tbuckley/cabot-search huggingface dataset:
Crossbridge scheme and the kinetic constants of elementary steps deduced from chemically skinned papillary and trabecular muscles of the ferret.
Authors: M Kawai, Y Saeki, Y Zhao
Journal: Circulation Research (1993)

Elementary steps of the crossbridge cycle in chemically skinned ferret myocardium were investigated with sinusoidal analysis. The muscle preparations were activated at pCa 4.82 and an ionic strength of 200 mM, and the effects of the change in the MgATP (S) and phosphate (Pi) concentrations on three exponential processes were studied at 20 degrees C. Results are consistent with the following crossbridge scheme: [formula: see text] where A is actin, M is myosin, D is MgADP, and Det includes all detached states (MS and MDP) and weakly attached states (AMS and AMDP). From our studies, we obtained K1a = 0.99 mM-1 (MgATP association), k1b = 270 s-1 (ATP isomerization), k-1b = 280 s-1 (reverse isomerization), K1b = k1b/k-1b = 0.95, k2 = 48 s-1 (crossbridge detachment), k-2 = 14 s-1 (reverse detachment), K2 = 3.5, k4 = 11 s-1 (crossbridge attachment), k-4 = 107 s-1 (reverse attachment), K4 = 0.11, and K5 = 0.06 mM-1 (Pi association). K6 is the rate-limiting step, and it is the slowest forward reaction in the cycle, which results in the rigor-like AM state. K1a (MgATP binding) is four times that of rabbit psoas, and K5 (Pi binding) is 0.3 times that of psoas, demonstrating that crossbridges in myocardium bind MgATP more and Pi less than psoas. The rate constants of ATP isomerization (k1b, k-1b), crossbridge detachment (k2, k-2), and crossbridge attachment (k4) steps are generally an order of magnitude slower than rabbit psoas. The reverse attachment step (k-4) is similar to that in psoas, indicating that this step may occur irrespective of the myosin type and possibly spontaneously. The above scheme with the deduced kinetic constants predicts the following crossbridge distributions at 5 mM MgATP2- and 8 mM Pi:AM (3%), AM S (15%), AM*S (14%), Det (50%), AM*DP (6%), and AM*D (12%). The actual number of attached crossbridges was measured to be 51 +/- 4% by the stiffness ratio during activation and after rigor induction, and a strong correlation was seen with the prediction. Our results are consistent with the hypothesis that force generation occurs at the Det--&gt;AM*DPi transition, and the same force is maintained after the release of Pi.
Colonoscopic resection of lateral spreading tumours: a prospective analysis of endoscopic mucosal resection
Authors: D P Hurlstone
Journal: Gut (2004)

<b>Background:</b> Lateral spreading tumours are superficial spreading neoplasms now increasingly diagnosed using chromoscopic colonoscopy. The clinicopathological features and safety of endoscopic mucosal resection for lateral spreading tumours (G-type "aggregate" and F-type "flat") has yet to be clarified in Western cohorts. <b>Methods:</b> Eighty two patients underwent magnification chromoscopic colonoscopy using the Olympus CF240Z by a single endoscopist. All patients had received a previous colonoscopy where an endoscopic diagnosis of lateral spreading tumour was made. All lesions were examined initially using indigo carmine chromoscopy to delineate contour followed by crystal violet for magnification crypt pattern analysis. A 20 MHz "mini probe" ultrasound was used if T2 disease was suspected. Following endoscopic mucosal resection, patients were followed up at 3, 6, 12, and 24 months using total colonoscopy. <b>Results:</b> Eighty two lateral spreading tumours were diagnosed in 80 patients (32% (26/82) F-type and 68% (56/82) G-type). G-type lesions were larger than F-type (G-type mean 42 (SD 14) mm <i>v</i> F-type 24 (6.4) mm; p&lt;0.01). F-type lesions were more common in the right colon (F-type 77% (20/26) compared with G-type 39% (22/56); p&lt;0.01) and more often associated with invasive disease (stage T2) (66% (10/15) <i>v</i> 33% (5/15); p&lt;0.001). Fifty eight lesions underwent endoscopic mucosal resection (G-type 64% (37/58)/F-type 36% (21/58)). Local recurrent disease was detected in 17% of patients (10/58), all within six months of the index resection. Piecemeal resection and G-type morphology were significantly associated with recurrent disease (p&lt;0.1). Overall "cure" rates for lateral spreading tumours using endoscopic mucosal resection at two years of follow-up was 96% (56/58). <b>Conclusions:</b> Endoscopic mucosal resection for lateral spreading tumours, staged as T1, is a safe and effective treatment despite their large size. Endoscopic mucosal resection may be an alternative to surgery in selected patients.
FoxM1 Mediates Resistance to Herceptin and Paclitaxel
Authors: Janai R. Carr, Hyun Jung Park, Zebin Wang, Megan M. Kiefer, Pradip Raychaudhuri
Journal: Cancer Research (2010)

Abstract Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In human breast cancer samples, overexpression of the oncogenic transcription factor FoxM1 has been suggested to be a marker of poor prognosis. In this study, we report that FoxM1 overexpression confers resistance to the human epidermal growth factor receptor 2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin-destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by small interfering RNA or an alternate reading frame (ARF)–derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer. Cancer Res; 70(12); 5054–63. ©2010 AACR.
Muscular Tremors, in their Relation to Lead-Poisoning
Authors: W. A. Hollis
Journal: BMJ (1872)

THE BRITISH MEDICAL _OURNAL.651were, therefore, simply damp, and on the outside appeared some patches of whitish mildew.The coffin-plates were in good preserva- tion, being only slightly rusted at the backs and edges.These parti- <culars are mentioned as bearing on the condition in which the bodies were found.
The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds
Authors: Lia Crotti, Carla Spazzolini, Peter J. Schwartz, Wataru Shimizu, Isabelle Denjoy, Eric Schulze-Bahr, Elena V. Zaklyazminskaya, Heikki Swan, Michael J. Ackerman, Arthur J. Moss, Arthur A.M. Wilde, Minoru Horie, Paul A. Brink, Roberto Insolia, Gaetano M. De Ferrari, Gabriele Crimi
Journal: Circulation (2007)

Background— The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)–causing mutation ( KCNQ1 -A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families. Methods and Results— Seventy-eight patients, all with a single KCNQ1 -A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484±42 versus 485±45 ms ( P =NS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485±43 versus 465±38 ms) (all P &lt;0.001). Arrhythmic risk remained higher ( P &lt;0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite β-blocker therapy. Conclusions— The hot spot KCNQ1 -A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS .
Viral clearance in hepatitis C (1b) infection: Relationship with human leukocyte antigen class II in a homogeneous population
Authors: Liam J. Fanning, John Levis, Elizabeth Kenny-Walsh, Freda Wynne, Michael Whelton, Fergus Shanahan
Journal: Hepatology (2000)

The aim of this study was to investigate the possibility of a significant relationship between human leukocyte antigen (HLA) class II and the clearance of hepatitis C virus (HCV). The study group consisted of 156 Irish women who iatrogenically received HCV 1b-contaminated Anti-D immunoglobulin between May 1977 and November 1978. Thus, the study population was homogeneous in terms of gender, source of infection, and ethnicity. On Screening in 1994, all individuals were anti-HCV antibody positive by recombinant immunoblot assay, while 46% (n = 72) of the group were HCV-positive by reverse transcriptase-polymerase chain reaction (RT-PCR). HLA DRB1 and DQB1 status was molecularly defined by high resolution reverse line probe hybridization methodology. Clearance of HCV 1b was found to be associated with DRB1*01. However, this association was lost after Bonferroni correction for multiple comparisons. Extended haplotype analysis between specific DRB1 and DQB1 allelic combinations identified a significant reduction in the frequency of DQB1*0501 in the presence of DRB1*0701 in the persistently infected individuals in the study group ( P &lt; .05). No associations with either viral clearance or persistence were found at the DQB1 locus. Our results suggest that HLA DRB1*01 appears to contribute to the spontaneous resolution of a primary HCV infection in the Irish population. The presence of DRB1*0701 in the absence of DQB1*0501 possibly reflects an influence of this allele in persistence of HCV infection. Defined and homogeneous patient populations offer the best opportunity to illuminate previously disguised immunogenetic factors important in the clearance of HCV 1b.
Dysregulation of Autoantigen Genes in ANCA-Associated Vasculitis Involves Alternative Transcripts and New Protein Synthesis
Authors: Elizabeth A. McInnis, Anshul K. Badhwar, Akhil Muthigi, Olivier M. Lardinois, S. Colby Allred, Jiajin Yang, Meghan E. Free, J. Charles Jennette, Gloria A. Preston, Ronald J. Falk, Dominic J. Ciavatta
Journal: Journal of the American Society of Nephrology (2014)

Proteinase 3 (PR3) and myeloperoxidase (MPO) are two major autoantigens in patients with vasculitis with ANCA. The genes encoding these autoantigens are abnormally expressed in peripheral granulocytes of patients with active ANCA-associated vasculitis. This study provides evidence that this transcriptional dysregulation results in a variety of mRNA processing events from the PRTN3 gene locus. In addition to elevated levels of PR3 message, leukocyte RNA from patients contained PR3 transcripts with an alternative 3' untranslated region. Furthermore, we detected usage of an alternative transcription start site within intron 1 of the PRTN3 gene locus that coincided with active disease (odds ratio, 3.3; 95% confidence interval, 1.3 to 8.4; P=0.01). This promoter may be developmentally regulated, because it was active in normal human bone marrow, multiple leukemia cell lines, MCF-7 cells, and subjects after GM-CSF treatment but not subjects with a neutrophil left shift. This transcript, which lacks exon 1 of PRTN3, encodes a 24-kD protein (p24(PR3/MBN)) with a sequence similar to that previously described for myeloblastin. Notably, PR3, p24(PR3/MBN), and MPO were synthesized in cultured neutrophils from patients with active ANCA-associated vasculitis, indicating that increased transcription results in newly synthesized autoantigens in peripheral neutrophils of patients. The synthesis of p24(PR3/MBN) seems to expand the autoantigen repertoire, because immunoblots showed that sera from patients recognized p24(PR3/MBN). These findings emphasize the importance of transcriptional dysregulation of the autoantigen in autoimmune disease.
The Glasgow Prognostic Score (GPS) as a novel and significant predictor of extranodal natural killer/T‐cell lymphoma, nasal type
Authors: Ya‐Jun Li, Wen‐Qi Jiang, Jia‐Jia Huang, Zhong‐Jun Xia, Hui‐Qiang Huang, Zhi‐Ming Li
Journal: American Journal of Hematology (2013)

The Glasgow Prognostic Score (GPS), an inflammation‐based prognostic score including C‐reactive protein and albumin, shows significant prognostic value in several types of solid tumors. The prognostic value of GPS in lymphoma remains unclear. We performed this study to evaluate the prognostic significance of GPS in extranodal natural killer (NK)/T‐cell lymphoma (ENKL). We retrospectively analyzed 164 patients with newly diagnosed ENKL. The prognostic value of GPS was evaluated and compared with that of International Prognostic Index (IPI), Prognostic Index for Peripheral T‐cell lymphoma unspecified (PIT), and Korean Prognostic Index (KPI). Patients with higher GPS tended to have more adverse clinical characteristics, lower rates of complete remission ( P &lt; 0.001), inferior progression‐free survival (PFS, P &lt; 0.001), and inferior overall survival (OS, P &lt; 0.001). Multivariate analysis demonstrated that high GPS, age &gt; 60 years, and elevated LDH were independent adverse predictors of OS. GPS was found superior to IPI, PIT, and KPI in discriminating patients with different outcomes in low‐risk groups (all P &lt; 0.05). GPS is an independent predictor of survival outcomes in ENKL. Inflammatory response might play an important role in the progression of ENKL and survival of patients with ENKL. Am. J. Hematol. 88:394–399, 2013. © 2013 Wiley Periodicals, Inc.
Evidence for in vivo transport of bioactive nitric oxide in human plasma
Authors: Tienush Rassaf, Michael Preik, Petra Kleinbongard, Thomas Lauer, Christian Heiß, Bodo-Eckehard Strauer, Martin Feelisch, Malte Kelm
Journal: Journal of Clinical Investigation (2002)

Although hitherto considered as a strictly locally acting vasodilator, results from recent clinical studies with inhaled nitric oxide (NO) indicate that NO can exert effects beyond the pulmonary circulation. We therefore sought to investigate potential remote vascular effects of intra-arterially applied aqueous NO solution and to identify the mechanisms involved. On bolus application of NO into the brachial artery of 32 healthy volunteers, both diameter of the downstream radial artery and forearm blood flow increased in a dose-dependent manner. Maximum dilator responses were comparable to those after stimulation of endogenous NO formation with acetylcholine and bradykinin. Response kinetics and pattern of NO decomposition suggested that despite the presence of hemoglobin-containing erythrocytes, a significant portion of NO was transported in its unbound form. Infusion of NO (36 μmol/min) into the brachial artery increased levels of plasma nitroso species, nitrite, and nitrate in the draining antecubital vein (by < 2-fold, 30-fold, and 4-fold, respectively), indicative of oxidative and nitrosative chemistry. Infused N-oxides were inactive as vasodilators whereas S-nitrosoglutathione dilated conduit and resistance arteries. Our results suggest that NO can be transported in bioactive form for significant distances along the vascular bed. Both free NO and plasma nitroso species contribute to the dilation of the downstream vasculature.
Effect of Euglycemic Insulin Infusion on Plasma Levels of Branched-Chain Amino Acids in Cirrhosis
Authors: Giulio Marchesini, Gabriele Forlani, Marco Zoli, Cristina Dondi, Glampaolo Blanchi, Vlncenzo Bua, Pletro Vannini, Emilio Plsi
Journal: Hepatology (1983)

To test the hypothesis that hyperinsulinism is responsible for reduced branched-chain amino acids in cirrhotics, plasma amino acids were sequentially determined in 8 controls and 8 matched cirrhotics during continuous i.v. insulin infusion. An artificial endocrine pancreas which infused glucose was used to sustain euglycemia. Basal plasma insulin levels were high and branched-chain amino acids were reduced in cirrhotics. Insulin infusion raised insulin levels to 3 to 4 times basal values. During the test, the decline in branched-chain amino acids was markedly higher in controls who had similar steady-state insulin levels. Not only did the level of branched-chain amino acids in controls reach the values seen in cirrhotics after 60 min, but the levels continued to fall at a significantly higher rate throughout the second hour. Glucose consumption and the ratio of glucose infused/steady-state insulin--a measure of tissue sensitivity to insulin--were markedly reduced in cirrhotics and positively correlated with the decline in branched-chain amino acids. In cirrhotics, insulin effects on carbohydrate and branched-chain amino acid metabolism were reduced. Low branched-chain amino acid levels in cirrhotics are not likely to depend only on hyperinsulinism.
Improved Method for Cytogenetic Studies of Solid Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C J Kusyk, C L Edwards, F E Arrighi, M M Romsdahl
Journal: JNCI Journal of the National Cancer Institute (1979)

Solid human tumors were dissociated with collagenase, cultured for 16-48 hours, and harvested for cytogenetic preparation. Of the 19 tumors used, 14 showed sufficient numbers of metaphases to be useful for chromosome analysis.
Patterns and rates of intron divergence between humans and chimpanzees
Authors: Elodie Gazave, Tomàs Marqués-Bonet, Olga Fernando, Brian Charlesworth, Arcadi Navarro
Journal: Genome biology (2007)

Abstract Background Introns, which constitute the largest fraction of eukaryotic genes and which had been considered to be neutral sequences, are increasingly acknowledged as having important functions. Several studies have investigated levels of evolutionary constraint along introns and across classes of introns of different length and location within genes. However, thus far these studies have yielded contradictory results. Results We present the first analysis of human-chimpanzee intron divergence, in which differences in the number of substitutions per intronic site (K i ) can be interpreted as the footprint of different intensities and directions of the pressures of natural selection. Our main findings are as follows: there was a strong positive correlation between intron length and divergence; there was a strong negative correlation between intron length and GC content; and divergence rates vary along introns and depending on their ordinal position within genes (for instance, first introns are more GC rich, longer and more divergent, and divergence is lower at the 3' and 5' ends of all types of introns). Conclusion We show that the higher divergence of first introns is related to their larger size. Also, the lower divergence of short introns suggests that they may harbor a relatively greater proportion of regulatory elements than long introns. Moreover, our results are consistent with the presence of functionally relevant sequences near the 5' and 3' ends of introns. Finally, our findings suggest that other parts of introns may also be under selective constraints.
Membrane potassium currents in human radial artery and their regulation by nitric oxide donor
Authors: Y ZHANG, T TAZZEO, V CHU, L JANSSEN
Journal: Cardiovascular Research (2006)

The human radial artery has demonstrated superior long-term results as a graft in coronary bypass surgery, but undesirable post-surgical spasm limits its clinical application. Few have examined its excitatory properties, especially the underlying ion channel mechanisms. In this study, we investigated the kinetic and pharmacological properties of the smooth muscle membrane potassium currents of this important artery.Using whole cell patch-clamp techniques, we found the K(+) current to be voltage-dependent and outwardly rectifying. Voltage-dependent inactivation was observed, being half-maximal at +28.0 mV but incomplete even at +40 mV. The K(+) currents were predominantly sensitive to the K(Ca) blocker tetraethylammonium (TEA; 63.9+/-12.1% inhibition, p<0.05), less sensitive to the Kv blocker 4-aminopyridine (4-AP; 32.8+/-4.4% inhibition, p<0.05), and the K(ATP) blocker glibenclamide (28.7+/-8.5% inhibition), at -20 mV testing potential. Resting membrane potential was -52.0+/-6.8 mV (n=5), and suppression of K(+) currents by TEA and iberiotoxin (IbTx) caused membrane depolarization. Western blot analysis with channel-specific antibodies confirmed the presence of K(Ca) and Kv channel proteins. TEA evoked 20.7+/-9.9% of the contractile response to 60 mM KCl, whereas IbTx caused about 10% of the above response at 10(-7) M. The nitric oxide donor SNAP augmented membrane K(+) currents in a concentration-dependent fashion; the augmentation was completely suppressed by TEA, but was relatively insensitive to the guanylate cyclase inhibitor ODQ.The radial artery manifests mainly Ca(2+)-dependent K(+) currents at rest; this current is augmented by nitric oxide through a cGMP- and protein kinase G-independent action. The relatively depolarized membrane potential, as well as its muscular structure, predisposes the radial artery to spasm. Agents that activate the Ca(2+)-dependent K(+) current could be of therapeutic value in preventing post-surgical vasospasm.
Special design's centuries of success
Authors: Edward H. Hagen
Journal: Behavioral and Brain Sciences (2002)

The fitness maximization standard incorrectly assumes that most adaptations have high heritablility, and it imposes the difficult requirement that correlated phenotypic and environmental contributors to reproduction be controlled for. Despite infrequently recognized problems, the special design standard is the foundation of the spectacular successes of modern medicine. It also suggests that the ancestral environment provides a window into the functioning of the brain.
Helminths Infective to Man in the Syrian Hamster
Authors: J. M. Watson
Journal: BMJ (1946)

The penetrative and burning powers of liquid vesicant drops through various types and conditions of clothing were also investigated.Different sizes of drops were used, and they were dropped from a height on to the clothed subject and at a terminal velocity corresponding to that of spray.From the results of these experiments calculations were made to estimate the degree of vesicant contamination required to make a soldier a casualty.The validity of these calculations was checked by direct exposure of soldier volunteers to vesicant spray in the field (see Fig. 2).A somewhat similar problem was presented by the request to determine the burning power of phosphorus through various types of clothing.Here known quantities of burning phosphorus were dropped from a height on to clothed volunteers.(The phosphorus was supported on a 1-amp.fuse wire which, on passage of an electric current, ignited the phosphorus and allowed it to fall.)Calculations similar to the vesicant calcula- tions were then made.The relation between vesicant-vapour dosage and reversible eye-damage was also determined, chiefly by means of a constant-flow method through an eye-mask.
Violet Lesley Lutwyche and Vivien Ursula Lutwyche Wilfrid Seymour Coltart K R "Claude" Dempster Marcia Hall Harold Witcomb Everley Jones Margaret Elizabeth Lace (nee Morgan) Eric Taylor Murray Alan George Sherman John Jeffrey Shipman Allan Beaumont Swarbreck
Authors: J. Tidey, S. Coltart, D. Dempster, D. Hall, M. Hall, J A Seymour-Jones, G. Pawan, P. R Murray, R. Archibald, R. H Armour, R W B Swarbreck
Journal: BMJ (2001)