, and DOPA decarboxylase. Highlanders also had consistently lower catecholamine secretion evoked by high nicotine, smaller adrenal medullae with fewer chromaffin cells, and a larger adrenal cortex compared with lowlanders across both acclimation environments. Our results suggest that plastic responses to chronic hypoxia along with evolved changes in adrenal function attenuate catecholamine release in deer mice at high altitude.
The relationships among spinal CSF flows, spinal cord geometry, and vascular correlations: evidence of intrathecal sources and sinks
Authors: Bert Robert J. , Settipalle Neesha , Tiwana Emily , Muddasani Dheeraj , Nath Ruponti , Wellman Brandon , Mihlon Frank , Negahdar Mohammadjavad , Amini Amir , Boakye Maxwell
Published: June 2019

We studied relationships of cerebral spinal fluid (CSF) pulsatile flow at cervical, thoracic, and lumbar levels using phase-contrast cine MRI (PCCMRI) to determine the following: 1) instantaneous and average net flows at cervical, thoracic, and lumbar levels, 2) stochastic correlations of CSF flow with major arterial supplies and major draining veins, and 3) whether adjustments of cord-flow curves—using cord cross-sectional areas, caudal lengths, and caudal volumes—would normalize flow curves from different levels. We scanned 15 healthy volunteers without anesthesia, ages 23–46 yr, using external, retrocardiac-gated, two-dimensional PCCMRI at 3T. Transverse scans of the subarachnoid space, arteries, and veins were acquired and analyzed at cervical, thoracic, and lumbar levels. Instantaneous CSF flow decreased craniocaudally along the full time course of a cardiac cycle. Downward net flow generally increased craniocaudally. During diastole, instantaneous CSF flow decreased proportionally to cross-sectional area, caudal residual length, and caudal residual volume of the cord. The proportionalities were less consistent during systole. CSF, internal carotid artery (ICA), vertebral artery, and lower aorta temporal correlations were highest in systole and decreased craniocaudally. CSF flow temporally correlated better with lower aorta flow than with the ICA at T7 and L2 during systole but not diastole. Inferior vena cava temporal correlation increased craniocaudally. We conclude that whereas instantaneous flow is attenuated cranial caudally, net downward flow, per cardiac cycle, increases caudally, becoming statistically significant at T7 and below the conus medullaris. We can explain the results with the assumption of cord CSF production and peripheral-dominated CSF absorption.
Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through induction of Tollip and negative regulation of IRAK-1
Authors: Watts Bruns A. , Tamayo Esther , Sherwood Edward R. , Good David W.
Published: June 2019

LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-extracellular signal-regulated kinase (ERK) pathway that is upregulated by sepsis. Pretreatment with the nontoxic immunomodulator monophosphoryl lipid A (MPLA) prevents inhibition by LPS through activation of a TLR4-TIR-domain-containing adaptor-inducing interferon-β (TRIF)-phosphatidylinositol 3-kinase (PI3K) pathway that prevents LPS-induced ERK activation. Here, we identified the molecular mechanisms that underlie the protective inhibitory interaction between the MPLA-PI3K and LPS-ERK pathways. Treatment of mouse MTALs with LPS in vitro increased phosphorylation of IL-1 receptor-associated kinase (IRAK)-1, a critical mediator of LPS signaling downstream of TLR4-MyD88. Activation of ERK by LPS was eliminated by a selective IRAK-1 inhibitor, establishing IRAK-1 as the upstream mediator of ERK activation. Pretreatment of MTALs with MPLA in vitro prevented LPS-induced IRAK-1 activation; this effect was dependent on PI3K. Treatment of MTALs with MPLA increased expression of Toll-interacting protein (Tollip), an inducible protein that negatively regulates LPS signaling by inhibiting IRAK-1. The MPLA-induced increase in Tollip protein level was prevented by PI3K inhibitors. In coimmunoprecipitation experiments, MPLA increased the amount of Tollip stably bound to IRAK-1, an interaction that inhibits IRAK-1 activation. These results support a mechanism whereby MPLA increases Tollip expression in the MTAL through a PI3K-dependent pathway. Tollip, in turn, inhibits LPS-induced TLR4 signaling by suppressing activation of IRAK-1, thereby preventing activation of ERK that inhibits [Formula: see text] absorption. These studies show that MPLA induces reprogramming of MTAL cells that protects against LPS stimulation and identify IRAK-1 and Tollip as new therapeutic targets to prevent renal tubule dysfunction in response to infectious and inflammatory stimuli.
Smooth muscle-specific deletion of MnSOD exacerbates diabetes-induced bladder dysfunction in mice
Authors: Elrashidy Rania A. , Kavran Michael , Asker Mervat E. , Mohamed Hoda E. , Daneshgari Firouz , Liu Guiming
Published: June 2019

Bladder dysfunction in diabetes progresses gradually over time. However, the mechanisms of the development are not clear. We tested the hypothesis that oxidative stress plays a key role in the development of diabetic bladder dysfunction using an inducible smooth muscle (SM)-specific superoxide dismutase 2 ( Sod2) gene knockout (SM- Sod2 KO) mouse model. Eight-week-old male Sod2lox/lox, SM-CreERT2(ki)Cre/+mice and wild-type mice were assigned to diabetic or control groups. 4-Hydroxytamoxifen was injected into Sod2lox/lox, SM-CreERT2(ki)Cre/+mice to activate CreERT2-mediated deletion of Sod2. Diabetes was induced by injection of streptozotocin, whereas control mice were injected with vehicle. Nine weeks later, bladder function was evaluated, and bladders were harvested for immunoblot analysis. Wild-type diabetic mice presented compensated bladder function along with increased nitrotyrosine and MnSOD in detrusor muscle. Induction of diabetes in SM- Sod2 KO mice caused deteriorated bladder function and even greater increases in nitrotyrosine compared with wild-type diabetic mice. Expression levels of apoptosis regulator Bax and cleaved caspase-3 were increased, but apoptosis regulator Bcl-2 expression was decreased in detrusor muscle of both diabetic groups, with more pronounced effects in SM- Sod2 KO diabetic mice. Our findings demonstrate that exaggerated oxidative stress can accelerate the development of bladder dysfunction in diabetic mice and the enhanced activation of apoptotic pathways in the bladder may be involved in the process.
APOL1 and kidney cell function
Authors: Kumar Vinod , Singhal Pravin C.
Published: June 2019

The apolipoprotein L1 (APOL1) gene is unique to humans and gorillas and appeared ~33 million years ago. Since the majority of the mammals do not carry APOL1, it seems to be dispensable for kidney function. APOL1 renal risk variants (RRVs; G1 and G2) are associated with the development as well as progression of chronic kidney diseases (CKDs) at higher rates in populations with African ancestry. Cellular expression of two APOL1 RRVs has been demonstrated to induce cytotoxicity, including necrosis, apoptosis, and pyroptosis, in several cell types including podocytes; mechanistically, these toxicities were attributed to lysosomal swelling, K+depletion, mitochondrial dysfunction, autophagy blockade, protein kinase receptor activation, ubiquitin D degradation, and endoplasmic reticulum stress; notably, these effects were found to be dose dependent and occurred only in overtly APOL1 RRV-expressing cells. However, cellular protein expressions as well as circulating blood levels of APOL1 RRVs were not elevated in patients suffering from APOL1 RRV-associated CKDs. Therefore, the question arises as to whether it is gain or loss of function on the part of APOL1 RRVs contributing to kidney cell injury. The question seems to be more pertinent after the recognition of the role of APOL1 nonrisk (G0) in the transition of parietal epithelial cells and preservation of the podocyte molecular phenotype through modulation of the APOL1-miR-193a axis. With this background, the present review analyzed the available literature in terms of the known function of APOL1 nonrisk and how the loss of these functions could have contributed to two APOL1 RRV-associated CKDs.
A model-based reassessment of the three-dimensional tuning of head direction cells in rats
Authors: Laurens Jean , Angelaki Dora E.
Published: June 2019

In a recent study, Shinder and Taube (Shinder ME, Taube JS. J Neurophysiol 121: 4–37, 2019) concluded that head direction cells in the anterior thalamus of rats are tuned to one-dimensional (1D, yaw-only) motion, in contrast to recent findings in bats, mice, and rats. Here we reinterpret the author’s experimental results using model comparison and demonstrate that, contrary to their conclusions, experimental data actually supports the dual-axis rule (lson JJ, Jeffery KJ. J Neurophysiol 119: 192–208, 2018) and tilted azimuth model (Laurens J, Angelaki DE. Neuron 97: 275–289, 2018), where head direction cells use gravity to integrate 3D rotation signals about all cardinal axes of the head. We further show that the Shinder and Taube study is inconclusive regarding the presence of vertical orientation tuning; i.e., whether head direction cells encode 3D orientation in the horizontal and vertical planes conjunctively. Using model simulations, we demonstrate that, even if 3D tuning existed, the experimental protocol and data analyses used by Shinder and Taube would not have revealed it. We conclude that the actual experimental data of Shinder and Taube are compatible with the 3D properties of head direction cells discovered by other groups, yet incorrect conclusions were reached because of incomplete and qualitative analyses.

NEW & NOTEWORTHY We conducted a model-based analysis previously published data where rat head direction cells were recorded during three-dimensional motion (Shinder ME, Taube JS. J Neurophysiol 121: 4–37, 2019). We found that these data corroborate previous models (“dual-axis rule,” Page HJI, Wilson JJ, Jeffery KJ. J Neurophysiol 119: 192–208, 2018; and “tilted azimuth model,” Laurens J, Angelaki DE. Neuron 97: 275–289, 2018) where head direction cells integrate rotations along all three head axes to encode head orientation in a gravity-anchored reference frame.
Human motor unit characteristics of the superior trapezius muscle with age-related comparisons
Authors: Kirk Eric A. , Gilmore Kevin J. , Stashuk Daniel W. , Doherty Timothy J. , Rice Charles L.
Published: June 2019

Current understanding of human motor unit (MU) control and aging is mostly derived from hand and limb muscles that have spinal motor neuron innervations. The aim here was to characterize and test whether a muscle with a shared innervation supply from brainstem and spinal MU populations would demonstrate similar age-related adaptations as those reported for other muscles. In humans, the superior trapezius (ST) muscle acts to elevate and stabilize the scapula and has primary efferent supply from the spinal accessory nerve (cranial nerve XI) located in the brainstem. We compared electrophysiological properties obtained from intramuscular and surface recordings between 10 young (22–33 yr) and 10 old (77–88 yr) men at a range of voluntary isometric contraction intensities (from 15 to 100% of maximal efforts). The old group was 41% weaker with 43% lower MU discharge frequencies compared with the young (47.2 ± 9.6 Hz young and 26.7 ± 5.8 Hz old, P < 0.05) during maximal efforts. There was no difference in MU number estimation between age groups (228 ± 105 young and 209 ± 89 old, P = 0.33). Furthermore, there were no differences in needle detected near fiber (NF) stability parameters of jitter or jiggle. The old group had lower amplitude and smaller area of the stimulated compound muscle action potential and smaller NF MU potential area with higher NF counts. Thus, despite age-related ST weakness and lower MU discharge rates, there was minimal evidence of MU loss or compensatory reinnervation.

NEW & NOTEWORTHY The human superior trapezius (ST) has shared spinal and brainstem motor neuron innervation providing a unique model to explore the impact of aging on motor unit (MU) properties. Although the ST showed higher MU discharge rates compared with most spinally innervated muscles, voluntary strength and mean MU rates were lower in old compared with young at all contraction intensities. There was no age-related difference in MU number estimates with minimal electrophysiological evidence of collateral reinnervation.
Anesthetics: from modes of action to unconsciousness and neurotoxicity
Authors: Iqbal Fahad , Thompson Andrew J. , Riaz Saba , Pehar Marcus , Rice Tiffany , Syed Naweed I.
Published: June 2019

Modern anesthetic compounds and advanced monitoring tools have revolutionized the field of medicine, allowing for complex surgical procedures to occur safely and effectively. Faster induction times and quicker recovery periods of current anesthetic agents have also helped reduce health care costs significantly. Moreover, extensive research has allowed for a better understanding of anesthetic modes of action, thus facilitating the development of more effective and safer compounds. Notwithstanding the realization that anesthetics are a prerequisite to all surgical procedures, evidence is emerging to support the notion that exposure of the developing brain to certain anesthetics may impact future brain development and function. Whereas the data in support of this postulate from human studies is equivocal, the vast majority of animal research strongly suggests that anesthetics are indeed cytotoxic at multiple brain structure and function levels. In this review, we first highlight various modes of anesthetic action and then debate the evidence of harm from both basic science and clinical studies perspectives. We present evidence from animal and human studies vis-à-vis the possible detrimental effects of anesthetic agents on both the young developing and the elderly aging brain while discussing potential ways to mitigate these effects. We hope that this review will, on the one hand, invoke debate vis-à-vis the evidence of anesthetic harm in young children and the elderly, and on the other hand, incentivize the search for better and less toxic anesthetic compounds.
Human 8- to 10-Hz pulsatile motor output during active exploration of textured surfaces reflects the textures’ frictional properties
Authors: Dione Mariama , Wessberg Johan
Published: June 2019

Active sensing in biological system consists of emitting/receiving a periodic signal to explore the environment. The signal can be emitted toward distant objects, as in echolocation, or in direct contact with the object, for example, whisking in rodents. We explored the hypothesis that a similar mechanism exists in humans. Humans generate periodic signals at ~10 Hz during voluntary finger movements, which reflects a pulsatile motor command in the central nervous system. In the present study, we tested whether the ~10-Hz signal persists during the active exploration of textures and whether the textures’ features can modulate the signal. Our results confirm our assumptions. The ~10-Hz signal persisted during active touch, and its amplitude increased with textures of higher friction. These findings support the idea that the ~10-Hz periodic signal generated during voluntary finger movements is part of an active sensing mechanism acting in a pulse-amplitude modulation fashion to convey relevant tactile information to the brain.

NEW & NOTEWORTHY For the first time, we show that pulsatile motor output during voluntary movement of a finger persists during active exploration of a surface. We propose that this is part of an active sensing system in humans, with generation of an ~10-Hz signal during active touch that reinforces extraction of information about features of the touched surface.