tbuckley/cabot-search huggingface dataset:
Hepatocyte Growth Factor Receptor in Acute Tubular Necrosis
Authors: Ralph Rabkin, Fernando Fervenza, Tanny Tsao, Richard Sibley, Michael Friedlaender, Fay Hsu, Charles Lassman, Michael Hausmann, Phil Huie, Ralph H. Schwall
Journal: Journal of the American Society of Nephrology (2001)

Abstract. In acute tubular necrosis, there are early transient increases in circulating and local bioactive hepatocyte growth factor (HGF) levels and renal HGF receptor (c-MET) gene expression. It has therefore been suggested that endogenous HGF may play a role in initiating renal repair. To test this hypothesis, changes in the levels, activity, and anatomic distribution of c-MET protein were characterized in relation to the onset and localization of DNA synthesis in kidneys of rats with ischemia-induced acute tubular necrosis. Whole-kidney c-MET protein levels were significantly increased in the injured kidneys 12 h after injury and rose to a maximum after 1 d, exceeding the control values by sevenfold. Eight days after injury, c-MET levels, although decreasing, were still elevated above control values. An increase in the levels of activated c-MET, i.e. , tyrosine-phosphorylated c-MET, was also evident as early as 12 h after injury. Histologic analyses demonstrated that the increase in c-MET immunoreactivity was most marked in the most severely damaged nephron segments in the outer medulla. In injured proximal tubules, the receptor was redistributed from an apical location to an intracellular location. DNA synthesis was increased in the injured kidneys, especially in the outer medulla, where the increase in c-MET protein levels was most prominent. The increase in DNA synthesis was first detected 12 h after the initial increase in activated c-MET levels. It is concluded that the early increases in the levels of c-MET protein and activated receptor support the hypothesis that HGF participates in the initiation of renal regeneration. In addition, the persistent elevation of c-Met protein levels suggests that prolonged and even late treatment with HGF may be of therapeutic value
High Cancer-Specific Expression of Mesothelin (<i>MSLN</i>) Is Attributable to an Upstream Enhancer Containing a Transcription Enhancer Factor–Dependent MCAT Motif
Authors: Tomas Hucl, Jonathan R. Brody, Eike Gallmeier, Christine A. Iacobuzio-Donahue, Iain K. Farrance, Scott E. Kern
Journal: Cancer Research (2007)

Abstract Identification of genes with cancer-specific overexpression offers the potential to efficiently discover cancer-specific activities in an unbiased manner. We apply this paradigm to study mesothelin (MSLN) overexpression, a nearly ubiquitous, diagnostically and therapeutically useful characteristic of pancreatic cancer. We identified an 18-bp upstream enhancer, termed CanScript, strongly activating transcription from an otherwise weak tissue-nonspecific promoter and operating selectively in cells having aberrantly elevated cancer-specific MSLN transcription. Introducing mutations into CanScript showed two functionally distinct sites: an Sp1-like site and an MCAT element. Gel retardation and chromatin immunoprecipitation assays showed the MCAT element to be bound by transcription enhancer factor (TEF)-1 (TEAD1) in vitro and in vivo. The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments. The cancer specificity seemed to be provided by a putative limiting cofactor of TEF-1 that could be outcompeted by exogenous TEF-1 only in a MSLN-overexpressing cell line. A CanScript concatemer offered enhanced activity. These results identify a TEF family member as a major regulator of MSLN overexpression, a fundamental characteristic of pancreatic and other cancers, perhaps due to an upstream and highly frequent aberrant cellular activity. The CanScript sequence represents a modular element for cancer-specific targeting, potentially suitable for nearly a third of human malignancies. [Cancer Res 2007;67(19):9055–65]
Cervical cancers diagnosed after negative results on cervical cytology.
Authors: J A Gray
Journal: BMJ (1990)

for years developed their technical skills, usually far advanced in comparison with those of their medical and surgical contemporaries, by using the "phantom head."The simulations were good because they had real teeth.Of course surgeons will always require to gain the "ultimate" experience in the operating theatre.But the notion that simulators have a minimal role flies in the face of the existing facts, let alone those yet to be gathered.
Restin suppressed epithelial-mesenchymal transition and tumor metastasis in breast cancer cells through upregulating mir-200a/b expression via association with p73
Authors: Zhenduo Lu, Dechuang Jiao, Jianghua Qiao, Sen Yang, Min Yan, Shude Cui, Zhenzhen Liu
Journal: Molecular Cancer (2015)

Restin belongs to MAGE superfamily and is known as MAGE H1. Restin was firstly cloned from HL-60 cells treated with all-trans retinoic acid (ATRA). Previous studies showed a pro-apoptotic role of Restin in several cell lines. However, little information is available on its expression patterns and functions in vivo. Our study was performed to detect if Restin plays a role in breast cancer cells in vitro and in vivo. Real-time PCR and western blot were conducted to detect Restin expression in multiple breast cancer cell lines and Restin level was negatively related with cell motility. Restin overexpression and knockdown stable cell lines were established by transducing lentivirus into MCF-7 and MDA-MB-231 cells. Cell morphology, wound closure assay, transwell migration and invasion assays were performed to detect if Restin inhibited EMT. Our data showed that Restin overexpressed cells exhibited classical epithelial cell morphology, and Restin overexpression resulted in activation of epithelial markers and suppression of mesenchymal markers, and inhibition of cell migration and invasion. Tumor xenograft model was used to characterize the biological functions of Restin in vivo. We found that Restin overexpression led to reduced lung metastasis. Real-time PCR, western blot, luciferase assay and ChIP assay were performed to identify the potential targets of Restin and the underlying molecular mechanisms. Among several master regulators of EMT, only ZEB1/2 levels were dramatically inhibited by Restin. Unexpectedly, Restin indirectly regulated ZEB1/2 expression at post-transcriptional level. We further identified mir-200a/b, well-characterized mediators controlling ZEB1/2 expression, were transcriptionally activated by Restin and the regulation was dependent on the p53 binding site in mir-200b/a/429 promoter. Further mechanical studies demonstrated Restin interacted with p73, one of p53 family members, which contributed to Restin-mediated activation of mir-200a/b and suppression of ZEB1/2. Taken together, our results suggest that Restin inhibits EMT and tumor metastasis by controlling the expression of the tumor metastasis suppressor mir-200a/b via association with p73. Our findings not only establish a mechanistic link between Restin, EMT and tumor metastasis, but also provide strong evidence supporting the notion that MAGE Group II proteins may exert a tumor suppressive effect in vivo.
<i>An Introduction to Forensic Psychiatry in the Criminal Courts.</i>By W. Norwood East, M. D., (Lond.) Medical Inspector H. M. Prisons, England and Wales; Lecturer on Criminology and Forensic Psychiatry, Maudsley Hospital, etc. (<i>London: J. &amp; A. Churchill; New York: Wm. Wood, 1927.</i>)
Authors: Karl A. Menninger
Journal: American Journal of Psychiatry (1928)
Defining Diastolic Heart Failure
Authors: Michael F. O’Rourke
Journal: Circulation (2001)

Defining Diastolic Heart FailureThe diagnosis of diastolic heart failure suggested by Vasan and Levy 1 and Grossman, 2 as definite, probable, or possible, presently hinges on the demonstration of diastolic left ventricular (LV) dysfunction at cardiac catheterization or echocardiography.It is likely that a far simpler measure, which is based on an analysis of the arterial pulse measured noninvasively, can be used.The studies of Brutsaert et al 3 and others 4 have confirmed that diastolic dysfunction with slowed relaxation in diastole is associated with a prolongation of systole as well.This can be gauged from the ejection duration, as measured in the carotid or radial pressure pulse by applanation tonometry or other techniques. 4The value in diagnosing diastolic dysfunction is enhanced by the fact that in LV systolic dysfunction, ejection duration at any heart rate is usually shortened. 4,5t would be fascinating to know if such information on ejection duration is available in any of the formal invasive clinical studies on diastolic LV dysfunction to which Vasan and Levy 1 and Grossman 2 referred.If such a correlation (which is fundamental to the mechanism of diastolic LV dysfunction) was confirmed, the study of this important but elusive condition could be pursued far more easily, with better distinction between possible, probable, and definite diastolic LV failure.
Effect of the ouabain-quinidine interaction on left ventricular and left atrial function in conscious dogs.
Authors: S Goldman, W D Hager, M Olajos, D Perrier, M Mayersohn
Journal: Circulation (1983)

The effect of the ouabain-quinidine interaction was examined in 10 conscious dogs. Left ventricular (LV) pressure, LV dP/dt, LV diameter and left atrial (LA) diameter were measured with high-fidelity micromanometers and sonomicrometer crystals. Ouabain, 0.025 mg/kg, significantly (p less than 0.05) increased LV dP/dt, LV and LA fractional shortening and LV and LA velocity of circumferential fiber shortening (Vcf). In a separate experiment, quinidine was administered as a bolus dose, 3.85 mg/kg, followed by an infusion, 0.28 mg/kg/min. This resulted in steady-state quinidine concentrations that produced no change in wall motion or hemodynamics. When ouabain was given 1 hour into the quinidine infusion, only LV dP/dt increased significantly (p less than 0.05). Ouabain alone increased LV dP/dt 26.4 +/- 3.5%, whereas ouabain during the quinidine infusion increased it by 9.5 +/- 2.3%. Similar differences were seen in the responses to ouabain in the absence and presence of quinidine: LV Vcf, 22.4 +/- 4.9% vs 6.0 +/- 2.1%, LV fractional shortening, 23.1 +/- 4.6% vs 5.8 +/- 2.1%, LA Vcf, 22.7 +/- 5.9 vs 4.6 +/- 2.0% and LA fractional shortening, 21.8 +/- 7% vs 7.8 +/- 3.3%. Thus, in the presence of quinidine the increase in intropy usually seen with ouabain was markedly attenuated. These data suggest that the quinidine-induced increase in digoxin serum concentrations is accompanied by a decrease in the contractile response of the heart to digoxin.
Failure of renin suppression by angiotensin II in hypertension.
Authors: G H Williams, N K Hollenberg, T J Moore, R G Dluhy, S Z Bavli, H S Solomon, J H Mersey
Journal: Circulation Research (1978)

Angiotensin II was infused at rates varying from 0.1 to 10 ng/kg per minute into 49 subjects with hypertension and 26 normotensive subjects and changes in blood pressure, plasma angiotensin II, and plasma renin activity (PRA) were determined after 20 and 30 minutes at each dose. Similar dose-related increases in angiotensin II and blood pressure occurred with a threshold of 1 ng/kg per minute in the normotensive and hypertensive subjects. Whereas angiotensin II induced a significant, dose-related decrement in renin activity in the normotensive subjects, with a threshold of 1.0 ng/kg per minute, no significant change in renin activity occurred in either the normal-renin or high-renin hypertensive subjects. In a separate study, nine normotensive and six hypertensive sodium-restricted subjects were given a converting enzyme inhibitor, SQ 20881, 30 microgram/kg. Despite a significantly greater fall in blood pressure (P less than 0.006) and angiotensin II concentration (P less than 0.045) in the hypertensive subjects, they did not have a greater rise in plasma renin activity. We conclude that angiotensin II reduces renin release in normal man at infusion rates that yield plasma angiotensin II levels within the physiological range but has a strikingly reduced influence on renin release in hypertension. In high-renin hypertension due to renal artery stenosis or nephrosclerosis, renin release is presumed to be relatively autonomous because of a dominant, intrarenal mechanism. The mechanism in normal-renin essential hypertension is not clear, but the abnormality could well be related to the pathogenesis of the hypertension.
Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non-inferiority randomised controlled trial
Authors: Xavier Mariette, Stephanie Rouanet, Jean Sibilia, Bernard Combe, Xavier Le Loët, Jacques Tebib, Rosemary Jourdan, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The licensed dose of rituximab in rheumatoid arthritis (RA) is two doses of 1000 mg given 2 weeks apart. A lower dose has never been specifically studied in patients with an inadequate response to anti-tumour necrosis factor (TNF) agents. <h3>Objective</h3> To compare the efficacy and safety of rituximab repeat treatment with two doses (1000 mg×1 and 1000 mg×2) following initial treatment with 1000 mg×2. <h3>Methods</h3> We set up an open-label, prospective, multicentre, non-inferiority study comprising a non-controlled period (24 weeks) followed by a randomised controlled period (weeks 24–104) in patients with RA and an inadequate response to anti-TNF agents. All patients received one course of rituximab (1000 mg×2) with methotrexate. At week 24, patients achieving a EULAR response (moderate or good) were randomised to rituximab retreatment at 1000 mg×1 (Arm A) or 1000 mg×2 (Arm B). The primary objective measure was disease activity in 28 joints C-reactive protein (DAS28-CRP) area under the curve (AUC) over 104 weeks with a non-inferiority margin defined by 20% (444) of the mean DAS28-CRP AUC (mean±SD 2218±967) of the reference data. <h3>Results</h3> The intent-to-treat and per-protocol (PP) populations comprised 143 (A/B: 70/73) and 100 (A/B: 51/49) patients, respectively. The adjusted mean difference in DAS28-CRP AUC (PP) was 51.4 (95% CI −131.2 to 234), demonstrating non-inferiority between arms A and B. The overall rituximab safety profile was similar with both retreatment regimens. <h3>Conclusions</h3> Following a clinical response to a first course of rituximab in RA at the licensed dose of 1000 mg×2, retreatment with rituximab at 1000 mg×1 results in efficacy outcomes that are non-inferior to those achieved with retreatment at 1000 mg×2. <h3>ClinicalTrials.gov registration number:</h3> NCT01126541.
PREVENTION OF POST-TRANSFUSION HEPATITIS
Authors: A. Arndt-Hanser, R. Ananthakrishnan, K. Ewe, K.-H. Holtermüller, A. Köhler, H. Fiedler, G. Maass, V. Reinicke, E. Dybkjær, G. Rossi, C. Vermylen
Journal: The Lancet (1974)
Waiting for Cardiac Surgery
Authors: A. Andrew Ray, Karen J. Buth, John A. Sullivan, David E. Johnstone, Gregory M. Hirsch
Journal: Circulation (2001)

The Queen Elizabeth II Health Sciences Centre uses a weekly peer-review conference of cardiovascular experts to prioritize each surgical case to 1 of 4 queues with the use of standardized criteria of coronary anatomy, stress test result, and symptoms. We examined the hazard of waiting as well as the impact of waiting on surgical outcomes.Analysis was performed for 2102 consecutive patients queued for CABG, aortic valve replacement, or CABG+aortic valve replacement between January 1, 1998, and December 31, 1999. Among 1854 patients undergoing surgery, median waiting times on the respective queues were as follows: in-house urgent group, 8 days; semiurgent A group, 37 days; semiurgent B group, 64 days; and elective group, 113 days. There were 13 deaths (12 cardiac) that occurred during the waiting period (0.7% of the patients). Of the 8.7% patients upgraded to a more urgent queue, 86.1% required hospitalization before surgery. Although female sex was not associated with prolonged waiting time, it was predictive of urgent status (P=0.001). The incidence of postoperative complications was 25.0%, and operative mortality was 2.86%. Both were more frequent among patients undergoing surgery early (P=0.01); however, this difference was attributable to the in-house urgent queue. The median length of stay was 7 days for all patients and was not affected by waiting time.Death and upgrades while the patients were waiting tended to occur early in the queuing process, and prolonged waiting was not associated with worse surgical outcomes. The cost of reducing waiting times could in part be offset by prevention of hospital admissions among upgraded patients.
Most UK cases of vCJD are being detected, experts tell MPs
Authors: A. O'Dowd
Journal: BMJ (2014)

Very few cases of variant Creutzfeldt-Jakob disease (vCJD) are missed by doctors, experts have told MPs. However, the precise number of people with the degenerative brain disease is still very difficult to determine, as there is no test for it.

The disease, which is sometimes called the human form of bovine spongiform encephalopathy (BSE), emerged after widespread exposure to BSE prions in the late 1980s and early 1990s through contaminated meat products in the food chain.

A study published in the BMJ 1 last October estimated that 1 in 2000 people in the United Kingdom carried vCJD proteins, although only 177 clinical cases of vCJD have occurred so far in the UK.

The House …
A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy
Authors: I. Ogilvie
Journal: Journal of Clinical Investigation (2005)

NADH:ubiquinone oxidoreductase (complex I) deficiency is a common cause of mitochondrial oxidative phosphorylation disease. It is associated with a wide range of clinical phenotypes in infants, including Leigh syndrome, cardiomyopathy, and encephalomyopathy. In at least half of patients, enzyme deficiency results from a failure to assemble the holoenzyme complex; however, the molecular chaperones required for assembly of the mammalian enzyme remain unknown. Using whole genome subtraction of yeasts with and without a complex I to generate candidate assembly factors, we identified a paralogue (B17.2L) of the B17.2 structural subunit. We found a null mutation in B17.2L in a patient with a progressive encephalopathy and showed that the associated complex I assembly defect could be completely rescued by retroviral expression of B17.2L in patient fibroblasts. An anti-B17.2L antibody did not associate with the holoenzyme complex but specifically recognized an 830-kDa subassembly in several patients with complex I assembly defects and coimmunoprecipitated a subset of complex I structural subunits from normal human heart mitochondria. These results demonstrate that B17.2L is a bona fide molecular chaperone that is essential for the assembly of complex I and for the normal function of the nervous system.
Angioedema and Angioedema Management From Asteria I and Asteria II: Phase III Studies To Evaluate The Efficacy and Safety Of Omalizumab In Patients With Chronic Idiopathic/Spontaneous Urticaria Who Remain Symptomatic Despite H1 Antihistamine Treatment
Authors: James Zazzali, Karin Rosen, Mary S. Bradley, Karina Raimundo
Journal: Journal of Allergy and Clinical Immunology (2014)
Contact allergy to clotrimazole.
Authors: J A Roller
Journal: BMJ (1978)

Contact allergy to clotrimazoleClotrimazole (Canesten; diphenyl-2-chlorophenyl-1-imidazolylmethane) is an effective broad-spectrum antifungal agent that has been used in Great Britain since 1973.In clinical trials only a few patients have been irritated by clotrimazole and no cases of contact allergy have been reported.I describe a patient who developed contact allergic dermatitis to clotrimazole. Case historyA 48-year-old policeman had had perineal and perianal pruritus for many years.In September 1977 he was prescribed Canesten cream, which he used intermittently for the next few months.In December, after applying Canesten cream, he noticed an increase in the pruritus accompanied by an erythematous, oozing rash over his scrotum, upper thighs, and natal cleft.He discontinued the Canesten, and Tri-Adcortyl cream was prescribed.His rash gradually improved.Patch tests were applied for 48 hours using the Finn Chamber method and inspected at 48 and 96 hours.At both times reactions were seen to Canesten cream, 1 % clotrimazole in ethyl methyl ketone, and 1 % ethylene diamine in yellow soft paraffin.Results were negative with Canesten cream base and Tri-Adcortyl cream.
GH (Growth Hormone)-Dependent STAT5 Signaling Plays an Important Role in Hepatic Lipid Metabolism
Authors: Johanna L. Barclay, Caroline N. Nelson, Mayumi Ishikawa, Lauren A. Murray, Linda M. Kerr, Timothy R. McPhee, Elizabeth E. Powell, Michael J. Waters
Journal: Endocrine Reviews (2010)

GH deficiency is known to be clinically associated with a high incidence of nonalcoholic fatty liver disease, and this can be reversed by GH administration. Here we investigated the mechanistic basis for this phenomenon using engineered male mice lacking different signaling elements of the GH receptor, hepatic stat5a/b−/− mice and a mouse hepatoma line. We found deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identifies putative targets of STAT5 signaling responsible for the steatosis seen on a normal diet. These targets were verified with liver-specific stat5a/b deletion in vivo, and in vitro we show that dominant-negative (DN) STAT5 increases lipid uptake in a mouse hepatoma line. Because loss of STAT5 signaling results in elevated STAT1 and STAT3 activity and intracellular lipid accumulation, we have used the hepatoma line DN-STAT5a/b, DN-STAT1, CA-STAT3, or addition of oleate/palmitate to assign which of these apply to individual targets in active STAT5 deficiency. These findings and published mouse models of steatosis enable us to propose elevated cd36, pparγ, and pgc1α/β expression as primary instigators of the steatosis along with elevated fatty acid synthase, lipoprotein lipase, and very low-density lipoprotein receptor expression. Decreased fgf21 and insig2 expression may also contribute. In conclusion, despite normal plasma free fatty acids and minimal obesity, absent GH activation leads to steatosis because phosphorylated STAT5 prevents hepatic steatosis. These results raise the possibility of low-dose GH treatment for nonalcoholic fatty liver disease.