tbuckley/cabot-search huggingface dataset:
Early Thickening of the Reticular Basement Membrane in Children with Difficult Asthma
Authors: Donald N. R. Payne, Andrew V. Rogers, Ellinor Ädelroth, Venkata Bandi, Kalpalatha K. Guntupalli, Andrew Bush, Peter K. Jeffery
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Remodeling of the airway wall occurs in adults with asthma, and reticular basement membrane (RBM) thickening is pathognomonic of the asthma process. To investigate whether RBM thickening is present in children with difficult asthma and comparable to that seen in adults with asthma, we used light microscopy to measure RBM thickness in plastic-embedded endobronchial biopsy sections from 19 children with difficult asthma who were prescribed 1,600 microg/day or more of inhaled steroids (age range, 6-16 years), 10 children without asthma (7-16 years), and three adult groups: 8 healthy control subjects (21-42 years), 10 mild steroid-naive subjects with asthma (18-41 years), and 6 adults (3 steroid naive and 3 on inhaled steroids) intubated after a life-threatening attack of asthma (20-64 years). RBM thickness in the children with asthma was similar to that in adults with either mild or life-threatening asthma (median 8.2 [range 5.4-11.1] versus 8.1 [5.8-10.0] and 7.2 [2.8-10.0] microm, respectively) and greater than either adult or pediatric control subjects (8.2 [5.4-11.1] versus 4.4 [3.2-6.3] microm, p < 0.01, and 4.9 [3.7-8.3] microm, p < 0.01). We conclude that RBM thickening is already present in children with difficult asthma and to a similar extent to that seen in adults with asthma. In addition, we find no association with age, symptom duration, lung function, or concurrent eosinophilic airway inflammation.
Development Times, Clinical Testing, Postmarket Follow-up, and Safety Risks for the New Drugs Approved by the US Food and Drug Administration
Authors: Thomas J. Moore, Curt D. Furberg
Journal: JAMA Internal Medicine (2013)

The US Food and Drug Administration (FDA) has advanced multiple proposals to promote biomedical innovation by making new drugs available more quickly but with shorter, smaller, and more selective clinical trials and less rigorous end points.To inform the debate about appropriate standards, we studied the development times, clinical testing, postmarket follow-up, and safety risks for the new drugs approved by the FDA in 2008, when most provisions of current law, regulation, and policies were in effect.Descriptive study of the drugs classified as new molecular entities using preapproval FDA evaluation documents, agency drug information databases, prescribing information, and other primary data sources.Comparison of drugs that received standard review and those deemed sufficiently innovative to receive expedited review with regard to clinical development and FDA review time, the size and duration of efficacy trials, safety issues, and postmarket follow-up.In 2008, the FDA approved 20 therapeutic drugs, 8 with expedited review and 12 with standard review. The expedited drugs took a median of 5.1 years (range, 1.6-10.6 years) of clinical development to obtain marketing approval compared with 7.5 years (range, 4.7-19.4 years) for the standard review drugs (P = .05). The expedited drugs were tested for efficacy in a median of 104 patients receiving the active drug (range, 23-599), compared with a median of 580 patients (range, 75-1207) for standard review drugs (P = .003). Nonclinical testing showed that 6 therapeutic drugs were animal carcinogens, 5 were in vitro mutagens, and 14 were animal teratogens. Other safety concerns resulted in 5 Boxed Warnings; 8 drugs required risk management plans. The FDA required 85 postmarket commitments. By 2013, 5 drugs acquired a new or expanded Boxed Warning; 26 of 85 (31%) of the postmarketing study commitments had been fulfilled, and 8 (9%) had been submitted for agency review.For new drugs approved by the FDA in 2008, those that received expedited review were approved more rapidly than those that received standard review. However, considerably fewer patients were studied prior to approval, and many safety questions remained unanswered. By 2013, many postmarketing studies had not been completed.
Assessment of clonality in gastrointestinal cancer by DNA fingerprinting.
Authors: M F Fey, R A Wells, J S Wainscoat, S L Thein
Journal: Journal of Clinical Investigation (1988)

DNA fingerprinting with three different probes (33.15, 33.6, and alpha-globin 3'HVR) was investigated as a method for the determination of clonality in gastrointestinal tumors. In 29/44 carcinomas the tumor DNA showed clonal somatic mutations that were not seen in the corresponding peripheral blood and normal mucosa samples. The changes consisted of either novel fingerprint bands, losses of bands, or both. The probe 33.15 yielded the highest rate of abnormal DNA fingerprints (21/44 carcinomas). Sequential use of the probes increased the number of cases where clonal fingerprint markers could be detected. One out of five colorectal adenomas also showed a clonal loss of a fingerprint band. In two cases of gastric cancer, DNA from the metastatic tumor had a different DNA fingerprint from that found in the primary carcinoma. DNA fingerprinting offers a novel approach to determining clonality in tumors and may prove useful for the study of tumor progression.
Pelvic floor function in multiple sclerosis.
Authors: J S Jameson, J Rogers, Y W Chia, J J Misiewicz, M M Henry, M Swash
Journal: Gut (1994)

The aim of this study was to define pelvic floor function in patients with multiple sclerosis and bowel dysfunction, either incontinence (MSI) or defecation difficulties without incontinence (MSC). Normal controls and patients with idiopathic neurogenic faecal incontinence without multiple sclerosis (FI, disease controls) were also studied. Thirty eight multiple sclerosis patients (20 incontinent, 18 incontinent) 73 normal controls, and 91 FI patients were studied. The FI group showed the characteristic combined sensorimotor deficit previously described in these patients of low resting and voluntary contraction and pressures, increased sensory threshold to mucosal stimulation, and increased pudendal nerve terminal motor latencies and fibre densities. MSI patients had significantly lower anal resting pressures (80 (30-140) cm H2O, median (range) v 98 (30-200), normal controls, p = 0.002) and both MSC and MSI patients had significantly lower anal maximum voluntary contraction pressures (65 (0-260) cm H2O, MSC and 25 (0-100), MSI v 120 (30-300), normal controls, p = &lt; 0.0004) and higher external anal sphincter fibre densities (1.7 (1.1-2.6), MSC and 1.7 (1.1-2.4), MSI v 1.5 (1.1-1.75), normal controls, p &lt; 0.006) compared with normal controls but pudendal nerve terminal motor latencies were similar and no sensory deficit was found. This contrasted with the idiopathic faecal incontinent patients who, in addition to significantly higher fibre densities (1.8 (1.1-3), p = 0.001) had increased pudendal latencies (2.5 (1.1-5.5) mS v 2.08 (1.4-2.6), p = 0.001) compared with normal controls. The idiopathic faecal incontinent group had significantly lower resting anal pressures (50 (10-160) cm H2O, p=0.02) than the MSI group. Comparison with the incontinent and continent multiple sclerosis groups showed that incontinence was associated with lower voluntary anal contraction pressures (25 (0-100) v 65 (0-260), p=0.03) but that there were no other differences between these two groups. Pelvic floor function is considerably disturbed in multiple sclerosis, showing muscular weakness with preservation of peripheral motor nerve conduction, providing indirect evidence that this is mainly a result of lesions within the central nervous system.
A Novel Tetrodotoxin-Sensitive Na sup + Current in Cultured Human Coronary Myocytes
Authors: Jean-Francois Quignard, Frederique Ryckwaert, Bernard Albat, Joel Nargeot, Sylvain Richard
Journal: Circulation Research (1997)

Voltage-gated Na sup + currents (I Na s) are usually not found in arterial smooth muscle. We enzymatically isolated myocytes from the media of left coronary arteries of heart transplant patients with ischemic cardiopathy. Using the whole-cell voltage-clamp technique (20 degrees C to 22 degrees C), we detected no I Na in any of the freshly isolated myocytes. In contrast, when the cells were grown in culture, we could record a large I Na . This I Na was characterized by a biexponential decay comprising a fast inactivating and sustained components that could not be separated by their electrophysiological and pharmacological properties. I Na activated at depolarizations positive to -50 mV, was maximal at 0 mV, and was available from relatively low resting membrane potentials (half-inactivation at -46 mV). I Na was modulated by several ligands known to bind selectively at different sites of Na sup + channels. It was blocked with high affinity by tetrodotoxin (IC 50 , [nearly =]10 nmol/L) and local anesthetics (bupivacaine and lidocaine; IC 50 , [nearly =]100 nmol/L) and by Cd 2 + (IC 50 , [nearly =]300 micro mol/L). I Na was modulated by Na sup + channel agonists such as toxin AsV from Anemonia sulcata and veratridine, which slowed current kinetics dramatically. In conclusion, human coronary myocytes in culture can express an atypical tetrodotoxin-sensitive I Na with a large sustained component, which is expected to contribute to massive Na sup + influx into these cells. Phenotypic modulation of the expression of this I Na may be related to cell dedifferentiation and proliferation.
Soil and Rhizosphere Associated Fungi in Gray Mangroves (<i>Avicennia Marina</i>) from the Red Sea — A Metagenomic Approach
Authors: Marta Filipa Simões, André Antunes, Cristiane A. Ottoni, Mohammad Shoaib Amini, Intikhab Alam, Hanin Alzubaidy, Noor-Azlin Mokhtar, John A.C. Archer, Vladimir B. Bajic
Journal: Genomics Proteomics & Bioinformatics (2015)

Abstract Covering a quarter of the world’s tropical coastlines and being one of the most threatened ecosystems, mangroves are among the major sources of terrestrial organic matter to oceans and harbor a wide microbial diversity. In order to protect, restore, and better understand these ecosystems, researchers have extensively studied their microbiology, yet few surveys have focused on their fungal communities. Our lack of knowledge is even more pronounced for specific fungal populations, such as the ones associated with the rhizosphere. Likewise, the Red Sea gray mangroves (Avicennia marina) remain poorly characterized, and understanding of their fungal communities still relies on cultivation-dependent methods. In this study, we analyzed metagenomic datasets from gray mangrove rhizosphere and bulk soil samples collected in the Red Sea coast, to obtain a snapshot of their fungal communities. Our data indicated that Ascomycota was the dominant phylum (76%–85%), while Basidiomycota was less abundant (14%–24%), yet present in higher numbers than usually reported for such environments. Fungal communities were more stable within the rhizosphere than within the bulk soil, both at class and genus level. This finding is consistent with the intrinsic patchiness in soil sediments and with the selection of specific microbial communities by plant roots. Our study indicates the presence of several species on this mycobiome that were not previously reported as mangrove-associated. In particular, we detected representatives of several commercially-used fungi, e.g., producers of secreted cellulases and anaerobic producers of cellulosomes. These results represent additional insights into the fungal community of the gray mangroves of the Red Sea, and show that they are significantly richer than previously reported.
Hemophilus Influenza Infection of an Implantable Insulin-Pump Pocket
Authors: Richard P Levy, Mark D Borchelt, Richard M Kremer, Stephen J Francis, Carol A O'Connor
Journal: Diabetes Care (1992)

OBJECTIVE To increase awareness of adverse events associated with the use of implantable insulin pumps. RESEARCH DESIGN AND METHODS A descriptive case report of a pump implant infection. RESULTS This is a case report of one implanted insulin pump-pocket infection among a series of 15 patients. After exposure to a child with a respiratory infection on PID 30, V.L.C. (the patient) developed a fulminant pump-pocket infection. H. influenza was recovered from it. Despite aggressive antibiotic therapy, the infection could not be controlled. Insulin delivery ceased, and the pump was explanted. The pump-pocket infection rapidly resolved with pump removal, permitting later reimplantation. CONCLUSIONS We have adopted the American Heart Association indications and antimicrobial prophylaxis regimens recommended for prevention of endocarditis in patients with prosthetic values for patients with implanted insulin pumps.
Prevalence, Trends, and Risk Factors for Fecal Incontinence in United States Adults, 2005–2010
Authors: Ivo Ditah, Pardha Devaki, Henry N. Luma, Chobufo Ditah, Basile Njei, Charles Jaiyeoba, Augustine Salami, Calistus Ditah, Oforbuike Ewelukwa, Lawrence Szarka
Journal: Clinical Gastroenterology and Hepatology (2013)
Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma
Authors: Rosita L. ten Berge, Chris J. L. M. Meijer, Danny F. Dukers, J. Alain Kummer, Bellinda A. Bladergroen, Wim Vos, C. Erik Hack, Gert J. Ossenkoppele, Joost J. Oudejans
Journal: Blood (2002)
Failure to Rescue As a Source of Variation in Hospital Mortality for Ovarian Cancer
Authors: Jason D. Wright, Thomas J. Herzog, Zainab Siddiq, Rebecca Arend, Alfred I. Neugut, William M. Burke, Sharyn N. Lewin, Cande V. Ananth, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2012)

Although the association between high surgical volume and improved outcomes from procedures is well described, the mechanisms that underlie this association are uncertain. There is growing recognition that high-volume hospitals may not necessarily have lower complication rates but rather may be better at rescuing patients with complications. We examined the role of complications, failure to rescue from complications, and mortality based on hospital volume for ovarian cancer.The Nationwide Inpatient Sample was used to identify women who underwent surgery for ovarian cancer from 1988 to 2009. Hospitals were ranked on the basis of their procedure volume. We determined the risk-adjusted mortality, major complication rate, and "failure to rescue" rate (mortality in patients with a major complication) for each tertile. Univariate and multivariate associations were then compared.We identified 36,624 patients. The mortality rate for the cohort was 1.6%. The major complication rate was 20.4% at low-volume, 23.4% at intermediate-volume, and 24.6% at high-volume hospitals (P < .001). However, the rate of failure to rescue (death after a complication) was markedly higher at low-volume (8.0%) compared with high-volume hospitals (4.9%; P < .001). After accounting for patient and hospital characteristics, women treated at low-volume hospitals who experienced a complication were 48% more likely (odds ratio [OR], 1.48; 95% CI, 1.11 to 1.99) to die than patients with a complication at a high-volume hospital.Mortality is lower for patients with ovarian cancer treated at high-volume hospitals. The reduction in mortality does not appear to be the result of lower complications rates but rather a result of the ability of high-volume hospitals to rescue patients with complications.
A Phase I Pharmacokinetic and Pharmacodynamic Study of TKI258, an Oral, Multitargeted Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
Authors: Debashis Sarker, Rhoda Molife, T.R. Jeffrey Evans, Maryon Hardie, Cheryl Marriott, Priska Butzberger-Zimmerli, Rosemary Morrison, Judith A. Fox, Carla Heise, Sharianne Louie, Natasha Aziz, Felix Garzon, Glenn Michelson, Ian R. Judson, Dalal Jadayel, Edgar Braendle, Johann S. de Bono
Journal: Clinical Cancer Research (2008)

To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258).A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule.Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels.The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.
Psoriasis: snapshots of the unspoken: using novel methods to explore patients' personal models of psoriasis and the impact on well‐being
Authors: C. Bundy, M. Borthwick, H. McAteer, L. Cordingley, L. Howells, P. Bristow, S. McBride
Journal: British Journal of Dermatology (2014)

People with psoriasis report high levels of undermanaged distress. This is compounded by the problem that some patients find it difficult to discuss their emotions. Distress prevents optimal self-management, which may exacerbate psoriasis flares, thereby creating a vicious cycle.To offer people with psoriasis a novel way of expressing their personal models of psoriasis in order to gain a better understanding of their experiences of living with the condition.We used a qualitative technique - asking people with psoriasis to complete a postcard entitled 'Dear Psoriasis...' - to collect survey data on their personal models of psoriasis.One hundred and four returned postcards provided new insights into the extent of and reasons for distress in psoriasis. Seven dominant themes emerged: identity and relationships; battleground; control; emotional consequences; hypervigilance; coping; treatment burden.Reports of distress were common, and for many it was long-standing. Some reported low self-esteem and self-denigration bordering on self-loathing, and described being hypervigilant and in a constant battle with their skin. Many people did not expect to have intimate relationships, resulting in reduced social support for patients in the future. This research underscores the need for patient support and psychological treatment to be made available as part of routine care.
Irofulven Cytotoxicity Depends on Transcription-Coupled Nucleotide Excision Repair and Is Correlated with XPG Expression in Solid Tumor Cells
Authors: Florence Koeppel, Virginie Poindessous, Vladimir Lazar, Eric Raymond, Alain Sarasin, Annette K. Larsen
Journal: Clinical Cancer Research (2004)

Abstract Background: Irofulven is a novel alkylating agent with promising clinical activity, particularly toward ovarian and hormone-refractory prostate cancers. To facilitate additional clinical development, we have aimed to identify biological markers associated with sensitivity to the compound. Methods: Fibroblasts derived from patients with xeroderma pigmentosum or Cockayne’s syndrome along with a panel of 20 human cancer cell lines (eight different tumor types) were examined to establish the importance of nucleotide excision repair proteins in the sensitivity to irofulven. Results: Human cells deficient in nucleotide excision repair are up to 30-fold more sensitive to the cytotoxic effects of irofulven compared with repair-proficient controls, clearly indicating that nucleotide excision repair plays a crucial role in the sensitivity to the drug. Interestingly, our results show that irofulven-induced lesions are recognized by transcription-coupled repair but not by global genome repair. Another unique feature is the pronounced sensitivity of XPD and XPB helicase-deficient cells to the drug. Comparison of the IC50 values for irofulven, cisplatin, and ecteinascidin 743 with the expression levels of ERCC1, XPD, and XPG genes in different solid tumor cell lines shows no correlation between the expression levels of any of the three nucleotide excision repair proteins and the sensitivity to ecteinascidin 743. In contrast, expression of the XPG endonuclease was correlated with the cytotoxicity for irofulven and, to a lesser degree, for cisplatin. Importantly, XPG expression was also correlated with cellular nucleotide excision repair activity. Conclusions: Increasing evidence indicates that compromised nucleotide excision repair activity is frequent in several solid tumor types. The results presented here suggest that XPG expression in such tumors may be a useful marker to predict their sensitivity to irofulven.
Macrophage-Mediated, Antibody-Dependent Destruction of Tumor Cells in DBA/2 Mice: In Vitro Identification of an In Situ Mechanism<xref ref-type="fn" rid="fn2">2</xref>, <xref ref-type="fn" rid="fn3">3</xref>
Authors: M Key, S Haskill
Journal: JNCI Journal of the National Cancer Institute (1981)

A macrophage-mediated, antibody-dependent phagocytic mechanism of in situ tumor cell destruction was evident in the T1699 mammary adenocarcinoma model. The tumor-associated effector macrophages (TuM theta) required immune serum at low effector-to-target-cell ratios for rapid phagocytosis and destruction of cultured T1699 cells in vitro. Whereas TuM theta were inactive against such cultured T1699 cells, TuM theta rapidly engulfed and destroyed target cells isolated from the same tumor as the macrophages themselves. TuM theta containing intact and partially degraded tumor cells were both isolated from regressing tumors and identified in histologic sections. [3H]thymidine pulse-labeling studies of rergressing tumors in DBA/2 mice indicated that TuM theta phagocytosis of recently dividing tumor cells was common. This supports the concept that macrophage-mediated antibody-dependent tumor cell destruction, though not the only process involved in tumor regression, could be a potentially efficient and relevant mechanism for in vivo tumor cell destruction. Although the data do not formally prove that the phagocytosed tumor cells were undamaged prior to ingestion, the indication is that a particular class of macrophage was relevant in situ for tumor cell destruction either solely through phagocytosis or a combination of events. Inasmuch as TuM theta contained more than 10% of the tumor cells in regressing tumors, the importance of these macrophages to the process appeared relevant. These data also suggest that, inasmuch as phagocytosed intact tumor cells have a life-span of less than 2 hours, the infrequent description of this phenomenon in both experimental and clinical situations may be partly a result of difficulties in detection.