bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design and rationale of the Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis (SEAM-PsA)
Authors: Mease Philip J , Gladman Dafna D , Samad Ahmed S , Coates Laura C , Liu Lyrica X H , Aras Girish A , Collier David H , Chung James B 
Published: February 2018

ObjectiveTo evaluate the efficacy of etanercept and methotrexate as monotherapies and as combination therapy in subjects with active psoriatic arthritis (PsA).MethodsThe Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis (SEAM-PsA) is an ongoing, global, double-blind, 48-week, randomised, controlled study. Subjects are randomised (1:1:1) to etanercept monotherapy, methotrexate monotherapy or etanercept-methotrexate combination therapy. Endpoints include rates of ACR20 response and Minimal Disease Activity, measures to characterise extra-articular manifestations (dactylitis, enthesitis, nail disease) and safety.ConclusionSEAM-PsA will characterise the effects of etanercept with and without background methotrexate and methotrexate alone on PsA manifestations, and provide information of practical importance to clinicians on the optimal treatment of PsA.
Gullies and debris-flows in Ladakh Himalaya, India: a potential Martian analogue
Authors: Sinha Rishitosh K. , Vijayan S. , Shukla Anil D. , Das Priyabrata , Bhattacharya Falguni 
Published: February 2018

Abstract
We conducted comparative morphological analysis of gullies within two high-latitude Martian craters (Domoni and Maricourt) in the northern hemisphere of Mars with (1) the debris-flow gully systems in the Ladakh Himalaya and (2) Istok Crater in the southern mid-latitudes of Mars where water-bearing debris-flow deposits have been previously reported. Our findings suggest that the debris-flow landforms preserved on gully and alluvial fans in the Ladakh Himalaya are potential analogues for the deposits preserved over the equator-facing slopes of Domoni and Maricourt Craters. Further, we found that the morphological attributes of channels and deposits (including overlapping terminal lobes, levées, tongue-shaped/lobate deposits and broad/small depositional deposits) within both the study craters and Istok Crater are similar. As a result, the studied craters emerge as additional sites in which possible evidence of water-bearing debris-flows are preserved on Mars. By comparison to our Earth analogue, we further propose that episodic melting of snow accumulated within the sheltered alcoves is the most likely source of water for the formation of such gullies. Taken together, our findings suggest that debris-flow may not be a rare process in gully formation on Mars and evidence may be preserved in other unexplored areas.
Cratonic basins with reference to the Michigan basin
Authors: Sleep Norman H. 
Published: February 2018

Abstract

Seafloor and passive margins gradually subside as a result of thermal contraction of the underlying lithosphere. Thermal subsidence is also an attractive mechanism for the Michigan basin. For subsidence to occur within this previously stable continental region, some mechanism is needed to heat the lithosphere and to reduce the buoyancy of the continental crust. Mechanical stretching of the lithosphere along with its crust does both at the same time. The ponding of plume material beneath the crust supplies heat, but does not directly thin the crust. The British Isles and the Congo basin provide analogies to the Michigan basin. Continental stretching before subsidence is evident within the British Isles and the Congo basin. Stretching is not obvious in Michigan, but undetected rifts extending from the Iapetus break-up margin may exist. A closed region of thin lithosphere beneath the Irish Sea may have trapped hot buoyant material from the Iceland plume; the Michigan basin may have trapped material from an Iapetus age plume near Montreal. Cratonic basins provide information on the tail of the subsidence curve, unlike more ephemeral oceanic crust and passive margins. The poorly resolved tails in the Michigan and the Congo basins are consistent with the time subsidence constant,
c.
280 myr predicted by stagnant lid convection formalism.
Organic solute transporter OSTα/β is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury
Authors: Malinen Melina M. , Ali Izna , Bezençon Jacqueline , Beaudoin James J. , Brouwer Kim L. R. 
Published: February 2018

The heteromeric steroid transporter organic solute transporter α/β (OSTα/β, SLC51A/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OSTα/β. Based on observations first reported here that hepatic OSTα/β is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTα/β function and interaction with drugs and bile acids. OSTα/β expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTα/β-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OSTα/β-mediated transport was evaluated. Expression of OSTα/β was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTα/β was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTα/β-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTα/β inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic, fidaxomicin. Additionally, some drugs (e.g., digoxin) consistently stimulated taurocholate uptake in OSTα/β-overexpressing cells. Our findings demonstrate that OSTα/β is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OSTα/β is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTα/β substrates exhibit rapid, linear, and concentration-driven transport in an OSTα/β-overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTα/β-mediated taurocholate transport. These data suggest that hepatic OSTα/β plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.
Muscle glycogen depletion does not alter segmental extracellular and intracellular water distribution measured using bioimpedance spectroscopy
Authors: Shiose Keisuke , Yamada Yosuke , Motonaga Keiko , Takahashi Hideyuki 
Published: February 2018

Although each gram of glycogen is well known to bind 2.7–4.0 g of water, no studies have been conducted on the effect of muscle glycogen depletion on body water distribution. We investigated changes in extracellular and intracellular water (ECW and ICW) distribution in each body segment in muscle glycogen-depletion and glycogen-recovery condition using segmental bioimpedance spectroscopy technique (BIS). Twelve male subjects consumed 7.0 g/kg body mass of indigestible (glycogen-depleted group) or digestible (glycogen-recovered group) carbohydrate for 24 h after a glycogen-depletion cycling exercise. Muscle glycogen content using13C-magnetic resonance spectroscopy, blood hydration status, body composition, and ECW and ICW content of the arm, trunk, and leg using BIS were measured. Muscle glycogen content at the thigh muscles decreased immediately after exercise (glycogen-depleted group, 71.6 ± 12.1 to 25.5 ± 10.1 mmol/kg wet wt; glycogen-recovered group, 76.2 ± 16.4 to 28.1 ± 16.8 mmol/kg wet wt) and recovered in the glycogen-recovered group (72.7 ± 21.2 mmol/kg wet wt) but not in the glycogen-depleted group (33.2 ± 12.6 mmol/kg wet wt) 24 h postexercise. Fat-free mass decreased in the glycogen-depleted group ( P < 0.05) but not in the glycogen-recovered group 24 h postexercise. However, no changes were observed in ECW and ICW content at the leg in both groups. Our results suggested that glycogen depletion per se does not alter body water distribution as estimated via BIS. This information is valuable in assessing body composition using BIS in athletes who show variable glycogen status during training and recovery.NEW & NOTEWORTHY Segmental bioimpedance spectroscopy analysis reveals the effect of muscle glycogen depletion on body segmental water distribution in controlled conditions. Despite the significant difference in the muscle glycogen levels at the leg, no difference was observed in body resistance and the corresponding water content of the extracellular and intracellular compartments.
Dynamic cerebral autoregulation during cognitive task: effect of hypoxia
Authors: Ogoh Shigehiko , Nakata Hiroki , Miyamoto Tadayoshi , Bailey Damian Miles , Shibasaki Manabu 
Published: February 2018

Changes in cerebral blood flow (CBF) subsequent to alterations in the partial pressures of oxygen and carbon dioxide can modify dynamic cerebral autoregulation (CA). While cognitive activity increases CBF, the extent to which it impacts CA remains to be established. In the present study we determined whether dynamic CA would decrease during a cognitive task and whether hypoxia would further compound impairment. Fourteen young healthy subjects performed a simple Go/No-go task during normoxia and hypoxia (inspired O2 fraction = 12%), and the corresponding relationship between mean arterial pressure (MAP) and mean middle cerebral artery blood velocity (MCA Vmean) was examined. Dynamic CA and steady-state changes in MCA V in relation to changes in arterial pressure were evaluated with transfer function analysis. While MCA Vmean increased during the cognitive activity ( P < 0.001), hypoxia did not cause any additional changes ( P = 0.804 vs. normoxia). Cognitive performance was also unaffected by hypoxia (reaction time, P = 0.712; error, P = 0.653). A decrease in the very low- and low-frequency phase shift (VLF and LF; P = 0.021 and P = 0.01) and an increase in LF gain were observed ( P = 0.037) during cognitive activity, implying impaired dynamic CA. While hypoxia also increased VLF gain ( P < 0.001), it failed to cause any additional modifications in dynamic CA. Collectively, our findings suggest that dynamic CA is impaired during cognitive activity independent of altered systemic O2 availability, although we acknowledge the interpretive complications associated with additional competing, albeit undefined, inputs that could potentially distort the MAP-MCA Vmean relationship. NEW & NOTEWORTHY During normoxia, cognitive activity while increasing cerebral perfusion was shown to attenuate dynamic cerebral autoregulation (CA) yet failed to alter reaction time, thereby questioning its functional significance. No further changes were observed during hypoxia, suggesting that impaired dynamic CA occurs independently of altered systemic O2 availability. However, impaired dynamic CA may reflect a technical artifact, given the confounding influence of additional inputs that could potentially distort the mean arterial pressure-mean middle cerebral artery blood velocity relationship.
Methylene blue counteracts cyanide cardiotoxicity: cellular mechanisms
Authors: Cheung Joseph Y. , Wang JuFang , Zhang Xue-Qian , Song Jianliang , Tomar Dhanendra , Madesh Muniswamy , Judenherc-Haouzi Annick , Haouzi Philippe 
Published: February 2018

In adult left ventricular mouse myocytes, exposure to sodium cyanide (NaCN) in the presence of glucose dose-dependently reduced contraction amplitude, with ~80% of maximal inhibitory effect attained at 100 µM. NaCN (100 µM) exposure for 10 min significantly decreased contraction and intracellular Ca2+concentration ([Ca2+]i) transient amplitudes, systolic but not diastolic [Ca2+]i, and maximal L-type Ca2+current ( ICa) amplitude, indicating acute alteration of [Ca2+]ihomeostasis largely accounted for the observed excitation-contraction abnormalities. In addition, NaCN depolarized resting membrane potential ( Em), reduced action potential (AP) amplitude, prolonged AP duration at 50% (APD50) and 90% repolarization (APD90), and suppressed depolarization-activated K+currents but had no effect on Na+-Ca2+exchange current ( INaCa). NaCN did not affect cellular adenosine triphosphate levels but depolarized mitochondrial membrane potential (ΔΨm) and increased superoxide (O2·−) levels. Methylene blue (MB; 20 µg/ml) added 3 min after NaCN restored contraction and [Ca2+]itransient amplitudes, systolic [Ca2+]i, Em, AP amplitude, APD50, APD90, ICa, depolarization-activated K+currents, ΔΨm, and O2·−levels toward normal. We conclude that MB reversed NaCN-induced cardiotoxicity by preserving intracellular Ca2+homeostasis and excitation-contraction coupling ( ICa), minimizing risks of arrhythmias ( Em, AP configuration, and depolarization-activated K+currents), and reducing O2·−levels.NEW & NOTEWORTHY Cyanide poisoning due to industrial exposure, smoke inhalation, and bioterrorism manifests as cardiogenic shock and requires rapidly effective antidote. In the early stage of cyanide exposure, adenosine triphosphate levels are normal but myocyte contractility is reduced, largely due to alterations in Ca2+homeostasis because of changes in oxidation-reduction environment of ion channels. Methylene blue, a drug approved by the U.S. Food and Drug Administration, ameliorates cyanide toxicity by normalizing oxidation-reduction state and Ca2+channel function.
Mito-Tempo prevents nicotine-induced exacerbation of ischemic brain damage
Authors: Li Chun , Sun Hong , Xu Guodong , McCarter Kimberly D. , Li Jiyu , Mayhan William G. 
Published: February 2018

Nicotine may contribute to the pathogenesis of cerebrovascular disease via the generation of reactive oxygen species (ROS). Overproduction of ROS leads to brain damage by intensifying postischemic inflammation. Our goal was to determine the effect of Mito-Tempo, a mitochondria-targeted antioxidant, on ischemic brain damage and postischemic inflammation during chronic exposure to nicotine. Male Sprague-Dawley rats were divided into four groups: control, nicotine, Mito-Tempo-treated control, and Mito-Tempo-treated nicotine. Nicotine (2 mg·kg−1·day−1) was administered via an osmotic minipump for 4 wk. Mito-Tempo (0.7 mg·kg−1·day−1ip) was given for 7 days before cerebral ischemia. Transient focal cerebral ischemia was induced by occlusion of the middle cerebral artery for 2 h. Brain damage and inflammation were evaluated after 24 h of reperfusion by measuring infarct volume, expression of adhesion molecules, activity of matrix metalloproteinase, brain edema, microglial activation, and neutrophil infiltration. Nicotine exacerbated infarct volume and worsened neurological deficits. Nicotine did not alter baseline ICAM-1 expression, matrix metallopeptidase-2 activity, microglia activation, or neutrophil infiltration but increased these parameters after cerebral ischemia. Mito-Tempo did not have an effect in control rats but prevented the chronic nicotine-induced augmentation of ischemic brain damage and postischemic inflammation. We suggest that nicotine increases brain damage following cerebral ischemia via an increase in mitochondrial oxidative stress, which, in turn, contributes to postischemic inflammation.NEW & NOTEWORTHY Our findings have important implications for the understanding of mechanisms contributing to increased susceptibility of the brain to damage in smokers and users of nicotine-containing tobacco products.
STW 5 (Iberogast) Therapy in Gastrointestinal Functional Disorders
Authors: Malfertheiner Peter 
Published: February 2018

<b><i>Background:</i></b> Functional gastrointestinal disorders (FGIDs) are very common and affect populations worldwide. A majority of patients are affected by a variety of heterogenous gastrointestinal symptoms (GIS) related to the upper and lower digestive system with frequent overlap and mostly of mild to moderate degree. The herbal medicinal preparation STW 5 is documented as an effective therapeutic option for treating FGID. <b><i>Studies Conducted in Summary:</i></b> STW 5 has been in use for more than 50 years in clinical practice and proven to be effective and safe in the management of FGID. The high efficacy of STW 5 on symptoms clustered in functional dyspepsia (FD) and irritable bowel syndrome (IBS) as well as on individual abdominal symptoms is demonstrated in 5 controlled, randomized double-blind studies in FD and in one trial conducted in patients with IBS. In addition the beneficial therapeutic effect of STW 5 on FGD as well as safety issues have been reported in a series of non interventional studies conducted in several thousands of adult patients and including 980 children. An additional study has been performed addressing the question as to how quickly the therapeutic effect is obtained after STW 5 administration. <b><i>Key Messages from These Studies:</i></b> STW 5 is an effective phyto-medication for treating patients with FD and IBS. STW 5 acts beneficially on abdominal symptom clusters as well as on individual GIS in adults and children. The time to onset of action is rapid, well tolerated and safe. The repetitive use of STW 5 is an appropriate option in clinical practice for patients with FGID.
Herbal Preparation STW 5 for Functional Gastrointestinal Disorders: Clinical Experience in Everyday Practice
Authors: Lapina Tatiana L. , Trukhmanov Alexander S. 
Published: February 2018

<b><i>Background:</i></b> The most common functional gastrointestinal disorders (FGID) are functional dyspepsia (FD) and irritable bowel syndrome (IBS), with a prevalence in the general population of 15–20% (FD) and 10% (IBS), respectively. The complexity of pathophysiologic mechanisms and limitations in therapeutic options make the management of FD and IBS patients a challenge in routine clinical practice. <b><i>Summary:</i></b> Syndromes classified as FGID frequently overlap, and coexist with gastroesophageal reflux disease (GERD). Patients with overlapping symptoms are more likely to seek medical care. The challenge for routine clinical practice is to find the best approach for treatment of multiple symptoms. STW 5, a combination of 9 herbal extracts, was shown to have multi-target effects: it normalizes the disturbed gastrointestinal motility, alleviates hypersensitivity, inhibits inflammation, suppresses gastric hypersecretion, and modulates the microbiota. Controlled randomized studies proved STW 5 to be efficacious both in FD and IBS, with control over the full spectrum of upper and lower gastrointestinal symptoms. STW 5 reduced concomitant heartburn in FD patients. STW 5 was well tolerated in the examined populations, independent of concomitant diseases and concomitant medication. <b><i>Key Messages:</i></b> The clinical use of the herbal preparation STW 5 in FD and IBS is evidence-based. STW 5 is an example for the concept of multi-target therapy. It offers treatment opportunities in routine clinical practice with high prevalence of overlap of FGID and concomitant GERD. Considering that FD and IBS are typically chronic and recurrent conditions, the clinically observed good tolerability and safety of STW 5 is an advantage.
Mechanism of Action of STW 5 in Functional Dyspepsia and IBS: The Origin of Multi-Target
Authors: Allescher Hans-Dieter , Abdel-Aziz Heba 
Published: February 2018

<b><i>Background:</i></b> STW 5 is a complex herbal combination preparation composed of 9 different herbal extracts. As an herbal medicinal product, this preparation is indicated for treating functional dyspepsia (FD) and irritable bowel syndrome (IBS). Its efficacy and practical applicability was demonstrated in several clinical studies. <b><i>Summary:</i></b> Each herbal constituent of STW 5 has distinct effects on the gastrointestinal tract, and each shows activity through different mechanisms of action: among others, the single extracts have effects on nerves, smooth muscles, epithelial, and inflammatory cells. For example, they have relaxing or tonicizing effects on gastrointestinal muscles, and they counteract inflammation through different physiological systems, contributing to the clinical efficacy through modulation of multiple therapeutic targets. <b><i>Key Messages:</i></b> STW 5 is a role model for the concept of multi-targeting in therapy. Especially in complex syndromes such as FD and IBS, simultaneous multi-targeting of different functional causes seems to be a more promising approach than the classical paradigm of one disease – one receptor – one effect.
Phytotherapy in Functional Gastrointestinal Disorders
Authors: Kelber Olaf , Bauer Rudolf , Kubelka Wolfgang 
Published: February 2018

<b><i>Background:</i></b> Phytotherapy is an important therapeutic option in functional gastrointestinal diseases (FGID). It has a large tradition, with different approaches in different regions of the world, some of which have made their way into modern evidence-based medicine (EBM). <b><i>Summary:</i></b> Taking into account the number of herbs in use, and also the cumulated scientific evidence on them, FGID are possibly the most important indication in phytotherapy. This does not only apply for European phytotherapy, but also for other regions, such as Asia. Within European phytotherapy, herbs active in FGID are usually classified according to their main active constituents and their activities. Typically, the herbs used in FGID are grouped into amara, aromatica, amara aromatica combining both properties, herbs stimulating gastric secretion, herbs containing spasmolytic and carminative essential oils or spasmolytic alkaloids, mucilaginosa soothing the mucosa, and flavonoid containing drugs with anti-inflammatory properties. In phytotherapy, different plants are frequently combined to maximize effectiveness and specificity of action. Very potent combination products can be developed when the mechanisms of action of the combination partners are complementary. This approach can be demonstrated by the example of STW 5. For this herbal combination product, therapeutic efficacy in FGID has been clinically proven according to the highest standards of EBM. This example also underlines that modern rational phytotherapy is definitely part of modern EBM. <b><i>Key Messages:</i></b> FGID is one of the most important indications in phytotherapy and rationally combined herbal preparations are established evidence-based therapeutic options.