tbuckley/cabot-search huggingface dataset:
Cardiac sodium channel and inherited arrhythmia syndromes
Authors: C Bezzina
Journal: Cardiovascular Research (2001)

Time for primary review 32 days. 

The voltage-gated cardiac sodium channel is responsible for the generation of the rapid upstroke of the myocardial action potential and thereby plays a central role in excitability of myocardial cells. In addition, since the action potential upstroke velocity — in conjunction with the extent of intercellular communication via gap junctions [1] — also determines impulse conduction velocity in cardiac tissue, this channel also plays a vital role in impulse propagation. Mutations in the gene encoding this channel ( SCN 5 A ; Section 2.1) have been linked to three forms of primary electrical disease — the long QT syndrome (LQTS) [2], the Brugada syndrome (BS) [3] and cardiac conduction defects [4]. The elucidation of the pathophysiological mechanisms of these mutant Na+ channels would ultimately enable more specific pharmacological intervention in the management of these syndromes and other related arrhythmias.

The cardiac Na+ channel (see Ref. [5] for review) is a member of the voltage-dependent family of Na+ channels (see Ref. [6] for review). These channels consist of heteromeric assemblies of an α-subunit, the pore-forming component, the function of which is modulated by association with one or two ancillary β-subunits.

### 2.1 α-Subunit

The human cardiac Na+ channel α-subunit is a heavily glycosylated protein of ∼260 kDa consisting of 2016 amino acid residues [7]. It is encoded by the SCN 5 A gene [8], which is located on chromosome 3p21 [9]. At least 11 other different genes that encode highly homologous sodium channel α-subunit isoforms expressed in the heart, muscle and nervous system have been hitherto identified in man (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide). They display a modular architecture (Fig. 1), which consists of four internally homologous domains (DI–DIV) each made up of six transmembrane segments (S1–S6). The interdomain linkers and the N- and … 

* Corresponding author. Tel.: +31-20-566-3265; fax: +31-20-697-5458 a.a.wilde{at}amc.uva.nl
Newly Developed Techniques to Study and Diagnose Acute Renal Failure
Authors: Pierre C. Dagher, Stefan Herget-Rosenthal, Stefan G. Ruehm, Sang-Kyung Jo, Robert A. Star, Rajiv Agarwal, Bruce A. Molitoris
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Progress in treating human acute renal failure (ARF) is dependent on developing techniques that allow for the rapid diagnosis, quantification of injury, further understanding of the pathophysiology, and the effects of therapy. Therefore, four techniques that will facilitate this progress are described and illustrated by four different investigative teams. Techniques to measure rapid changes in GFR are available for rapid diagnosis and quantification of ARF in humans. State-of-the-art magnetic resonance imaging (MRI) presently allows for enhanced resolution of regional renal blood flow and functional evaluations in patients. Furthermore, new probes and techniques for MRI that allow for identification and quantitation of inflammation, applicable to human ARF, are being developed and tested in animal models. Finally, two-photon microscopy will allow for four-dimensional cellular and subcellular studies in animal models of ARF providing rapid insights into pathophysiology and the therapeutic effects of a variety of promising agents. Further development and utilization of these techniques, especially in concert with genetic, proteomic, and molecular approaches, will allow for needed insights into the pathophysiology and therapy in human ARF. E-mail: [email protected]
Lymphoma occurring in patients over 90 years of age: characteristics, outcomes, and prognostic factors. A retrospective analysis of 234 cases from the LYSA
Authors: A. Trebouet, T. Marchand, R. Lemal, E. Gyan, F. Broussais-Guillaumot, Y. Guillermin, H. Monjanel, G. Salles, S. Le Gouill, P. Godmer, C. Fruchart, G. Damaj, P. Feugier, C. Thieblemont, M. Maynadié, A. Monnereau, X. Troussard, D. Rossille, T. Lamy, R. Houot
Journal: Annals of Oncology (2013)
Survey of flexible fibreoptic bronchoscopy in the United Kingdom
Authors: C.M. Smyth, R.J. Stead
Journal: European Respiratory Journal (2002)

The practice of flexible bronchoscopy is not standardized. Current guidelines are concerned primarily with safety aspects of the procedure. In view of this, and the authors' own observations of individual variation in preparation and technique, a national survey of bronchoscopic procedure was performed to assess physicians' methods. A structured questionnaire was mailed to 547 consultant physicians in adult respiratory medicine. Physicians' routines of patient preparation, drug therapy, sampling methods, and experience of complications with the flexible bronchoscope were assessed. A 60% response (328 physicians) was obtained. Patient consent was obtained by a junior doctor in 31% of replies. 205 (63%) physicians gave benzodiazepine sedation, 46 (14%) used opioid, and 38 (12%) administered both. Ninety-four (29%) physicians prescribed an antimuscarinic agent, and 235 (74%) gave antibiotics to patients with mechanical heart valves. Only 22% of physicians monitored electrocardiogram and 10% monitored blood pressure during all procedures. Marked variance was noted in sampling routines of suspected lung tumours. Physicians who used fluoroscopic guidance for transbronchial lung biopsy reported a significantly lower incidence of pneumothorax requiring drain insertion over the previous 12 months compared to those who did not (2.68 of 1000 versus 9.17 of 1000, (p&lt;0.03)), but no difference in the total incidence of pneumothorax. Only 87 (27%) of responders had performed transbronchial needle aspiration sampling over the previous 12 months. The preparation and practice of flexible bronchoscopy varies greatly for each physician. Use of radiographical screening for performing transbronchial lung biopsy was associated with a lower likelihood of pneumothorax requiring chest tube drainage.
Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells
Authors: Florian Kuchenbauer, Sarah M. Mah, Michael Heuser, Andrew McPherson, Jens Rüschmann, Arefeh Rouhi, Tobias Berg, Lars Bullinger, Bob Argiropoulos, Ryan D. Morin, David Lai, Daniel T. Starczynowski, Aly Karsan, Connie J. Eaves, Akira Watahiki, Yuzhuo Wang, Samuel A. Aparicio, Arnold Ganser, Jürgen Krauter, Hartmut Döhner, Konstanze Döhner, Marco A. Marra, Fernando D. Camargo, Lars Palmqvist, Christian Buske, R. Keith Humphries
Journal: Blood (2011)
Muscular reflex and baroreflex influences on heart rate during isometric contractions
Authors: K. A. STREATFEILD, N. S. DAVIDSON, D. I. McCLOSKEY
Journal: Cardiovascular Research (1977)

Isometric hindlimb contractions were induced in anaesthetised dogs by stimulation of appropriate spinal ventral roots. During such contractions there were appreciable reflex systemic pressor responses accompanied by small increases in heart rate. The heart rate responses during contractions were small because the primary cardioacceleratory reflexes from muscle were partly masked during contractions by opposing baroreceptor-cardiodepressor reflexes.
Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes
Authors: Attila Oláh, Balázs I. Tóth, István Borbíró, Koji Sugawara, Attila G. Szöllõsi, Gabriella Czifra, Balázs Pál, Lídia Ambrus, Jennifer Kloepper, Emanuela Camera, Matteo Ludovici, Mauro Picardo, Thomas Voets, Christos C. Zouboulis, Ralf Paus, Tamás Bíró
Journal: Journal of Clinical Investigation (2014)

The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.
Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results
Authors: Hope S. Rugo, Roy S. Herbst, Glenn Liu, John W. Park, Merrill S. Kies, Heidi M. Steinfeldt, Yazdi K. Pithavala, Steven D. Reich, James L. Freddo, George Wilding
Journal: Journal of Clinical Oncology (2005)

Purpose We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. Patients and Methods Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. Results Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. Conclusion In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.
Overexpression of p73 as a Tissue Marker for High-Risk Gastritis
Authors: Gonzalo Carrasco, Jose Diaz, Jose R. Valbuena, Paulina Ibanez, Paz Rodriguez, Gabriela Araya, Carolina Rodriguez, Javiera Torres, Ignacio Duarte, Edmundo Aravena, Fernando Mena, Carlos Barrientos, Alejandro H. Corvalan
Journal: Clinical Cancer Research (2010)

Histologic assessment of high-risk gastritis for the development of gastric cancer is not well defined. The identification of tissue markers together with the integration of histologic features will be required for this assessment.Matched tumor/nontumor adjacent mucosa (NTAM) of 91 early gastric cancer and 148 chronic gastritis cases were evaluated for histologic characteristics (atrophy, intestinal metaplasia, chronic inflammation, polymorphonuclear infiltration, and Helicobacter pylori) by the Sydney System. Atrophy risk assessment was also evaluated by the Operative Link on Gastritis Assessment (OLGA) staging system. Eight tissue markers (BRCA1, HSP90, STAT1, FHIT, EGFR, p73, p53, p16INK4a) and EBV were also evaluated by tissue microarray/immunohistochemistry/in situ hybridization platform. Data were analyzed by contingency tables (2 x 2) using Fisher's exact two-tailed test (P < 0.001) and integrated by Significance Analysis of Microarrays (SAM) and clustering analysis.Histologically, NTAM have severe intestinal metaplasia/chronic inflammation and severe atrophy assessed by Sydney and OLGA staging systems. H. pylori infection was similar in both groups, and EBV was found only in 5.5% of the tumor samples. Overexpression of p73 was higher in NTAM (50.5%) than in chronic gastritis (10.8%; P < 0.0001). Integration of histologic features and tissue markers showed that overexpression of p73, severe atrophy, and OLGA stage 4 were the most relevant features in NTAM. Clustering analysis correctly assigned NTAM and control cases (P < 0.0001).Overexpression of p73 should be considered for the assessment of high-risk chronic gastritis. SAM allows the integration of histology and tissue markers for this assessment.
A simple method to improve the dissolution of repaglinide and exploration of its mechanism
Authors: Zhaolu Zhu, Tianzhi Yang, Yanan Zhao, Nannan Gao, Donglei Leng, Pingtian Ding
Journal: Asian Journal of Pharmaceutical Sciences (2014)

In the present study, a simple and rapid method was developed to improve the in vitro dissolution of repaglinide, an oral antidiabetic drug, which was based on addition of meglumine in 50% (v/v) ethanol to dissolve repaglinide, and the drug dissolved in meglumine/50% ethanol was used directly with a binder to prepare tablets. The mechanism of solubilization of repaglinide by meglumine was studied by using infrared spectrum (IR), ultraviolet (UV) measurement through dual wavelength, differential scanning calorimetry (DSC) and X-ray powder diffraction methods. Dissolution tests of repaglinide tablets were performed in the media with different pH values and the repaglinide concentrations were analyzed by High Performance Liquid Chromatography (HPLC) method. The solubility data showed that with the meglumine concentration increasing, the solubility of repaglinide was increased. Meanwhile, tablets with the molar ratio of repaglinide and meglumine 1:2 (n/n) resulted in a significant increase in dissolution compared to the repaglinide tablets without using meglumine, and nearly equal to the commercial preparations of NovoNorm®, which concluded that meglumine had a great role in promoting the dissolution of repaglinide. The results of IR and UV dual wavelength methods suggested the formation of repaglinide–meglumine (REP–MEG) molecular complex. DSC results showed that the melting peak of repaglinide disappeared in the REP–MEG coprecipitate, which indicated that repaglinide was stable when existing at amorphous or molecular state. The experiment of X-ray powder diffraction showed that with the solubilization of meglumine, the crystal diffraction peak of repaglinide disappeared, which further inferred that repaglinide was formed complexes with meglumine. It was demonstrated that the method of improving repaglinide with meglumine was reliable and could be suitable for repaglinide tablets production in industry. This study also provides a feasible way to enhance the dissolution of drugs with low solubility, which will be leading to improved bioavailability of these drugs.
Does spinal MRI add incremental diagnostic value to MRI of the sacroiliac joints alone in patients with non-radiographic axial spondyloarthritis?
Authors: Ulrich Weber, Veronika Zubler, Zheng Zhao, Robert GW Lambert, Stanley M Chan, Susanne J Pedersen, Mikkel Østergaard, Kaspar Rufibach, Walter P Maksymowych
Journal: Annals of the Rheumatic Diseases (2014)

Objective To assess the incremental diagnostic value of spine MRI evaluated separately from and combined with sacroiliac joint (SIJ) MRI in non-radiographic axial spondyloarthritis (nr-axSpA) compared with SIJ MRI alone. Methods The study sample comprised two independent cohorts A/B of 130 consecutive patients aged ≤50 years with back pain, newly referred to two university clinics, and 20 healthy controls. Patients were classified according to clinical examination and pelvic radiographs as having nr-axSpA (n=50), ankylosing spondylitis (n=33), or non-specific back pain (n=47). Four readers assessed SIJ and spine MRI separately 6 months apart, and 1–12 months later both scans simultaneously using standardised modules. Readers recorded presence/absence of SpA and their level of confidence in this conclusion on a 0–10 scale (0=definitely not; 10=definite). We analysed differences between SIJ MRI versus spine MRI alone, and SIJ MRI alone versus combined MRI, descriptively by the number/percentage of subjects according to the mean of four readers. Results In cohorts A/B, 15.8%/24.2% of patients with nr-axSpA having a negative SIJ MRI were reclassified as being positive for SpA by global evaluation of combined scans. However, 26.8%/11.4% of non-specific back pain controls and 17.5% of healthy volunteers with a negative SIJ MRI were falsely reclassified as having SpA by combined MRI. Low confidence in a diagnosis of SpA by SIJ MRI increased to high confidence by combined MRI in 6.6%/7.3% of patients with nr-axSpA. Conclusions Combined spine and SIJ MRI added little incremental value compared with SIJ MRI alone for diagnosing patients with nr-axSpA and enhancing confidence in this diagnosis.
Functional development of the creatine kinase system in perinatal rabbit heart.
Authors: J A Hoerter, A Kuznetsov, R Ventura-Clapier
Journal: Circulation Research (1991)

The functional development of the creatine kinase system has been studied in rabbit heart during perinatal growth. Fiber bundles were obtained from left ventricles of fetal rabbits at the 30th day of gestation, newborn rabbits aged 1, 3, 8, and 17 days, and adult rabbits. Total creatine kinase activity was constant during perinatal development, whereas myofibrillar bound creatine kinase activity increased 15-fold during the first postnatal week. Functional activity of myofibrillar creatine kinase was assayed in Triton X-100-skinned fibers by its ability to induce active tension in the absence of ATP or to relax rigor tension. It was very low in 1-day-old newborns and increased during the first 2 weeks to reach adult levels 17 days after birth. Functional activity of mitochondrial creatine kinase was determined in saponin-skinned fibers. Creatine-stimulated respiration appeared only after birth and increased gradually between 1 and 17 days after birth. The results show that, although the two creatine kinase isoforms (mitochondrial and myofibrillar) are expressed at different stages during development, their functional activities appear in parallel in mitochondria and myofibrils. Early postnatal development is characterized by binding of creatine kinase isoenzymes to intracellular organelles. Such compartmentation participates in the postnatal cardiac cellular maturation.
D-dimer as a possible prognostic marker of operable hormone receptor-negative breast cancer
Authors: A.P.B. Batschauer, C.P. Figueiredo, E.C. Bueno, M.A. Ribeiro, L.M.S. Dusse, A.P. Fernandes, K.B. Gomes, M.G. Carvalho
Journal: Annals of Oncology (2009)
Model T Muscle CARs Can Treat Brain Tumors
Authors: Laura A. Johnson
Journal: Clinical Cancer Research (2012)

Despite standard treatment with resection, radiation, and chemotherapy, glioblastoma remains a deadly disease with a dismal prognosis. Redirecting patient T cells to target the glioblastoma-associated antigen, IL13Rα2, offers a promising translational immunotherapy with the potential to make a meaningful impact for patients with this disease.
Impact of Early Neonatal Breast-Feeding on Psychomotor and Neuropsychological Development in Children of Diabetic Mothers
Authors: Andreas Plagemann, Thomas Harder, Rainer Kohlhoff, Sonja Fahrenkrog, Elke Rodekamp, Kerstin Franke, Joachim W. Dudenhausen
Journal: Diabetes Care (2005)

OBJECTIVE—In general, breast-feeding positively influences development of psychomotor function and cognition in children. Offspring of diabetic mothers (ODM) have delayed psychomotor and cognitive development. Recently, we observed a dose-dependent negative effect of early neonatal ingestion of breast milk from diabetic mothers (diabetic breast milk [DBM]) on the risk of overweight during early childhood. Here, we investigated the influence of early neonatal intake of DBM on neurodevelopment in ODM. RESEARCH DESIGN AND METHODS—A total of 242 ODM were evaluated for age of achieving major developmental milestones (Denver Developmental Scale) according to the volume of DBM ingested during the first week of life, using Kruskal-Wallis and Kaplan-Meier analysis. RESULTS—Children in the upper tertile of early neonatal ingestion of DBM achieved early psychomotor developmental milestones (“lifting head while prone,” “following with eyes”) earlier than those in lower tertiles (P = 0.002). In contrast, a delay in the onset of speaking was observed in children who had ingested larger volumes of DBM compared with those with lower DBM intake (P = 0.002). This negative impact of DBM ingestion was not confounded by birth characteristics, total milk intake, or socioeconomic/educational status. CONCLUSIONS—Our data indicate differential effects of early neonatal DBM ingestion on psychomotor and cognitive development. Ingesting larger compared with smaller volumes of DBM may normalize early psychomotor development in ODM but delays onset of speaking as a parameter indicative of cognitive development. This effect may result from qualitative alterations in the composition of DBM. Further studies are urgently recommended on the benefits and harms of breast-feeding in ODM.
Managing Overly Rapid Correction of Chronic Hyponatremia
Authors: Kamel S. Kamel, Mitchell L. Halperin
Journal: Journal of the American Society of Nephrology (2010)

Rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome (ODS) and devastating neurologic sequelae.[1][1] The rate of rise in plasma sodium concentration (PNa) in patients with chronic hyponatremia should be <8 mmol/L per d[2][2] and even lower in patients at higher risk