tbuckley/cabot-search huggingface dataset:
TWO CASES OF CARDIAC DISEASE
Authors: W. B. Jones
Journal: BMJ (1909)

Low voltage-activated (T-type) Ca<sup>2+</sup> channels are responsible for generating low-threshold spikes (LTS) that facilitate burst firing and transmitter release in neurons. The T-type Ca<sup>2+</sup> channels contain a regulatory α1 subunit, and several isoforms of the α1 subunit (Cav3.1, 3.2, 3.3) have been cloned. The Cav 3.1 α1 subunit is abundantly expressed in the hypothalamus. Previously, we found that 17 β-estradiol (E2) increased the number of arcuate neurons expressing LTS. Therefore, we used an ovariectomized female guinea pig model to measure the distribution and regulation of Cav3.1 mRNA expression by E2. Guinea pig Cav3.1 α1 subunit sequences, which were cloned by PCR, were used in ribonuclease protection (RPA) and <i>in situ</i> hybridization assays to evaluate mRNA expression. Based on a RPA, E2 significantly increased the mRNA expression of Cav3.1 α1 subunit in the mediobasal hypothalamus and the pituitary. <i>In situ</i> hybridization analysis revealed that E2 significantly increased Cav 3.1 mRNA expression in medial preoptic nuclei, bed nuclei stria terminalis, and the arcuate nucleus. Whole-cell patch recordings in arcuate neurons revealed that E2 treatment significantly increased the peak T-type Ca<sup>2+</sup> current density by twofold without affecting the activation/inactivation characteristics and augmented the rebound excitation by threefold to fourfold. These results suggest that estrogen regulates the mRNA expression of T-type calcium channels, which leads to increased functional expression of the channel. Increased expression of T-type channels could be one mechanism by which estrogen augments burst firing and transmitter release in hypothalamic neurons.
Clinical outcome of patients with various advanced cancer types vaccinated with an optimized cryptic human telomerase reverse transcriptase (TERT) peptide: results of an expanded phase II study
Authors: A. Kotsakis, E.-K. Vetsika, S. Christou, D. Hatzidaki, N. Vardakis, D. Aggouraki, G. Konsolakis, V. Georgoulias, Ch. Christophyllakis, P. Cordopatis, K. Kosmatopoulos, D. Mavroudis
Journal: Annals of Oncology (2011)
Terlipressin and arterial blood volume after paracentesis for tense ascites in cirrhosis
Authors: G S. Ranger
Journal: Gut (2002)

Moreau et al described the use of terlipressin, a vasopressin analogue, in ameliorating the reduction in effective arterial blood volume which can occur after paracentesis for tense ascites in cirrhosis ( Gut 2002: 50 :90–4).

The article states that the first 1 mg intravenous bolus dose of terlipressin was given at the …
Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo
Authors: Toyotaka Yada, Hiroaki Shimokawa, Osamu Hiramatsu, Tatsuya Kajita, Fumiyuki Shigeto, Etsuro Tanaka, Yoshiro Shinozaki, Hidezo Mori, Takahiko Kiyooka, Masashi Katsura, Seitaro Ohkuma, Masami Goto, Yasuo Ogasawara, Fumihiko Kajiya
Journal: Journal of the American College of Cardiology (2005)
Genetic Testing for Cancer Predisposition
Authors: Charis Eng, Heather Hampel, Albert de la Chapelle
Journal: Annual Review of Medicine (2001)

▪ Abstract Clinical cancer genetics is becoming an integral part of the care of cancer patients. This review describes the clinical aspects, genetics, and clinical genetic management of most of the major hereditary cancer susceptibility syndromes. Multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial adenomatous polyposis are examples of syndromes for which genetic testing to identify at-risk family members is considered the standard of care. Genetic testing for these syndromes is sensitive and affordable, and it will change medical management. Cancer genetic counseling and testing is probably beneficial in other syndromes, such as the hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis. There are also hereditary cancer syndromes for which testing is not yet available and/or is unlikely to change medical management, including Li-Fraumeni syndrome and hereditary malignant melanoma. Thorough medical care requires the identification of families likely to have a hereditary cancer susceptibility syndrome for referral to cancer genetics professionals.
The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study
Authors: Donald S Silverberg, Dov Wexler, David Sheps, Miriam Blum, Gad Keren, Ron Baruch, Doron Schwartz, Tatyana Yachnin, Shoshana Steinbruch, Itzhak Shapira, Shlomo Laniado, Adrian Iaina
Journal: Journal of the American College of Cardiology (2001)
Novel Mechanism whereby Nuclear Factor κB Mediates DNA Damage Repair through Regulation of <i>O</i>6-Methylguanine-DNA-Methyltransferase
Authors: Iris Lavon, Dana Fuchs, Daniel Zrihan, Gilat Efroni, Bracha Zelikovitch, Yakov Fellig, Tali Siegal
Journal: Cancer Research (2007)

O(6)-Methylguanine-DNA-methyltransferase (MGMT) and nuclear factor kappaB (NF-kappaB) are two key effectors associated with the development of resistance to alkylating agent-based chemotherapy. This prompted us to hypothesize that NF-kappaB might be involved in MGMT regulation. Consistent with this hypothesis, we have discovered two putative NF-kappaB binding sites within the MGMT promoter region and showed a specific and direct interaction of NF-kappaB at each of these sites. Forced expression of the NF-kappaB subunit p65 in HEK293 cells induced an increase in MGMT expression whereas addition of the NF-kappaB super repressor DeltaNIkappaB completely abrogated the induction. We also found a significant correlation between the extent of NF-kappaB activation and MGMT expression in the glioma cell lines and the human glial tumors tested and showed that it was independent of MGMT promoter methylation. Our results are of potential clinical significance because we show that cell lines with ectopic p65 or high constitutive NF-kappaB activity are less sensitive to nitrosourea treatment and that suppression of MGMT activity with O(6)-benzylguanine completely abolishes the chemoresistance acquired by NF-kappaB. The findings of our study strongly suggest that NF-kappaB plays a major role in MGMT regulation and that MGMT is most probably the major player in NF-kappaB-mediated chemoresistance to alkylating agents.
Delayed Graft Function and the Risk for Death with a Functioning Graft
Authors: Shruti N. Tapiawala, Kathryn J. Tinckam, Carl J. Cardella, Jeffrey Schiff, Daniel C. Cattran, Edward H. Cole, S. Joseph Kim
Journal: Journal of the American Society of Nephrology (2009)

Delayed graft function (DGF) associates with an increased risk for graft failure, but its link with death with graft function (DWGF) is unknown. We used the US Renal Data System to assemble a cohort of all first, adult, deceased-donor kidney transplant recipients from January 1, 1998, through December 31, 2004. In total, 11,542 (23%) of 50,246 recipients required at least one dialysis session in the first week after transplantation. Compared with patients without DGF, patients with DGF were significantly more likely to die with a functioning graft (relative hazard 1.83 [95% confidence interval 1.73 to 1.93] and 1.53 [95% CI 1.45 to 1.63] for unadjusted and fully adjusted models, respectively). The risk for DWGF was slightly higher among women with DGF than among men. There was no significant heterogeneity among other subgroups, and the results were robust to sensitivity analyses. Acute rejection within the first year attenuated the DGF-DWGF association. Cardiovascular and infectious deaths were slightly more prevalent in the DGF group, but the relative hazards of cause-specific death were similar between DWGF and deaths during total follow-up. In summary, DGF associates with an increased risk for DWGF; the mechanisms underlying the negative impact of DGF require further study.
Ca <sup>2+</sup> Transients and Ca <sup>2+</sup> Waves in Purkinje Cells
Authors: Penelope A. Boyden, Jielin Pu, Judith Pinto, Hendrik E. D. J. ter Keurs
Journal: Circulation Research (2000)

Abstract —Purkinje cells contain sarcoplasmic reticulum (SR) directly under the surface membrane, are devoid of t-tubuli, and are packed with myofibrils surrounded by central SR. Several studies have reported that electrical excitation induces a biphasic Ca 2+ transient in Purkinje fiber bundles. We determined the nature of the biphasic Ca 2+ transient in aggregates of Purkinje cells. Aggregates (n=12) were dispersed from the subendocardial Purkinje fiber network of normal canine left ventricle, loaded with Fluo-3/AM , and studied in normal Tyrode’s solution (24°C). Membrane action potentials were recorded with fine-tipped microelectrodes, and spatial and temporal changes in [Ca 2+ ] i were obtained from fluorescent images with an epifluorescent microscope (×20; Nikon). Electrical stimulation elicited an action potential as well as a sudden increase in fluorescence (L 0 ) compared with resting levels. This was followed by a further increase in fluorescence (L 1 ) along the edges of the cells. Fluorescence then progressed toward the Purkinje cell core (velocity of propagation 180 to 313 μm/s). In 62% of the aggregates, initial fluorescent changes of L 0 were followed by focally arising Ca 2+ waves (L 2 ), which propagated at 158±14 μm/s (n=13). Spontaneous Ca 2+ waves (L 2 *) propagated like L 2 (164±10 μm/s) occurred between stimuli and caused slow membrane depolarization; 28% of L 2 * elicited action potentials. Both spontaneous Ca 2+ wave propagation and resulting membrane depolarization were thapsigargin sensitive. Early afterdepolarizations were not accompanied by Ca 2+ waves. Action potentials in Purkinje aggregates induced a rapid rise of Ca 2+ through I CaL and release from a subsarcolemmal compartment (L 0 ). Ca 2+ release during L 0 either induced further Ca 2+ release, which propagated toward the cell core (L 1 ), or initiated Ca 2+ release from small regions and caused L 2 Ca 2+ waves, which propagated throughout the aggregate. Spontaneous Ca 2+ waves (L 2 *) induce action potentials.
Maximal inspiratory pressure: does reproducibility indicate full effort?
Authors: T K Aldrich, P Spiro
Journal: Thorax (1995)

BACKGROUND--Maximal inspiratory pressure (MIP) is often relied upon as an index of inspiratory muscle strength, and reproducibility of MIP taken to indicate maximal effort. This study was designed to determine whether reproducibility is a valid indicator of maximal effort. METHODS--Ten normal subjects were studied, all of whom were familiar with the MIP test but none was an experienced subject. They were told that the purpose was to measure how accurately they could generate 50% of their MIP. Each performed nine MIP efforts and nine submaximal efforts. Means and coefficients of variation of peak negative inspiratory pressure (Pmax) and the ranges of the best three efforts were calculated for each type. RESULTS--Mean (SE) Pmax averaged-93.8 (6.0) cm H2O for the maximal efforts and -60.6 (7.7) cm H2O for the submaximal trials, with coefficients of variation averaging 8.71 (1.75)% and 14.58 (2.63)%, respectively and the ranges averaging 6.5 (1.1)% and 13.4 (3.5)%, respectively. There was no clear separation between the coefficients of variation or ranges of maximal and submaximal efforts. In four cases the ranges of the best three submaximal efforts were less than 5 cm H2O and less than 5% -criteria that have been used to validate MIP results. These four subjects had lower ranges for submaximal than maximal efforts, even when expressed as percentages of the means. CONCLUSION--Reproducibility should not be relied upon to indicate a valid MIP test, especially for research purposes when relatively small changes in inspiratory muscle strength must be discriminated.
Deep Divergences of Human Gene Trees and Models of Human Origins
Authors: M. G. B. Blum, M. Jakobsson
Journal: Molecular Biology and Evolution (2010)

Two competing hypotheses are at the forefront of the debate on modern human origins. In the first scenario, known as the recent Out-of-Africa hypothesis, modern humans arose in Africa about 100,000-200,000 years ago and spread throughout the world by replacing the local archaic human populations. By contrast, the second hypothesis posits substantial gene flow between archaic and emerging modern humans. In the last two decades, the young time estimates--between 100,000 and 200,000 years--of the most recent common ancestors for the mitochondrion and the Y chromosome provided evidence in favor of a recent African origin of modern humans. However, the presence of very old lineages for autosomal and X-linked genes has often been claimed to be incompatible with a simple, single origin of modern humans. Through the analysis of a public DNA sequence database, we find, similar to previous estimates, that the common ancestors of autosomal and X-linked genes are indeed very old, living, on average, respectively, 1,500,000 and 1,000,000 years ago. However, contrary to previous conclusions, we find that these deep gene genealogies are consistent with the Out-of-Africa scenario provided that the ancestral effective population size was approximately 14,000 individuals. We show that an ancient bottleneck in the Middle Pleistocene, possibly arising from an ancestral structured population, can reconcile the contradictory findings from the mitochondrion on the one hand, with the autosomes and the X chromosome on the other hand.
Kallikreins on Steroids: Structure, Function, and Hormonal Regulation of Prostate-Specific Antigen and the Extended Kallikrein Locus
Authors: Mitchell G. Lawrence, John Lai, Judith A. Clements
Journal: Endocrine Reviews (2010)

Abstract The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The kallikrein family is also emerging as a rich source of disease biomarkers with KLK3, commonly known as prostate-specific antigen, being the current serum biomarker for prostate cancer. The kallikrein locus is also notable because it is extraordinarily responsive to steroids and other hormones. Indeed, at least 14 functional hormone response elements have been identified in the kallikrein locus. A more comprehensive understanding of the transcriptional regulation of kallikreins may help the field make more informed hypotheses about the physiological functions of kallikreins and their effectiveness as biomarkers. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. We also focus on the transcriptional regulation of kallikreins by androgens, progestins, glucocorticoids, mineralocorticoids, estrogens, and other hormones in animal models and human prostate, breast, and reproductive tract tissues. The interaction of the androgen receptor with androgen response elements in the promoter and enhancer of KLK2 and KLK3 is also summarized in detail. There is evidence that all kallikreins are regulated by multiple nuclear receptors. Yet, apart from KLK2 and KLK3, it is not clear whether all kallikreins are direct transcriptional targets. Therefore, we argue that gaining more detailed information about the mechanisms that regulate kallikrein expression should be a priority of future studies and that the kallikrein locus will continue to be an important model in the era of genome-wide analyses.
Akt Kinase-Interacting Protein 1 Signals through CREB to Drive Diffuse Malignant Mesothelioma
Authors: Tadaaki Yamada, Joseph M. Amann, Koji Fukuda, Shinji Takeuchi, Naoya Fujita, Hisanori Uehara, Shotaro Iwakiri, Kazumi Itoi, Konstantin Shilo, Seiji Yano, David P. Carbone
Journal: Cancer Research (2015)

Diffuse malignant mesothelioma (DMM) is a tumor of serosal membranes with propensity for progressive local disease. Because current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve the outcomes of patients with this disease. Akt kinase interacting protein 1 (Aki1; Freud-1/CC2D1A) is a scaffold protein for the PI3K-PDK1-Akt signaling module that helps determine receptor signal selectivity for EGFR. Aki1 has been suggested as a therapeutic target, but its potential has yet to be evaluated in a tumor setting. Here, we report evidence supporting its definition as a therapeutic target in DMM. In cell-based assays, Aki1 silencing decreased cell viability and caused cell-cycle arrest of multiple DMM cell lines via effects on the PKA-CREB1 signaling pathway. Blocking CREB activity phenocopied Aki1 silencing. Clinically, Aki1 was expressed in most human DMM specimens where its expression correlated with phosphorylated CREB1. Notably, Aki1 siRNA potently blocked tumor growth in an orthotopic implantation model of DMM when administered directly into the pleural cavity of tumor-bearing mice. Our findings suggest an important role for the Aki1-CREB axis in DMM pathogenesis and provide a preclinical rationale to target Aki1 by intrathoracic therapy in locally advanced tumors.
Effects of components of ischemia and metabolic inhibition on delayed afterdepolarizations in guinea pig papillary muscle.
Authors: W A Coetzee, L H Opie
Journal: Circulation Research (1987)

Delayed afterdepolarizations (DADs) may develop into triggered automaticity and ventricular arrhythmias. However, the potential role of DADs in the genesis of ischemic arrhythmias is not clear. We studied the effects of different components of severe ischemia (acidosis, hypoxia, lactate, increased potassium, and the absence of glucose) on DADs. DADs were evoked using trains of 30-60 externally applied pulses at a rate of 4-5 Hz in the presence of isoproterenol (10(-7) M) or dibutyryl cyclic 3', 5' adenosine monophosphate (dB-cAMP, 10(-3) M). Acidosis, caused by the addition of protons (pH = 6.8), increased the amplitude of DADs from 3.2 +/- 0.4 to 5.9 +/- 0.5 mV (n = 8, p less than 0.001). DADs were abolished by hypoxia (pO2 less than 35 mm Hg, n = 7, p less than 0.001) from control values of 3.4 +/- 0.3 mV. DADs were also abolished by neutral lactate (20 mM, n = 7, p less than 0.001) in the absence of glucose. Acidotic lactate (20 mM, pH0 = 6.8), however, was unable to abolish DADs. Increasing the extracellular potassium concentration to 16.2 mM decreased DAD amplitude from 3.6 +/- 0.27 mV to 1.3 +/- 0.1 mV (n = 5, p less than 0.002) with an associated reduction of membrane potential from -86.2 +/- 0.9 to -58.6 +/- 0.9 mV. The overall effect of simulated ischemia (all components tested together) was to abolish DADs (n = 8, p less than 0.001), with hypoxia as the most important factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Are nutrition support teams useful? Results from the NCEPOD study into parenteral nutrition
Authors: N. E. Burch, J. Stewart, N. Smith
Journal: Gut (2011)

<h3>Introduction</h3> Recent emphasis has been placed on the importance of nutrition support teams (NSTs) in good nutritional care and management of patients on parenteral nutrition (PN). Evidence regarding their benefit, however, is surprisingly sparse, with the absence of large trials to evaluate their effectiveness. In 2010, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) published its report 'A Mixed Bag', which evaluated the care given to patients receiving PN in England, Wales, Northern Ireland and the Channel Islands. It found that only 19% of inpatients received care with respect to their PN that was considered good. Furthermore, there was evidence of inappropriate PN use, prescribing errors, inadequate monitoring and a high rate of avoidable metabolic complications. The aim of this sub-analysis was to evaluate the effectiveness of NSTs in management of this particular cohort of patients. <h3>Methods</h3> All patients in England and Wales who received PN between 1 January and 31 March 2008 were identified from pharmacy records. Two patients per consultant were identified. A clinical questionnaire was sent to be completed by the consultant for each patient, and then returned with a copy of the case notes. The questionnaires and case notes were then analysed by the Advisor group consisting of consultants, dieticians and pharmacists. <h3>Results</h3> Only 60% of responding hospitals had an NST. Of those teams, only 43% saw PN referrals. 53% of NSTs had complete autonomy in ordering/vetoing PN. Only half the patients within the study had an NST involved in the decision to commence PN, whereas PN composition was determined by the NST in 80% of cases. Patients who had an NST involved in their nutritional management were almost twice as likely to receive good care as those without NST support (27.4% vs 15.2%). Likelihood of 'less than satisfactory care' with respect to PN management was much lower in those with NST involvement (7% vs 11.5%). <h3>Conclusion</h3> These results demonstrate that involvement of a NST substantially improves quality of care with respect to PN management, although even with NST involvement there were still more than 70% cases where nutrition care was considered sub-optimal. There is currently enormous variation in the composition of NSTs, with 9% not having a doctor as part of the team. There is also wide variation in the function of the NST in different regions, which may explain why previous studies have shown conflicting results with respect to the effectiveness of NSTs in improving overall nutrition care. Perhaps standardisation of the composition and role of NSTs would be beneficial in order to truly evaluate their role in improving overall nutrition management.
Electrical Conduction in Canine Pulmonary Veins
Authors: Mélèze Hocini, Siew Y. Ho, Tokuhiro Kawara, André C. Linnenbank, Mark Potse, Dipen Shah, Pierre Jaïs, Michiel J. Janse, Michel Haïssaguerre, Jacques M.T. de Bakker
Journal: Circulation (2002)

Background — Paroxysmal atrial fibrillation in patients is often initiated by foci in the pulmonary veins. The mechanism of these initiating arrhythmias is unknown. The aim of this study was to determine electrophysiological characteristics of canine pulmonary veins that may predispose to initiating arrhythmias. Methods and Results — Extracellular recordings were obtained from the luminal side of 9 pulmonary veins in 6 Langendorff-perfused dog hearts after the veins were incised from the severed end to the ostium. Pulmonary veins were paced at the distal end, the ostium, and an intermediate site. During basic and premature stimulation, extracellular electrical activity was recorded with a grid electrode that harbored 247 electrode terminals. In 4 hearts, intracellular electrograms were recorded with microelectrodes. Myocyte arrangement immediately beneath the venous walls was determined by histological analysis in 3 hearts. Extracellular mapping revealed slow and complex conduction in all pulmonary veins. Activation delay after premature stimulation could be as long as 96 ms over a distance of 3 mm. Action potential duration was shorter at the distal end of the veins than at the orifice. No evidence for automaticity or triggered activity was found. Histological investigation revealed complex arrangements of myocardial fibers that often showed abrupt changes in fiber direction and short fibers arranged in mixed direction. Conclusions — Zones of activation delay were observed in canine pulmonary veins and correlated with abrupt changes in fascicle orientation. This architecture of muscular sleeves in the pulmonary veins may facilitate reentry and arrhythmias associated with ectopic activity.