tbuckley/cabot-search huggingface dataset:
Reentrant ventricular arrhythmias in the late myocardial infarction period. 6. Effect of the autonomic system.
Authors: N El-Sherif
Journal: Circulation (1978)

The effect of the autonomic system on conduction disorders in the infarction zone (IZ) and related reentrant ventricular arrhythmias (RVA) in the late myocardial infarction period in the dog was studied utilizing averaged recordings of the reentrant pathways from the epicardial surface of the IZ. Vagal (V) stimulation was found to have no significant direct electrophysiologic effect while sympathetic (S) stimulation resulted in a direct slight improvement of conduction in the IZ. However, because of the marked rate-dependency of conduction in the IZ, the effects of both V and S stimulation were modified through changes in the heart rate. The bradycardia produced by V stimulation resulted in improvement of conduction in the IZ and disappearance of RVA, while the tachycardia induced by S stimulation resulted in worsening of conduction in the IZ and the occurrence of RVA. Thus, in spite of its slight enhancing effect on conduction in the IZ, the propensity of S stimulation to induce RVA was primarily due to its tachycardiac effect.
Cholinergic constriction in the general circulation and its role in coronary artery spasm.
Authors: S Kalsner
Journal: Circulation Research (1989)

The release of acetylcholine from autonomic nerves in those tissues that receive a cholinergic innervation is widely believed to dilate blood vessels. Exogenously administered acetylcholine in vivo does dilate vascular beds and produce hypotension; however, this latter effect is indirect and probably the result of liberation of endothelium-derived relaxing factor (EDRF) from endothelial cells. Some blood vessels contain a substantial population of medial constrictor receptors for acetylcholine, and the implications of this presence for vascular control systems has been largely ignored, although it needs to be considered. A survey of the evolution of vasomotor control systems indicates that acetylcholine serves principally as an excitatory transmitter to blood vessels. Neurally mediated cholinergic constriction and not dilation is found in fish, amphibians, reptiles, and birds, with responses initiated by medial muscarinic receptors. Acetylcholine constricts many vascular preparations from these lower animals, but some vessels relax, reflecting the emergence of an EDRF responsive to acetylcholine. An examination of cholinergic responses in mammalian vessels reveals that cholinergic (neurogenic) dilation is limited to a very few vascular beds and to only a few species. Both experimental evidence and evolutionary considerations support the likelihood that cholinergic (neural) constriction operates in some vascular regions in mammals and, in particular, in the coronary circulation of some species, including humans. In fact, constriction, and not dilation, may be the dominant vascular response to activation of the cholinergic axis in most mammals, including humans. The complications and contradictions introduced by the simultaneous presence of both EDRF and a cholinergic constrictor innervation involving medial muscarinic receptors are discussed. A variety of evidence is also presented that implicates cholinergic constriction in at least some instances of coronary artery spasm and sudden death.
A Randomized, Double–Blind Trial Comparing Pegylated Interferon Alfa–2B to Interferon Alfa–2B As Initial Treatment for Chronic Hepatitis C
Authors: Karen L. Lindsay, Christian Trepo, Tobias Heintges, Mitchell L. Shiffman, Stuart C. Gordon, John C. Hoefs, Eugene R. Schiff, Zachary D. Goodman, Mark Laughlin, Ruji Yao, Janice K. Albrecht
Journal: Hepatology (2001)

This international, randomized, active–controlled, parallel–group, double–blind dose–finding study compared peginterferon alfa–2b (PegIntron™) to interferon alfa–2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three–times–weekly (TIW) interferon alfa–2b dose (3 MIU) or the once–weekly (QW) peginterferon alfa–2b (0.5, 1.0, or 1.5 μg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa–2b doses significantly ( P ≤ .042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow–up, as compared with interferon alfa–2b. Unlike the end–of–treatment virologic response, the sustained virologic response rate was not dose–related above 1.0 μg/kg peginterferon alfa–2b because of a higher relapse rate among patients treated with 1.5 μg/kg peginterferon alfa–2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa–2b doses decreased liver inflammation to a greater extent than did interferon alfa–2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa–2b maintained (0.5 μg/kg) or surpassed (1.0, 1.5 μg/kg) the clinical efficacy of interferon alfa–2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 μg/kg peginterferon alfa–2b in patients infected with genotype 1 and high viral levels warrants further evaluation.
Uncoupling Protein 2 Promoter Polymorphism −866G/A Affects Peripheral Nerve Dysfunction in Japanese Type 2 Diabetic Patients
Authors: Hiroshi Yamasaki, Hideyuki Sasaki, Kenichi Ogawa, Takeshi Shono, Shinobu Tamura, Asako Doi, Miyoshi Sasahara, Hiromichi Kawashima, Taisei Nakao, Hiroto Furuta, Masahiro Nishi, Kishio Nanjo
Journal: Diabetes Care (2006)

OBJECTIVE—To determine genetic predispositions for diabetic polyneuropathy, we investigated the relationship between the −866G/A polymorphism of uncoupling protein (UCP) 2 and neurological manifestations in 197 type 2 diabetic patients. RESEARCH DESIGN AND METHODS—We first examined whether UCP2 mRNA had been expressed in the dorsal root ganglion (DRG) in four Long-Evans Tokushima Otsuka rats using RT-PCR and electrophoresis. Genotyping of UCP2 promoter polymorphism −866G/A was then performed in 197 unrelated Japanese type 2 diabetic patients, who were subjected to nerve conduction, quantitative vibratory perception, head-up tilt, and heart rate variability tests, by PCR restriction fragment–length polymorphism. The relationships between UCP2 genotype and various nerve functions were analyzed by uni- and multivariable analysis. RESULTS—Expression of UCP2 mRNA was confirmed in rat DRG. Multiple regression analysis clarified the hypothesis that the G/A + A/A genotype was significantly related to decreased motor nerve conduction velocity and impaired blood pressure maintenance on the head-up tilt test. Multiple logistic regression analysis revealed that the G/A + A/A genotypes are a significant risk factor for sensory nerve conduction slowing and orthostatic hypotension. CONCLUSIONS—UCP2 promoter gene polymorphism −866 G/A was significantly associated with nerve conduction slowing and vasomotor sympathetic functions. These findings suggest that the higher UCP2 activity related to the A allele has an energy-depleting effect on peripheral nerve function in type 2 diabetic patients.
Addition of Bevacizumab to Bolus Fluorouracil and Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Trial
Authors: Fairooz F. Kabbinavar, Joseph Schulz, Michael McCleod, Taral Patel, John T. Hamm, J. Randolph Hecht, Robert Mass, Brent Perrou, Betty Nelson, William F. Novotny
Journal: Journal of Clinical Oncology (2005)

Purpose Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan. Patients and Methods Patients had metastatic CRC and one of the following characteristics: age ≥ 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin ≤ 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed. Results Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation. Conclusion Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.
Vaccination with Heat-killed Leishmania Antigen or Recombinant Leishmanial Protein and CpG Oligodeoxynucleotides Induces Long-Term Memory CD4<b>+</b>and CD8<b>+</b>T Cell Responses and Protection Against <i>Leishmania major</i> Infection
Authors: Elizabeth G. Rhee, Susana Mendez, Javeed A. Shah, Chang-you Wu, Joanna R. Kirman, Tara N. Turon, Dylan F. Davey, Heather Davis, Dennis M. Klinman, Rhea N. Coler, David L. Sacks, Robert A. Seder
Journal: The Journal of Experimental Medicine (2002)

CpG oligodeoxynucleotides (ODN) have potent effects on innate and adaptive cellular immune responses. In this report, the ability of CpG ODN to confer long-term immunity and protection when used as a vaccine adjuvant with a clinical grade of leishmanial antigen, autoclaved Leishmania major (ALM), or a recombinant leishmanial protein was studied. In two different mouse models of L. major infection, vaccination with ALM plus CpG ODN was able to control infection and markedly reduce lesion development in susceptible BALB/c and resistant C57BL/6 (B6) mice, respectively, up to 12 wk after immunization. Moreover, B6 mice immunized with ALM plus CpG ODNs were still protected against infectious challenge even 6 mo after vaccination. In terms of immune correlates of protection, ALM plus CpG ODN-vaccinated mice displayed L. major–specific T helper cell 1 and CD8+ responses. In addition, complete protection was markedly abrogated in mice depleted of CD8+ T cells at the time of vaccination. Similarly, mice vaccinated with a recombinant leishmanial protein plus CpG ODN also had long-term protection that was dependent on CD8+ T cells in vivo. Together, these data demonstrate that CpG ODN, when used as a vaccine adjuvant with either a recombinant protein or heat-killed leishmanial antigen, can induce long-term protection against an intracellular infection in a CD8-dependent manner.
Lnk-dependent axis of SCF–cKit signal for osteogenesis in bone fracture healing
Authors: Tomoyuki Matsumoto, Masaaki Ii, Hiromi Nishimura, Taro Shoji, Yutaka Mifune, Atsuhiko Kawamoto, Ryosuke Kuroda, Tomoaki Fukui, Yohei Kawakami, Tomoya Kuroda, Sang Mo Kwon, Hiroto Iwasaki, Miki Horii, Ayumi Yokoyama, Akira Oyamada, Sang Yang Lee, Shinya Hayashi, Masahiro Kurosaka, Satoshi Takaki, Takayuki Asahara
Journal: The Journal of Experimental Medicine (2010)

The therapeutic potential of hematopoietic stem cells/endothelial progenitor cells (HSCs/EPCs) for fracture healing has been demonstrated with evidence for enhanced vasculogenesis/angiogenesis and osteogenesis at the site of fracture. The adaptor protein Lnk has recently been identified as an essential inhibitor of stem cell factor (SCF)–cKit signaling during stem cell self-renewal, and Lnk-deficient mice demonstrate enhanced hematopoietic reconstitution. In this study, we investigated whether the loss of Lnk signaling enhances the regenerative response during fracture healing. Radiological and histological examination showed accelerated fracture healing and remodeling in Lnk-deficient mice compared with wild-type mice. Molecular, physiological, and morphological approaches showed that vasculogenesis/angiogenesis and osteogenesis were promoted in Lnk-deficient mice by the mobilization and recruitment of HSCs/EPCs via activation of the SCF–cKit signaling pathway in the perifracture zone, which established a favorable environment for bone healing and remodeling. In addition, osteoblasts (OBs) from Lnk-deficient mice had a greater potential for terminal differentiation in response to SCF–cKit signaling in vitro. These findings suggest that inhibition of Lnk may have therapeutic potential by promoting an environment conducive to vasculogenesis/angiogenesis and osteogenesis and by facilitating OB terminal differentiation, leading to enhanced fracture healing.
Cytidine Deaminase Residual Activity in Serum Is a Predictive Marker of Early Severe Toxicities in Adults After Gemcitabine-Based Chemotherapies
Authors: Joseph Ciccolini, Laetitia Dahan, Nicolas André, Alexandre Evrard, Muriel Duluc, Aurore Blesius, Chenguang Yang, Sarah Giacometti, Caroline Brunet, Caroline Raynal, Adrien Ortiz, Nicolas Frances, Athanassios Iliadis, Florence Duffaud, Jean-François Seitz, Cédric Mercier
Journal: Journal of Clinical Oncology (2009)

PURPOSE Anticipating toxicities with gemcitabine is an ongoing story, and deregulation in cytidine deaminase (CDA) could be associated with increased risk of developing early severe toxicities on drug exposure. PATIENTS AND METHODS A simple test to evaluate CDA phenotypic status was first validated in an animal model investigating relationships between CDA activity and gemcitabine-related toxicities. Next, relevance of this test as a marker for toxicities was retrospectively tested in a first subset of 64 adult patients treated with gemcitabine alone, then it was tested in a larger group of 130 patients who received gemcitabine either alone or combined with other drugs and in 20 children. Additionally, search for the 435 T>C, 208 G>A and 79 A>C mutations on the CDA gene was performed. Results In mice, CDA deficiency impacted on gemcitabine pharmacokinetics and had subsequent lethal toxicities. In human, 12% of adult patients experienced early severe toxicities after gemcitabine administration. A significant difference in CDA activities was observed between patients with and without toxicities (1.2 +/- 0.8 U/mg v 4 +/- 2.6 U/mg; P < .01). Conversely, no genotype-to-phenotype relationships were found. Of note, the patients who displayed particularly reduced CDA activity all experienced strong toxicities. Gemcitabine was well tolerated in children, and no CDA deficiency was evidenced. CONCLUSION Our data suggest that CDA functional testing could be a simple and easy marker to discriminate adult patients at risk of developing severe toxicities with gemcitabine. Particularly, this study demonstrates that CDA deficiency, found in 7% of adult patients, is associated with a maximum risk of developing early severe toxicities with gemcitabine.
Subcutaneous Compared With Intravenous Administration of Amifostine in Patients With Head and Neck Cancer Receiving Radiotherapy: Final Results of the GORTEC2000-02 Phase III Randomized Trial
Authors: Etienne Bardet, Laurent Martin, Gilles Calais, Marc Alfonsi, Nasr Eddine Feham, Claude Tuchais, Pierre Boisselier, Bernadette Dessard-Diana, Sok-Hun Seng, Pascal Garaud, Anne Aupérin, Jean Bourhis
Journal: Journal of Clinical Oncology (2010)

Purpose To compare compliance with and efficacy of intravenous (IV) and subcutaneous (SC) amifostine for the treatment of patients undergoing radiotherapy for head and neck cancer. Patients and Methods Patients with newly diagnosed squamous cell carcinoma of the head and neck, who were eligible for radiotherapy and who were not receiving concurrent chemotherapy, were randomly assigned to receive either IV amifostine (200 mg/m 2 daily for 3 minutes, 15 to 30 minutes before irradiation) or SC amifostine (500 mg; two sites; 20 to 60 minutes before irradiation). The primary end point was late xerostomia at 1 year as indicated by unstimulated and stimulated salivary flow rates, a patient benefit questionnaire score, and Radiation Therapy Oncology Group (RTOG) late toxicity grade. Results Results for IV (n = 143) versus SC (n = 148) administration were as follows. There was no significant difference in compliance (69% for IV v 71% for SC) in patients receiving a full dose of amifostine. Reasons for dose reduction were acute toxicity (25% for IV v 27% for SC; P = .51) and logistics (18% for IV v 9% for SC administration; P = .09). Acute toxicity differed significantly in terms of grade 1 to 2 hypotension (19% for IV v 8% for SC; P = .01), grade 1 to 2 skin rash (9% for IV v 21% for SC; P = .01), and local pain (0% for IV v 8% for SC; P = .003). The incidence of grade 2 or greater xerostomia was significantly higher for patients who received amifostine via SC administration (37% for IV v 62% for SC; P = .005) in the 127 patients (n = 67, IV; n = 60, SC) evaluable at 1 year but not at 2 or 3 years (36% for IV v 51% for SC administration; P = .19; 32% for IV v 41% for SC; P = .63). A generalized linear mixed-model analysis of all data revealed no significant difference in patient self-assessment of salivary function (P = .25), unstimulated or stimulated salivary flow rates (P = .054 and .82, respectively), or grade 2 or greater xerostomia (P = .23). Conclusion SC amifostine administration was not significantly superior to IV amifostine administration in terms of patient compliance or efficacy.
Keep community hospitals open, primary care trusts told
Authors: Adrian O'Dowd
Journal: BMJ (2006)

The government has warned primary care trusts to think again before closing community hospitals because of current financial pressures in the NHS. The health minister Lord Norman Warner told an audience of about 100 managers last week that he was concerned about panic decisions by primary care trusts to close such hospitals. Keeping them open could actually save the NHS money, he added.

Guidance on the future of community hospitals was due to be issued within the next couple of months, said Lord Warner, at the Shaping the Future conference held in London by the NHS Confederation, …
L-Arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats
Authors: Reinhard Schneider, Ulrike Raff, Nicole Vornberger, Monika Schmidt, Ralf Freund, Mark Reber, Lothar Schramm, Stepan Gambaryan, Christoph Wanner, Harald H H W Schmidt, Jan Galle
Journal: Kidney International (2003)
Colon Epithelium. IV. Human Colon Carcinogenesis. Changes in Human Colon Mucosa Adjacent to and Remote From Carcinomas of the Colon&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn4"&gt;4&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn5"&gt;5&lt;/xref&gt;
Authors: A K Shamsuddin, L Weiss, P C Phelps, B F Trump
Journal: JNCI Journal of the National Cancer Institute (1981)

To verify the popular belief that the mucosa of the colon remote from a carcinoma is normal, in a retrospective study colon mucosae from 30 patients were studied; 15 patients had colon carcinoma and the other 15 patients without any obvious tumor in their colons served as controls. All the patients having colon carcinoma showed definite abnormalities in the mucosa remote from the tumor. None of the 15 control patients showed such morphologic changes in the mucosal sections sampled at random. The mucous changes observed were: dilatation and distortion of the crypts with flattening of the lining cells, overcrowding of crypts with mucous cells and basophilic cells, lining of the crypt with eosinophilic surface epithelial cells, and focal cellular stratification in the crypts. These abnormalities were also consistently observed in the transitional mucosa adjacent to the tumor in all of the 15 patients with colon cancer. Histochemical studies for the detection of epithelial acidic mucosubstances showed that sialomucin predominated in the colon mucosa harboring a carcinoma irrespective of the location of the tumor, whereas colon mucosa from otherwise normal individuals and patients with noncarcinomatous diseases showed a predominance of sulfomucin. Therefore, mucosa of the colon harboring a carcinoma was conclusively demonstrated to be morphologically and histochemically abnormal. The significance of these abnormalities and their possible role in the de novo histogenesis of colon carcinoma are discussed.
Human endogenous retrovirus glycoprotein–mediated induction of redox reactants causes oligodendrocyte death and demyelination
Authors: Joseph M Antony, Guido van Marle, Wycliffe Opii, D Allan Butterfield, François Mallet, Voon Wee Yong, John L Wallace, Robert M Deacon, Kenneth Warren, Christopher Power
Journal: Nature Neuroscience (2004)
Reduced p21WAF1/CIP1 via Alteration of p53-DDX3 Pathway Is Associated with Poor Relapse-Free Survival in Early-Stage Human Papillomavirus–Associated Lung Cancer
Authors: De-Wei Wu, Wen-Shan Liu, John Wang, Chih-Yi Chen, Ya-Wen Cheng, Huei Lee
Journal: Clinical Cancer Research (2011)

DDX3 alteration has been shown to participate in hepatocellular tumorigenesis via p21(WAF1/CIP1) (p21) deregulation. We observed that DDX3 and p21 expression in lung tumors was negatively associated with E6 expression. Therefore, the aim of this study was to clarify whether deregulation of p21 by DDX3 via an E6-inactivated p53 pathway would enhance tumor progression in HPV-associated lung cancers.Real-time PCR, luciferase assays, immunoprecipitation, and chromatin immunoprecipitation (ChIP) were performed to determine whether DDX3 was regulated by p53 to synergistically enhance p21 transcriptional activity. Cell proliferation was examined by cell counting and colony formation assays. DDX3 and p21 expression were evaluated in 138 lung tumors by real-time PCR and immunohistochemistry. The prognostic value of p21 expression on relapse-free survival (RFS) was analyzed by Kaplan-Meier analysis.Real-time PCR, luciferase assays, and ChIP assays indicated that three putative p53 binding sites, located at -1,080/-1,070, -695/-685, and -283/-273 on the DDX3 promoter, were required for DDX3 transcription. DDX3 deregulation by the E6-inactivated p53 pathway could promote cell proliferation and the ability to form colonies via reduced Sp1 binding activity on the p21 promoter. Among tumors, p21 expression was positively associated with DDX3 expression and negatively related with E6 expression, particularly in early-stage (I + II) tumors. Interestingly, low p21 expression was associated with a poor RFS in early-stage lung cancer.The reduction of p21 by the alteration of the p53-DDX3 pathway plays an essential role in early-stage HPV-associated lung tumorigenesis and is correlated with poor RFS of lung cancer patients.