tbuckley/cabot-search huggingface dataset:
Telematics: a new tool for epidemiological surveillance of diarrhoeal diseases in the Aquitaine sentinel network.
Authors: S Maurice, F Megraud, C Vivares, F Dabis, C Toulouse, B Tilly, R Salamon
Journal: BMJ (1990)

A sentinel health information system using telematics and a network of general practitioners was set up in Aquitaine in south western France in 1986. Among the health problems under surveillance was acute diarrhoea. Data for each patient who fulfilled the usual case definition for acute diarrhoea were reported by general practitioners using home terminals (Minitels) connected to a central computer by telephone. Over one year 2234 cases of diarrhoea were reported, the incidence varying from 0.8 to 1.5 cases per doctor per week. Seasonal variations in incidence were observed, with peaks in the winter and in the summer. Only 379 (17%) episodes of diarrhoea were classified as severe, and these patients consulted their general practitioners earlier than patients whose diarrhoea was less severe. Foreign travel was rarely found in the patients' histories, but clusters of cases were found in communities (4.6%) and in families (22.3%). The advantages of this system were easy reporting and immediate feedback, but it was difficult to extrapolate the data, and the system was inadequate for intervening in outbreaks of diarrhoeal disease. Our knowledge of diarrhoeal diseases in south west France improved.
The Alveolar Epithelium Determines Susceptibility to Lung Fibrosis in Hermansky-Pudlak Syndrome
Authors: Lisa R. Young, Peter M. Gulleman, James P. Bridges, Timothy E. Weaver, Gail H. Deutsch, Timothy S. Blackwell, Francis X. McCormack
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Hermansky-Pudlak syndrome (HPS) is a family of recessive disorders of intracellular trafficking defects that are associated with highly penetrant pulmonary fibrosis. Naturally occurring HPS mice reliably model important features of the human disease, including constitutive alveolar macrophage activation and susceptibility to profibrotic stimuli.Objectives: To decipher which cell lineage(s) in the alveolar compartment is the predominant driver of fibrotic susceptibility in HPS.Methods: We used five different HPS and Chediak-Higashi mouse models to evaluate genotype-specific fibrotic susceptibility. To determine whether intrinsic defects in HPS alveolar macrophages cause fibrotic susceptibility, we generated bone marrow chimeras in HPS and wild-type mice. To directly test the contribution of the pulmonary epithelium, we developed a transgenic model with epithelial-specific correction of the HPS2 defect in an HPS mouse model.Measurements and Main Results: Bone marrow transplantation experiments demonstrated that both constitutive alveolar macrophage activation and increased susceptibility to bleomycin-induced fibrosis were conferred by the genotype of the lung epithelium, rather than that of the bone marrow–derived, cellular compartment. Furthermore, transgenic epithelial-specific correction of the HPS defect significantly attenuated bleomycin-induced alveolar epithelial apoptosis, fibrotic susceptibility, and macrophage activation. Type II cell apoptosis was genotype specific, caspase dependent, and correlated with the degree of fibrotic susceptibility.Conclusions: We conclude that pulmonary fibrosis in naturally occurring HPS mice is driven by intracellular trafficking defects that lower the threshold for pulmonary epithelial apoptosis. Our findings demonstrate a pivotal role for the alveolar epithelium in the maintenance of alveolar homeostasis and regulation of alveolar macrophage activation.
Abstract 2829: Preclinical characterization of TKM-080301, a lipid nanoparticle formulation of a small interfering RNA directed against polo-like kinase 1
Authors: Sean C. Semple, Adam D. Judge, Marjorie Robbins, Sandra Klimuk, Merete Eisenhardt, Erin Crosley, Ada Leung, Raymond Kwok, Ellen Ambegia, Kevin McClintock, Ian MacLachlan
Journal: Cancer Research (2011)

Small interfering RNAs (siRNAs) have tremendous potential for the selective inhibition, or 'silencing', of genes involved in cancer cell growth and division. This inhibition occurs through a process known as RNA interference (RNAi). Polo-like kinase 1 (PLK1) is a target that has multiple critical roles in cell cycle regulation and cytokinesis. Here we describe the preclinical characterization of TKM-080301, a lipid nanoparticle (LNP) formulation of an siRNA directed against human PLK1 mRNA. Studies were performed to assess the in vitro pharmacologic activity and inherent immune stimulatory potential of various siRNAs. PLK1 siRNA formulated in LNP resulted in potent anti-proliferative activity and gene-specific silencing in many cancer cell lines; and TKM-080301 exhibited strong anti-tumor activity in several xenograft models of human cancer, including tumors implanted intra-hepatically and subcutaneously. RNAi and the intended pharmacologic effects were confirmed in these models by histopathology, to visualize mitotic disruption, and by molecular methods, to confirm the presence of the RNAi-induced PLK1 mRNA cleavage product, the degree of PLK1 silencing relative to housekeeping genes, and the duration of silencing. In vivo, PLK1 silencing persisted for up to 7-10 days after a single administration and, importantly, occurred in the absence of any measurable stimulation of the innate immune system. Finally, unlike most small molecule PLK1 inhibitors, which are highly myelosuppresive, the toxicity profile of TKM-080301 was governed by the distribution profile of the LNP and toxicity was largely restricted to the liver and spleen. Collectively, these studies support the clinical evaluation of TKM-080301 as a new approach to targeting PLK1 in solid tumors.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2829. doi:10.1158/1538-7445.AM2011-2829
Tricyclic Plasma Levels
Authors: Vincent E. Ziegler
Journal: JAMA (1977)

Steady-state plasma tricyclic antidepressant levels were determined in 65 patients undergoing treatment for depression with either amitriptyline hydrochloride or nortriptyline hydrochloride to determine if common factors such as age, race, sex, or smoking status were predictors of steady-state drug levels that have been shown to vary up to 36-fold. Evaluation of these factors did not disclose differences in the rate of demethylation of amitriptyline to nortriptyline, or steady-state tricyclic levels in the amitriptyline-treated patients. No differences were found in the nortriptyline-treated patients except regarding race. Black patients had significantly higher (50%) nortriptyline plasma levels than did white patients, which may explain the more rapid response to tricyclic treatment demonstrated in blacks. Decreased rates of nortriptyline metabolism in blacks can result in increased side effects and treatment failure if the therapeutic plasma range is exceeded.
NPHS2 Variation in Sporadic Focal Segmental Glomerulosclerosis
Authors: Louise M. McKenzie, Sher L. Hendrickson, William A. Briggs, Richard A. Dart, Stephen M. Korbet, Michelle H. Mokrzycki, Paul L. Kimmel, Tejinder S. Ahuja, Jeffrey S. Berns, Eric E. Simon, Michael C. Smith, Howard Trachtman, Donna M. Michel, Jeffrey R. Schelling, Monique Cho, Yu C. Zhou, Elizabeth Binns-Roemer, Gregory D. Kirk, Jeffrey B. Kopp, Cheryl A. Winkler
Journal: Journal of the American Society of Nephrology (2007)

Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3' untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR = 0.5, P = 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.
Association of Oedema and Hypomagnesaemia with Hypocalcaemic Tetany of the Newborn
Authors: M. L. Chiswick
Journal: BMJ (1971)

The cases of 18 babies with hypocalcaemic tetany of the newborn are described. Studies were made before and 24 and 48 hours after therapy with calcium supplements. Twelve of the babies were non-oedematous and showed a positive correlation between serum calcium and magnesium levels. They showed a rise in serum magnesium levels during therapy with calcium. The other six had bilateral pitting oedema of the feet and greater weight gains in the first two weeks of life. They had abnormally low serum magnesium levels which did not correlate with the calcium levels. Furthermore, the serum magnesium levels, unlike those in the non-oedematous group, did not increase when calcium supplements were given. It is suggested that oedema in babies with hypocalcaemic tetany may be more common than is generally recognized, and that a contributory factor in the production of the hypomagnesaemia may be secondary aldosteronism.
Abstract P6-04-23: Targeting of endocrine therapy resistance through combined mTOR and histone deacetylase inhibition
Authors: P Ordentlich, S Flechsig, J Hoffmann
Journal: Cancer Research (2012)

Abstract Background: Primary and acquired resistance to endocrine therapy in advanced breast cancer presents a significant barrier to maximizing the clinical effectiveness of these agents. Preclinical data has demonstrated that up-regulation and/or constitutive activation of estrogen independent growth signaling pathways drive resistance to aromatase inhibitors and that targeting of these pathways is an effective strategy to overcoming the resistance. We recently reported in a randomized, placebo controlled phase 2 study that entinostat (ENT), an oral class 1 selective HDAC inhibitor, combined with exemestane extended PFS and OS in postmenopausal women with ER+ positive breast cancer that had progressed on a prior nonsteroidal aromatase inhibitor. Likewise, everolimus (EVE), a mTORi, combined with exemestane or tamoxifen (TAM) also significantly extended PFS in a similar patient population. In order to determine the potential benefit of combining ENT with EVE plus hormone therapy we have piloted a series of xenograft studies in primary human tumor models of TAM sensitivity and resistance. Methods: Athymic nude mice bearing xenografts of tissue derived directly from patient tumors (MaCa4049 – TAM sensitive; MaCa3366/TAM – partially resistant to TAM) were treated with A) vehicle B) 2 mg/kg EVE C) 2 mg/kg EVE + 10 mg/kg TAM D) 15 mg/kg ENT E) 2mg/kg EVE + 10mg/kg TAM + 15 mg/kg ENT. Tumor samples taken at the end of the study were cryoconserved for analysis of gene and protein expression and protein phosphorylation. Results: Growth of MaCa4049 tumors was inhibited in all treatment groups relative to vehicle in two independent studies conducted in this tumor model. Groups B, C and D demonstrated a similar level of activity while maximal inhibition was observed in Group E (combination of EVE + ENT + TAM). All treatments were generally well tolerated with weight loss similar in groups C and E. Treatment of MaCa3366/TAM tumors resulted in similar levels of tumor growth inhibition in groups B, C and E which were all highly effective in suppressing tumor growth in this model. As EVE alone was highly effective as a single agent in the MaCa3366/TAM model the contribution of ENT will be assessed through molecular analysis of tumors upon study completion. Efficacy results and analysis of tumor samples from completed studies will be presented to provide insight into mechanism of action for the triple combination. Conclusions: Preclinical data demonstrating enhanced activity of entinostat combined with everolimus and hormone therapy provides the rationale for clinical investigation of this novel therapeutic approach to targeting hormone therapy resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-23.
Delayed Type Hypersensitivity to Iodinated Contrast Media: Diagnosis and Cross-reactivity
Authors: L. Sánchez, P. Tornero, M. Tomas, M. De Barrio, T. Herrero, M. Rueda, M.L. Baeza, M. Rubio, A. Prieto
Journal: Journal of Allergy and Clinical Immunology (2009)
Enhanced CT and FDG PET/CT in Primary Malignant Peripheral Nerve Sheath Tumor of the Uterine Cervix
Authors: Aisheng Dong, Changjing Zuo, Yang Wang, Zhijun Zhai, Mingjuan Xu
Journal: Clinical Nuclear Medicine (2013)

Malignant peripheral nerve sheath tumor of the uterine cervix is extremely rare. A 45-year-old woman presented with intermittent vaginal bleeding for 1 month. Enhanced CT in the arterial and venous phases showed a hypervascular tumor in the uterine cervix. Colposcopy-directed biopsy revealed malignant peripheral nerve sheath tumor. FDG PET/CT showed intense FDG uptake (SUVmax, 8.8) of the tumor mimicking cervical cancer. Total laparoscopic radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy were performed.
Experimental Oral Carcinogenesis
Authors: B. M. Levy
Journal: CA A Cancer Journal for Clinicians (1959)

In any discussion of nialignant growth, a consideration of cancer of the mouth is of importance. in theUnitedStates, oral cancer occurs at a rate of about 25 per 100,000 population or in about 23,000 people a year.Moore reported that ofthe 19,192 patients treated at Memorial Hos pital, New York City, over a 12-year pe riod, 20 per cent had malignant disease of theintraoral and neighboring regions.Next to genitourinary cancer, oral cancer was the most common malignant tumor treated atthis hospital.Cancerofthemouth isprimarily a dis
FURTHER OBSERVATIONS ON INCREASED BLOOD COUNTS DUE TO HIGH ALTITUDE.
Authors: JOHN WEINZIRL
Journal: JAMA (1903)

That altitude produces an increase in the number of red corpuscles in the blood is a principle very generally accepted. The work of a number of investigators appears to show that the increase is directly proportional to the altitude. At sea level we have, according to Laasche, a blood count of 4,974,000 cells which is by many considered normal.† At an altitude of 9,500 feet Egger found a count of 7,000,000 cells; while Viault, who worked in the Cordilleras of South America at an altitude of 14,400 feet, found the high count of 8,000,000 cells. All these counts refer to human subjects. As a result of these and similar studies the principle of high blood counts in high altitudes is regularly found in our works on hematology, and is regularly taught in the medical schools. Further, more or less elaborate theories have been based on it to
Blood flow distributions by microsphere deposition methods
Authors: F Prinzen
Journal: Cardiovascular Research (2000)

The art and science of the use of deposition markers for the estimation of blood flow distributions throughout the body and within organs is reviewed. Development of diffusible tracer techniques started 50 years ago. Twenty years later, radioactive 15 micron microspheres became the standard marker. Early studies on small animals, fetal sheep in 1967 and rats in 1976, provoked much of the technical development. Needs for avoiding the use of radioactivity, for having long lasting labels, and for providing higher spatial resolution, are driving the continuing exploration of newer techniques using colored and fluorescent microspheres and molecular deposition markers. Strengths and weaknesses of the various methods are compared.
631 CHROMATIN-BASED ANALYSIS REVEALS THE COMPLEXITY OF THE ALPHA-IFN/STAT2 TRANSCRIPTOME AND IDENTIFIES FUNCTIONALLY DISTINCT SUBSETS OF STAT2 DIRECT TARGET GENES
Authors: B. Testoni, C. Scisciani, C. Voellenke, G. Blandino, M. Levrero
Journal: Journal of Hepatology (2008)
Abstract P2-05-08: Combined neoadjuvant iniparib and carboplatin in locally advanced or metastatic canine mammary tumors (MT) to support human clinical studies
Authors: F Morio, S Becavin, A Gogny, F Nguyen, O Albaric, S Labrut, C Séveno, P Vrignaud, P Juin, M Campone, J Abadie, C Ibisch
Journal: Cancer Research (2013)

Abstract INTRODUCTION Among breast cancers, the triple negative subtype (negative for hormone receptors and not overexpressing HER2) has the worst prognosis and its response to Iniparib has been investigated in clinical trials. Further investigations are needed to optimize drug schedule and patient selection criteria. Iniparib antitumor mechanism is not completely understood, as well as iniparib diffusion kinetic into tumoral tissues. We address these questions in spontaneous canine invasive mammary carcinomas, which are a good model for this cancer subtype (Ibisch et al., World Veterinary Cancer Congress 2012), in a neoadjuvant setting. To our knowledge, this is the first study of iniparib administration in cancer-bearing dogs. MATERIAL AND METHODS Twenty female dogs with spontaneous MT with malignant criteria (tumor size, speed of growth, ulceration, relapse, or metastasis) were included. All tumors were described as rapidly growing. Dogs received a first infusion of iniparib at day 0 and a combination of carboplatin and iniparib at day 7. Biological materials (tumor biopsies and blood) were collected before and 5 minutes after iniparib infusion for pharmacokinetic and metabolism studies. Tumor response was evaluated by caliper measurements and histopathological analysis of mammary tumors and draining lymph nodes. A chain mastectomy was performed 3 or 4 weeks later. Histological records included the subtype of carcinoma (WHO 1999), Elston &amp; Ellis grade, presence of emboli, lymph node metastasis and IHC stainings using ER, PR, Her2 (scored according to Wolff et al.2007), CK5/6, EGF-R and Ki67. Intensity of necrosis and apoptosis was evaluated using PAS coloration and immunohistochemistry for caspase 3, at DO on tumor biopsies and at surgery. Toxicity of the protocol was evaluated and its efficiency on invasive carcinomas was compared to surgery alone (control group of 27 female dogs with invasive mammary carcinomas treated by chain mastectomy alone). RESULTS Treated and control groups shared similar features concerning animal breeds, age, neutering status and tumor location. 75% of the treated MT were malignant. Necrosis and apoptosis were significantly increased in respectively 63 and 56% of iniparib treated tumors. Clinical evidence of toxicity was minimal (15% of dogs with nausea, 60% with transient polyuria-polydipsia). Tumor stabilization was observed before surgery in all dogs but one. Median survival has not been reached. CONCLUSION Iniparib at 35mg/kg combined with carboplatin at 300 mg/m2 seemed well tolerated in this study and deserves further investigations. The degree of necrosis and apoptosis in the treated tumors can be evaluated with these techniques. Iniparib pharmacokinetic and metabolism studies in cancer-bearing dogs are ongoing. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-08.
Successful Regional Delivery and Long-term Expression of a Dystrophin Gene in Canine Muscular Dystrophy: A Preclinical Model for Human Therapies
Authors: Zejing Wang, Rainer Storb, Christine L Halbert, Glen B. Banks, Tiffany M. Butts, Eric E. Finn, James M. Allen, A. Dusty Miller, Jeffrey S. Chamberlain, Stephen J. Tapscott
Journal: Molecular Therapy (2012)

Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a group of skeletal muscles in dystrophic dogs given a brief course of commonly used immunosuppressants. Robust c-µdys expression was obtained for at least two years and was associated with molecular reconstitution of the dystrophin-glycoprotein complex (DGC) at the muscle membrane. Importantly, c-µdys expression was maintained for at least 18 months after discontinuing immunosuppression. The results obtained in a relevant preclinical model of DMD demonstrate feasibility of widespread AAV-mediated muscle transduction and transgene expression in the presence of transient immunosuppression to achieve molecular reconstitution that can be directly translated to human trials. Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a group of skeletal muscles in dystrophic dogs given a brief course of commonly used immunosuppressants. Robust c-µdys expression was obtained for at least two years and was associated with molecular reconstitution of the dystrophin-glycoprotein complex (DGC) at the muscle membrane. Importantly, c-µdys expression was maintained for at least 18 months after discontinuing immunosuppression. The results obtained in a relevant preclinical model of DMD demonstrate feasibility of widespread AAV-mediated muscle transduction and transgene expression in the presence of transient immunosuppression to achieve molecular reconstitution that can be directly translated to human trials.
AUTOMATED QUANTITATIVE MODELING OF THE AORTIC VALVE AND ROOT IN AORTIC REGURGITATION USING VOLUME 3-D TRANSESOPHAGEAL ECHOCARDIOGRAPHY
Authors: Anna Calleja, Ionasec Razvan, Helene Houle, Shizhen Liu, Jennifer Dickerson, Paaladinesh Thavendiranathan, Chittoor Sai-Sudhakar, Juan Crestanello, Thomas Ryan, Mani Vannan
Journal: Journal of the American College of Cardiology (2010)
US scientists urge overhaul of clinical trials to restore confidence
Authors: Michael Day
Journal: BMJ (2006)

The US government's top biomedical scientists have called for an overhaul of clinical trials to protect the public and to restore trust in medicine. After a summit at the National Institutes of Health (NIH), in Maryland, the institutes' director, Elias Zerhouni, warned that failure to spot serious side effects of drugs quickly enough was gradually eroding public trust. He announced an eight point plan designed to improve clinical trials and reduce the likelihood of side effects being swept under the carpet.

A key recommendation is for equal weight to be given to determining the safety as well as the …