tbuckley/cabot-search huggingface dataset:
Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vitro.
Authors: A E Calogero, W T Gallucci, G P Chrousos, P W Gold
Journal: Journal of Clinical Investigation (1988)

To further our understanding of the functional role of catecholaminergic systems in regulating hypothalamic corticotropin-releasing hormone (CRH) secretion, we assessed the direct effects of a multiplicity of catecholamine agonists and antagonists on hypothalamic CRH secretion. To accomplish this, we used an in vitro rat hypothalamic organ culture system in which CRH secretion from single explants was evaluated by a specific RIA (IR-rCRH). Norepinephrine (NE) stimulated IR-rCRH secretion dose dependently, with peak effects in the nanomolar range. The effect of NE was antagonized by the mixed alpha antagonist phentolamine, the alpha 1 antagonist prazosin, and the alpha 2 antagonist yohimbine, but not by the beta blocker, L-propanolol. Compatible with these data were the findings that the alpha 1 agonist phenylephrine and the alpha 2 agonist clonidine both stimulated IR-rCRH secretion in a dose-dependent fashion. On the other hand, whereas the beta agonist, isoproterenol, caused a weak, non-dose-dependent increase in IR-rCRH secretion, this effect could not be antagonized by L-propanolol. Despite pretreatment with serotonin and acetylcholine antagonists, the effect of NE upon IR-rCRH secretion was undiminished, suggesting that NE-induced CRH secretion is not mediated by either neurotransmitter. On the other hand, pretreatment with gamma-aminobutyric acid (GABA) attenuated NE-induced IR-rCRH secretion. Whereas epinephrine (E) stimulated IR-rCRH secretion, this occurred only at higher concentrations, and was antagonized by phentolamine, but not by L-propanolol. Dopamine (DA) had a weak stimulatory effect that could be antagonized by the DA1 receptor antagonist, SCH 23390, but not by phentolamine. We conclude that NE and E stimulate hypothalamic IR-rCRH secretion via alpha 1 and alpha 2 receptors. The effect of NE upon IR-rCRH secretion is not apparently mediated by serotonergic or cholinergic interneurons, but is modulated by the inhibitory neurotransmitter, GABA. These data support the idea that the central catecholaminergic systems are excitatory rather than inhibitory upon CRH secretion when acting directly at the hypothalamic level.
Natalizumab and PML: a risky business?
Authors: D. B Clifford
Journal: Gut (2008)

The development of new treatments and their incorporation into the care of patients requires integration of a substantial body of information to achieve optimal outcomes for the greatest number of patients. Evidence based medical practice is evolving, and deserves support and encouragement, particularly as complicated risk–benefit decisions must be addressed in practice. In this issue, Verbeeck et al 1 ( see page 1393 ) provide useful observations for clinicians framing some of the risks associated with natalizumab (Tysabri), a drug approved by the US Food and Drug Administration (FDA) on 14 January 2008 for the treatment of Crohn’s disease.

Natalizumab is a humanized monoclonal antibody against α4-integrin first approved for treatment of relapsing, remitting multiple sclerosis (MS). This drug reduces the activity of MS as reflected by development of new magnetic resonance (MR) brain lesions, and by slowing progression of disability.2 Subsequently, studies support efficacy for Crohn’s disease.3 4 This efficacy is believed to result from blockade of integrin mediated migration of inflammatory cells involved with diseases such as MS or Crohn’s disease.

While critical disease-modifying activity is available through the use of natalizumab, its use has been impacted by toxicity. During the blinded clinical trials, the safety profile was excellent, but shortly after FDA approval of natalizumab for MS, three cases of progressive multifocal leukoencephalopathy (PML) were reported resulting in suspension of all dosing with this drug. Two cases were MS patients also on interferon β5 6 and one had Crohn’s disease concurrently treated with …
Large-Scale Profiling of Archival Lymph Nodes Reveals Pervasive Remodeling of the Follicular Lymphoma Methylome
Authors: J. Keith Killian, Sven Bilke, Sean Davis, Robert L. Walker, M. Scott Killian, Erich B. Jaeger, Yidong Chen, Jason Hipp, Stefania Pittaluga, Mark Raffeld, Robert Cornelison, William I. Smith,, Marina Bibikova, Jian-Bing Fan, Michael R. Emmert-Buck, Elaine S. Jaffe, Paul S. Meltzer
Journal: Cancer Research (2009)

Emerging technologies allow broad profiling of the cancer genome for differential DNA methylation relative to benign cells. Herein, bisulfite-modified DNA from lymph nodes with either reactive hyperplasia or follicular lymphoma (FL) were analyzed using a commercial C/UpG genotyping assay. Two hundred fifty-nine differentially methylated targets (DMT) distributed among 183 unique genes were identified in FL. Comparison of matched formalin-fixed, paraffin-embedded and frozen surgical pathology replicates showed the complete preservation of the cancer methylome among differently archived tissue specimens. Analysis of the DMT profile is consistent with a pervasive epigenomic remodeling process in FL that affects predominantly nonlymphoid genes.
Contact dermatitis with negative patch tests: the additive effect of allergens in combination
Authors: JANET McLELLAND, S. SHUSTER
Journal: British Journal of Dermatology (1990)

We deduced on theoretical grounds that conventional patch testing would be inadequate for the detection of sensitivity to multiple allergens. Fourteen patients with positive patch tests to two unrelated allergens were studied and the response to those two allergens was measured when tested singly or in combination, using 10 different pair combinations from 15 common allergens. With serial dilutions in chloroform (14 patients) and paraffin (four patients), the response was related to the log-dose of the allergen, and change in skin-fold thickness corresponded well with clinical grading. Single allergens diluted below the threshold for a patch-test response gave a response when given in combination, the threshold for a response to one allergen being lowered by the presence of another. On the linear part of the dose-response curves the response to the mixture of allergens was additive, the combined response being the sum of the individual components. Approaching the plateau region the response to the combination was greater than to the individual allergens but less than the sum of the single responses. The same results were obtained with allergens in paraffin. We conclude that conventional single allergen patch testing by itself is inadequate for the diagnosis of contact dermatitis.
Systematic review of scope and quality of electronic patient record data in primary care
Authors: K. Thiru
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To systematically review measures of data quality in electronic patient records (EPRs) in primary care. <b>Design</b> Systematic review of English language publications, 1980-2001. <b>Data sources</b> Bibliographic searches of medical databases, specialist medical informatics databases, conference proceedings, and institutional contacts. <b>Study selection</b> Studies selected according to a predefined framework for categorising review papers. <b>Data extraction</b> Reference standards and measurements used to judge quality. <b>Results</b> Bibliographic searches identified 4589 publications. After primary exclusions 174 articles were classified, 52 of which met the inclusion criteria for review. Selected studies were primarily descriptive surveys. Variability in methods prevented meta-analysis of results. Forty eight publications were concerned with diagnostic data, 37 studies measured data quality, and 15 scoped EPR quality. Reliability of data was assessed with rate comparison. Measures of sensitivity were highly dependent on the element of EPR data being investigated, while the positive predictive value was consistently high, indicating good validity. Prescribing data were generally of better quality than diagnostic or lifestyle data. <b>Conclusion</b> The lack of standardised methods for assessment of quality of data in electronic patient records makes it difficult to compare results between studies. Studies should present data quality measures with clear numerators, denominators, and confidence intervals. Ambiguous terms such as "accuracy" should be avoided unless precisely defined.
Giro, Tour, and Vuelta in the same season
Authors: A Lucia, J Hoyos, A Santalla, C P Earnest, J L Chicharro
Journal: British Journal of Sports Medicine (2003)

The exercise volume and intensity are reported of a male professional cyclist (age 30; V o 2 max 75.0 ml/kg/min) who successfully completed the 2001 Giro d’Italia (May), Tour de France (July), and Vuelta a España (September). The total exercise time during the Giro, Tour, and Vuelta was 90 hours 44 minutes (5444 minutes), 88 hours 23 minutes (5303 minutes), and 72 hours 59 minutes (4379 minutes) respectively. Heart rate telemetry during the races allowed the exercise intensity to be classified into three phases: I, below the first ventilatory threshold (VT1); II, between VT1 and the second ventilatory threshold (VT2); III, above VT2. Compared with the Giro and Tour, the lower exercise volume of the Vuelta (about 20% less total time) was compensated for by a considerably lower and higher contribution of phases I and III respectively. As a result, the total load (volume × intensity) in the three races was comparable.
Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm
Authors: Guangyao Kong, Mark Wunderlich, David Yang, Erik A. Ranheim, Ken H. Young, Jinyong Wang, Yuan-I Chang, Juan Du, Yangang Liu, Sin Ruow Tey, Xinmin Zhang, Mark Juckett, Ryan Mattison, Alisa Damnernsawad, Jingfang Zhang, James C. Mulloy, Jing Zhang
Journal: Journal of Clinical Investigation (2014)

Overactive RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML–initiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML–like phenotypes. In contrast, combined inhibition of MEK and JAK/STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/G12D animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and JAK/STAT in treating patients with JMML and MP-CMML.
Encephalomyelitis in a Case of Pink Disease
Authors: C. P. Lapage
Journal: BMJ (1941)

Encephalomyelitis in a Case of Pink DiseaseAlthough the symptoms and signs of pink disease are well known the cause is not yet established.Rocaz, however (Pink Disease, 1933, p. 129, supports the idea of an encephalitis due to a neurotropic virus.When it is considered that outbreaks of the disease take the form of individual cases scattered through any one area, the disease certainly does resemble poliomyelitis and polio-encephalitis in some respects.There is, however, little evidence of direct transmission from one child to another, and it is not usual for two members of a family to be affected.Another curious point to note is that the outbreaks are often limited to industrial areas, and occur among the children of the artisan class, although there is no observable relation to poverty.It is notable, too, that the disease only affects young children.The following case is interesting in that the necropsy supports the idea that an encephalomyelitic lesion was the cause of the symptoms and signs. CASE REPORTA child aged 1 year, one of a family of seven children, came from an industial area; the father was a meter collector earning £2 18s. a week.The child had had infantile eczema for six months, and had been losing weight for the past fort- night.He had been breast-fed, but weaned on to cows' milk, gravy, potatoes, milk puddings, etc. Had been suffering from diarrhoea for two weeks, with green foul-smelling stools.Had a cough for a week; no vomiting.Also suffering from insomnia, and profuse sweating especially in the head region.Condition on A dnission.-Thechild was somewhat dehydrated, and showed great hypotonia of the muscles, with flaccidity and wasting.-Therewas a rash, typical of pink disease, on the trunk, face, and legs.The child was irritable, scratching and rubbing the affected areas continually.The hands and feet were cold, pink, and shining.There was some desquamation.The general appearance suggested a case of pink disease of considerable severity and duration.Chest: poor resonance at both bases, with fine rales.Tongue furred.Abdomen retracted.
Renal Denervation in Moderate to Severe CKD
Authors: Dagmara Hering, Felix Mahfoud, Antony S. Walton, Henry Krum, Gavin W. Lambert, Elisabeth A. Lambert, Paul A. Sobotka, Michael Böhm, Bodo Cremers, Murray D. Esler, Markus P. Schlaich
Journal: Journal of the American Society of Nephrology (2012)

Sympathetic activation contributes to the progression of CKD and is associated with adverse cardiovascular outcomes. Ablation of renal sympathetic nerves reduces sympathetic nerve activity and BP in patients with resistant hypertension and preserved renal function, but whether this approach is safe and effective in patients with an estimated GFR (eGFR) < 45 ml/min per 1.73 m2 is unknown. We performed bilateral renal denervation in 15 patients with resistant hypertension and stage 3–4 CKD (mean eGFR, 31 ml/min per 1.73 m2). We used CO2 angiography in six patients to minimize exposure to contrast agents. Estimated GFR remained unchanged after the procedure, irrespective of the use of CO2 angiography. Mean baseline BP ± SD was 174±22/91±16 mmHg despite the use of 5.6±1.3 antihypertensive drugs. Mean changes in office systolic and diastolic BP at 1, 3, 6, and 12 months were −34/−14, −25/−11, −32/−15, and −33/−19 mmHg, respectively. Night-time ambulatory BP significantly decreased (P<0.05), restoring a more physiologic dipping pattern. In conclusion, this study suggests a favorable short-term safety profile and beneficial BP effects of catheter-based renal nerve ablation in patients with stage 3–4 CKD and resistant hypertension.
Cardiopulmonary stress during exercise training in patients with COPD
Authors: V. S. Probst, T. Troosters, F. Pitta, M. Decramer, R. Gosselink
Journal: European Respiratory Journal (2006)

Exercise training is an essential component of pulmonary rehabilitation. However, the cardiopulmonary stress imposed during different modalities of exercise training is not yet known. In the present study, the cardiopulmonary stress of a 12-week exercise training programme in 11 chronic obstructive pulmonary disease (COPD) patients (forced expiratory volume in one second 42±12%pred, age 69±6 yrs) was measured. Pulmonary gas exchange and cardiac frequency ( f C ) of three training sessions were measured with a portable metabolic system at the beginning, mid-term and end of the programme. Symptoms were assessed with Borg scores. The exercise intensity was compared with the recommendations for exercise training by the American College of Sports Medicine (ACSM). Training effects were significant (maximum change in work: 14±11 Watts, 6-min walk test: 44±36 m). Whole body exercises (cycling, walking and stair climbing) consistently resulted in higher cardiopulmonary stress (oxygen uptake ( V ′ O 2 ), minute ventilation and f C ) than arm cranking and resistance training. Dyspnoea was higher during cycling than resistance training. Patients exercised for &gt;70% (&gt;20 min) of the total exercise time at &gt;40% of the V ′ O 2 reserve and f C reserve (“moderate” intensity according to the ACSM) throughout the programme. The cardiopulmonary stress resistance training is lower than during whole-body exercise and results in fewer symptoms. In addition, exercise testing based on guidelines using a fixed percentage of baseline peak performance and symptom scores achieves and sustains training intensities recommended according to the American College of Sports Medicine.
Role of APP in neuronal function
Authors: Hui Zheng
Journal: Molecular Neurodegeneration (2013)

Background Genetic and biochemical studies establish a central role of the amyloid precursor protein (APP) in Alzheimer’s disease (AD): Genetic mutations and gene amplification of APP are linked to early onset of familial Alzheimer’s disease (FAD); APP processing generates b-amyloid (Ab) peptides, which are the principal components of the amyloid pathology. Therefore, understanding the role of APP in neuronal function and dysfunction will provide crucial insights to AD pathogenesis.
Molecular Grading of Urothelial Cell Carcinoma With Fibroblast Growth Factor Receptor 3 and MIB-1 is Superior to Pathologic Grade for the Prediction of Clinical Outcome
Authors: Bas W.G. van Rhijn, André N. Vis, Theo H. van der Kwast, Wim J. Kirkels, François Radvanyi, Engelbert C.M. Ooms, Dominique K. Chopin, Egbert R. Boevé, Adriaan C. Jöbsis, Ellen C. Zwarthoff
Journal: Journal of Clinical Oncology (2003)

Fibroblast growth factor receptor 3 (FGFR3) mutations were recently found at a high frequency in well-differentiated urothelial cell carcinoma (UCC). We investigated the relationship between FGFR3 status and three molecular markers (MIB-1, P53, and P27kip1) associated with worse prognosis and determined the reproducibility of pathologic grade and molecular variables.In this multicenter study, we included 286 patients with primary (first diagnosis) UCC. The histologic slides were reviewed. FGFR3 status was examined by polymerase chain reaction-single strand conformation polymorphism and sequencing. Expression levels of MIB-1, P53, and P27kip1 were determined by immunohistochemistry. Mean follow-up was 5.5 years (range, 0.4 to 18.4 years).FGFR3 mutations were detected in 172 (60%) of 286 UCCs. Grade 1 tumors had an FGFR3 mutation in 88% of patient samples and grade 3 tumors in 16% of patient samples. Conversely, aberrant expression patterns of MIB-1, P53, and P27kip1 were seen in 5%, 2%, and 3% of grade 1 tumors and in 85%, 60%, and 56% of grade 3 tumors, respectively. In multivariate analysis with recurrence rate, progression, and disease-specific survival as end points, the combination of FGFR3 and MIB-1 proved independently significant in all three cases. By using these two molecular markers, three molecular grades (mGs) could be identified: mG1 (mutation; normal expression), favorable prognosis; mG2 (two remaining combinations), intermediate prognosis; and mG3 (no mutation; high expression), poor prognosis. The molecular variables were more reproducible than pathologic grade (85% to 100% v 47% to 61%).The FGFR3 mutation represents the favorable molecular pathway of UCC. Molecular grading provides a new, simple, and highly reproducible tool for clinical decision making in UCC patients.
Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration
Authors: Ann H Milam, Christine A Curcio, Artur V Cideciyan, Samir Saxena, Sinoj K John, Howard S Kruth, Goldis Malek, John R Heckenlively, Richard G Weleber, Samuel G Jacobson
Journal: Ophthalmology (2000)
Presence of B Cells in Tertiary Lymphoid Structures Is Associated with a Protective Immunity in Patients with Lung Cancer
Authors: Claire Germain, Sacha Gnjatic, Fella Tamzalit, Samantha Knockaert, Romain Remark, Jérémy Goc, Alice Lepelley, Etienne Becht, Sandrine Katsahian, Geoffray Bizouard, Pierre Validire, Diane Damotte, Marco Alifano, Pierre Magdeleinat, Isabelle Cremer, Jean-Luc Teillaud, Wolf-Herman Fridman, Catherine Sautès-Fridman, Marie-Caroline Dieu-Nosjean
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

It is now well established that immune responses can take place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non-small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome.To study the role of follicular B cells in TLS and the potential link with a local humoral immune response in patients with NSCLC.The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performed by flow cytometry. A retrospective study was conducted in two independent cohorts of patients. Antibody specificity was analyzed by ELISA.Consistent with TLS organization, all stages of B-cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-term survival, both in patients with early-stage NSCLC and with advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome.B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity.
Magnitude of myocardial potassium changes during acute alterations in pacing frequency in the in situ pig heart
Authors: A. ILEBEKK, F. R ANDERSEN, O. M SEJERSTED
Journal: Cardiovascular Research (1986)

Journal Article Magnitude of myocardial potassium changes during acute alterations in pacing frequency in the in situ pig heart Get access ARNFINN ILEBEKK, ARNFINN ILEBEKK **From the University of Oslo, Institute for Experimental Medical Research, Ullevaal Hospital, Oslo Search for other works by this author on: Oxford Academic PubMed Google Scholar FRANK R ANDERSEN, FRANK R ANDERSEN †From the Institute of Muscle Physiology, Oslo, Norway Search for other works by this author on: Oxford Academic PubMed Google Scholar OLE M SEJERSTED OLE M SEJERSTED †From the Institute of Muscle Physiology, Oslo, Norway Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 20, Issue 3, March 1986, Pages 176–181, https://doi.org/10.1093/cvr/20.3.176 Published: 01 March 1986