tbuckley/cabot-search huggingface dataset:
Clarifying Adverse Drug Events: A Clinician's Guide to Terminology, Documentation, and Reporting
Authors: Jonathan R. Nebeker, Paul Barach, Matthew H. Samore
Journal: Annals of Internal Medicine (2004)

Adverse drug events cause substantial morbidity and mortality, yet they remain underappreciated and misunderstood. The terminology to describe errors and patient harm associated with medications causes much confusion. This article uses the case study of a patient with multiple adverse drug events to clarify key terms, such as adverse event, adverse drug reaction, adverse drug event, medication error, and side effect. The case discussion illustrates clinical approaches to analyzing the causal connection between a suspect drug and an adverse event. Examples and rationale for meaningful documentation of adverse drug events are provided, along with an outline of the types of events that should be reported to regulatory agencies.
Combination of Quantitative IMP3 and Tumor Stage: A New System to Predict Metastasis for Patients with Localized Renal Cell Carcinomas
Authors: Zhong Jiang, Peigou G. Chu, Bruce A. Woda, Qin Liu, K.C. Balaji, Kenneth L. Rock, Chin-Lee Wu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To create an easily applicable system based on a combination of the quantitative level of IMP3 (an oncofetal protein) and tumor stage to more accurately predict postoperative metastasis of localized renal cell carcinoma. Experimental Design: Three hundred sixty nine patients with localized renal cell carcinoma (without metastasis during nephrectomy) were investigated by the use of survival analysis. The expression of IMP3 was evaluated by immunohistochemistry and quantitated with a computerized image analyzer. Based on combining quantitative IMP3 results with tumor staging (QITS system), patients were divided into four distinct risk groups for the development of metastasis. Results: The four groups of patients in the QITS system showed significant differences in their metastasis-free (P &amp;lt; 0.0001) and overall survivals (P &amp;lt; 0.0001). Almost all patients of group IV with localized renal cell carcinomas developed metastasis and died after nephrectomy. The 5- and 10-year metastasis-free survival rates for the QITS groups were as follows: for group I, 97% and 91%; II, 62% and 55%; III, 46% and 19%; and IV, 17% and 4%, respectively. The 5- and 10-year overall survival rates for the QITS groups were as follows: for group I, 89% and 72%; II, 58% and 41%; III, 38% and 17%; and IV, 14% and 4%, respectively. Conclusions: The QITS is a simple and accurate system for the prediction of tumor metastasis. This system not only provides important prognostic information but also can be used at initial diagnosis of localized renal cell carcinoma to identify high-risk patients who may benefit from early systematic therapy.
A possible role for non-gamma oscillations in conscious perception: Implications for hallucinations in schizophrenia
Authors: Ian J. Kirk
Journal: Behavioral and Brain Sciences (2004)

Behrendt &amp; Young (B&amp;Y) propose a useful theoretical framework for the study of processes underlying perception and hallucinations. It focuses on gamma oscillations in thalamocortical networks and the role of the reticular thalamic nucleus in modulating these oscillations. I suggest that their theoretical model might also be applied to the investigation of temporal encoding deficits in disorders such as dyslexia. I further suggest, however, that a role for slower rhythms, such as theta, might also be considered when investigating perceptual experience.
c-MYC Functions as a Molecular Switch to Alter the Response of Human Mammary Epithelial Cells to Oncostatin M
Authors: Charlene E. Kan, Rocky Cipriano, Mark W. Jackson
Journal: Cancer Research (2011)

Cytokines play an important role in creating an inflammatory microenvironment, which is now considered a hallmark of cancer. Although tumor cells can exploit cytokine signaling to promote growth, invasion, and metastasis, the response of normal and premalignant epithelial cells to cytokines present in a developing tumor microenvironment remains unclear. Oncostatin M (OSM), an IL-6 family cytokine responsible for STAT3 activation, has been implicated in cancer development, progression, invasion, and metastasis. Paradoxically, OSM can also suppress the growth of normal cells and certain tumor-derived cell lines. Using isogenic human mammary epithelial cells (HMEC) at different stages of neoplastic transformation, we found that OSM signaling suppressed c-MYC expression and engaged a p16- and p53-independent growth arrest that required STAT3 activity. Inhibition of STAT3 activation by expressing a dominant-negative STAT3 protein or a STAT3-shRNA prevented the OSM-mediated arrest. In addition, expression of c-MYC from a constitutive promoter also abrogated the STAT3-mediated arrest, and strikingly, cooperated with OSM to promote anchorage-independent growth (AIG), a property associated with malignant transformation. Cooperative transformation by c-MYC and OSM required PI3K and AKT signaling, showing the importance of multiple signaling pathways downstream of the OSM receptor in defining the cellular response to cytokines. These findings identify c-MYC as an important molecular switch that alters the cellular response to OSM-mediated signaling from tumor suppressive to tumor promoting.
Triamcinolone and prednisolone affect contractile properties and histopathology of rat diaphragm differently.
Authors: P N Dekhuijzen, G Gayan-Ramirez, V de Bock, R Dom, M Decramer
Journal: Journal of Clinical Investigation (1993)

Diaphragm atrophy and weakness occur after administration of massive doses of corticosteroids for short periods. In the present study the effects of prolonged administration of moderate doses of fluorinated and nonfluorinated steroids were investigated on contractile properties and histopathology of rat diaphragm. 60 rats received saline, 1.0 mg/kg triamcinolone, or 1.25 or 5 mg/kg i.m. prednisolone daily for 4 wk. Respiratory and peripheral muscle mass increased similarly in control and both prednisolone groups, whereas triamcinolone caused severe muscle wasting. Maximal tetanic tension averaged 2.23 +/- 0.54 kg/cm2 (SD) in the control group. An increased number of diaphragmatic bundles in the 5-mg/kg prednisolone group generated maximal tetanic tensions < 2.0 kg/cm2 (P < 0.05). In addition, fatigability during the force-frequency protocol was most pronounced in this group (P < 0.05). In contrast, triamcinolone caused a prolonged half-relaxation time and a leftward shift of the force-frequency curve (P < 0.05). Histological examination of the diaphragm showed a normal pattern in the control and 1.25-mg/kg prednisolone group. Myogenic changes, however, were found in the 5-mg/kg prednisolone group and, more pronounced, in the triamcinolone group. Selective type IIb fiber atrophy was found in the latter group, but not in the prednisolone groups. In conclusion, triamcinolone induced type IIb fiber atrophy, resulting in reduced respiratory muscle strength and a leftward shift of the force-frequency curve. In contrast, 5 mg/kg prednisolone caused alterations in diaphragmatic contractile properties and histological changes without fiber atrophy.
Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: A biomarker for the early detection of cancer
Authors: Guoping Sui, Shaoyu Zhou, Jean Wang, Marcia Canto, Edward E Lee, James R Eshleman, Elizabeth A Montgomery, David Sidransky, Joseph A Califano, Anirban Maitra
Journal: Molecular Cancer (2006)

Abstract Background Somatic mutations of mitochondrial DNA (mtDNA) are common in many human cancers. We have described an oligonucleotide microarray ("MitoChip") for rapid sequencing of the entire mitochondrial genome (Zhou et al, J Mol Diagn 2006), facilitating the analysis of mtDNA mutations in preneoplastic lesions. We examined 14 precancerous lesions, including seven Barrett esophagus biopsies, with or without associated dysplasia; four colorectal adenomas; and three inflammatory colitis-associated dysplasia specimens. In all cases, matched normal tissues from the corresponding site were obtained as germline control. MitoChip analysis was performed on DNA obtained from cryostat-embedded specimens. Results A total of 513,639 bases of mtDNA were sequenced in the 14 samples, with 490,224 bases (95.4%) bases assigned by the automated genotyping software. All preneoplastic lesions examined demonstrated at least one somatic mtDNA sequence alteration. Of the 100 somatic mtDNA alterations observed in the 14 cases, 27 were non-synonymous coding region mutations (i.e., resulting in an amino acid change), 36 were synonymous, and 37 involved non-coding mtDNA. Overall, somatic alterations most commonly involved the COI , ND4 and ND5 genes. Notably, somatic mtDNA alterations were observed in preneoplastic lesions of the gastrointestinal tract even in the absence of histopathologic evidence of dysplasia, suggesting that the mitochondrial genome is susceptible at the earliest stages of multistep cancer progression. Conclusion Our findings further substantiate the rationale for exploring the mitochondrial genome as a biomarker for the early diagnosis of cancer, and confirm the utility of a high-throughput array-based platform for this purpose from a clinical applicability standpoint.
Brain Natriuretic Peptide and Exercise Capacity in Lung Fibrosis and Pulmonary Hypertension
Authors: Hanno H. Leuchte, Claus Neurohr, Rainer Baumgartner, Michael Holzapfel, Wolfgang Giehrl, Michael Vogeser, Jürgen Behr
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Pulmonary hypertension (PH) can develop in lung fibrosis, and contributes to increased morbidity and mortality. Noninvasive parameters in the evaluation of PH in lung disease could aid in the management of these subjects. In this study, we aimed to characterize the role of brain natriuretic peptide (BNP) and the six-minute walk distance (6-MWD) in the assessment of pulmonary hypertension (PH) in subjects with lung fibrosis. Subjects with lung fibrosis and elevated BNP levels (n = 20) had significantly more severe PH during right heart catheterization than those with lung fibrosis, and normal BNP levels (mean pulmonary arterial pressure (40.85 ± 3.2 mm Hg vs. 23.42±1.44 mm Hg, respectively) (n = 19) (p < 0.001). Significant correlations between lung volumes and BNP concentrations were not observed. A weak correlation existed between capillary pO2 and 6-MWD (r = 0.42; p < 0.001). The presence of moderate–severe PH was associated with significant reduction of the 6-MWD. BNP concentrations predicted moderate–severe PH with 100% sensitivity and high specificity (89%). We conclude that BNP is an excellent marker for the presence of PH in patients with lung fibrosis. In addition, our data suggest that PH contributes significantly to exercise limitation in patients with severe lung fibrosis, raising the possibility that treatment of PH may be beneficial in these patients.
Consolidation Therapy With Subcutaneous Alemtuzumab After Fludarabine and Rituximab Induction Therapy for Previously Untreated Chronic Lymphocytic Leukemia: Final Analysis of CALGB 10101
Authors: Thomas S. Lin, Kathleen A. Donohue, John C. Byrd, Margaret S. Lucas, Eva E. Hoke, Elizabeth M. Bengtson, Kanti R. Rai, James N. Atkins, Brian K. Link, Richard A. Larson
Journal: Journal of Clinical Oncology (2010)

To determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS) after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia.Patients (n = 102) received fludarabine 25 mg/m(2) intravenously days 1 to 5 and rituximab 50 mg/m(2) day 1, 325 mg/m(2) day 3, and 375 mg/m(2) day 5 of cycle 1 and then 375 mg/m(2) day 1 of cycles 2 to 6; fludarabine plus rituximab (FR) administration was repeated every 28 days for six cycles. Three months after completion of FR, patients with stable disease or better response received subcutaneous alemtuzumab 3 mg day 1, 10 mg day 3, and 30 mg day 5 and then 30 mg three times per week for 5 weeks.Overall response (OR), complete response (CR), and partial response (PR) rates were 90%, 29%, and 61% after FR, respectively; 15% of patients were minimal residual disease (MRD) negative. Of 102 patients, 58 received alemtuzumab; 28 (61%) of 46 patients achieving PR after FR attained CR after alemtuzumab. By intent to treat (n = 102), OR and CR rates were 90% and 57% after alemtuzumab, respectively; 42% of patients became MRD negative. With median follow-up of 36 months, median PFS was 36 months, 2-year PFS was 72%, and 2-year OS was 86%. In patients achieving CR after FR, alemtuzumab was associated with five deaths resulting from infection (viral and Listeria meningitis and Legionella, cytomegalovirus, and Pneumocystis pneumonias), which occurred up to 7 months after last therapy. The study was amended to exclude CR patients from receiving alemtuzumab.Alemtuzumab consolidation improved CR and MRD-negative rates after FR induction but caused serious infections in patients who had already achieved CR after induction and did not improve 2-year PFS or survival.
Degenerated and healthy cartilage are equally vulnerable to blood-induced damage
Authors: N W D Jansen, G Roosendaal, J W J Bijlsma, J DeGroot, M Theobald, F P J G Lafeber
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> Joint bleeds have a direct adverse effect on joint cartilage, leading to joint deterioration and, ultimately, to disability. <h3>Objective:</h3> To examine the hypothesis that because degenerated cartilage has a limited repair capacity, it is more susceptible than healthy cartilage to blood-induced cartilage damage. <h3>Methods:</h3> Healthy, degenerated (preclinical osteoarthritic) and osteoarthritic (clinically defined) human cartilage was exposed to 10% vol/vol whole blood for 2 days, followed by a recovery period of 12 days in the absence of blood. The effect of exposure to blood on cartilage was determined by measuring proteoglycan synthesis rate, release and content, as well as protease (matrix metalloproteinase (MMP)) activity. <h3>Results:</h3> In general, exposure to blood led to a decrease in proteoglycan synthesis rate, an increase in the release of proteoglycans and in MMP activity, and therefore, ultimately, in a decrease of the proteoglycan content of the tissue. Impaired cartilage was as least as susceptible as healthy cartilage to this blood-induced damage. <h3>Conclusion:</h3> These results demonstrate that degenerated cartilage is not more susceptible than healthy cartilage to blood-induced damage. Even though these are just in vitro findings, it remains of great importance, also, in joints already affected, to prevent joints bleeds, and when they do occur, to treat them adequately.
Single-Dose Azithromycin for the Treatment of Cholera in Adults
Authors: Debasish Saha, Mohammad M. Karim, Wasif A. Khan, Sabeena Ahmed, Mohammed A. Salam, Michael L. Bennish
Journal: New England Journal of Medicine (2006)

Single-dose azithromycin is effective in the treatment of severe cholera in children, but its effectiveness in adults has not been evaluated.We conducted a double-blind, randomized trial comparing the equivalence of azithromycin and ciprofloxacin (each given in a single 1-g dose of two 500-mg tablets) among 195 men with severe cholera caused by Vibrio cholerae O1 or O139. Patients were hospitalized for five days. A stool culture was performed daily. Primary outcome measures were clinical success (the cessation of watery stools within 48 hours after drug administration) and bacteriologic success (the inability to isolate V. cholerae after 48 hours).Therapy was clinically successful in 71 of 97 patients receiving azithromycin (73 percent) and in 26 of 98 patients receiving ciprofloxacin (27 percent) (P<0.001) and bacteriologically successful in 76 of 97 patients receiving azithromycin (78 percent) and in 10 of 98 patients receiving ciprofloxacin (10 percent) (P<0.001). Patients who were treated with azithromycin had a shorter duration of diarrhea than did patients treated with ciprofloxacin (median, 30 vs. 78 hours); a lower frequency of vomiting (43 percent vs. 67 percent); fewer stools (median, 36 vs. 52); and a lower stool volume (median, 114 vs. 322 ml per kilogram of body weight). The median minimal inhibitory concentration of ciprofloxacin for the 177 isolates of V. cholerae O1 was 0.25 mug per milliliter, which was 11 to 83 times as high as that in previous studies at this site.Single-dose azithromycin was effective in the treatment of severe cholera in adults. The lack of efficacy of ciprofloxacin may result from its diminished activity against V. cholerae O1 strains currently circulating in Bangladesh. (ClinicalTrials.gov number, NCT00229944.).
Evolutionary History of Pearl Millet (Pennisetum glaucum [L.] R. Br.) and Selection on Flowering Genes since Its Domestication
Authors: J. Clotault, A.-C. Thuillet, M. Buiron, S. De Mita, M. Couderc, B. I. G. Haussmann, C. Mariac, Y. Vigouroux
Journal: Molecular Biology and Evolution (2011)

The plant domestication process is associated with considerable modifications of plant phenotype. The identification of the genetic basis of this adaptation is of great interest for evolutionary biology. One of the methods used to identify such genes is the detection of signatures of selection. However, domestication is generally associated with major demographic effects. It is therefore crucial to disentangle the effects of demography and selection on diversity. In this study, we investigated selection in a flowering time pathway during domestication of pearl millet. We first used a random set of 20 genes to model pearl millet domestication using approximate Bayesian computation. This analysis showed that a model with exponential growth and wild–cultivated gene flow was well supported by our data set. Under this model, the domestication date of pearl millet is estimated at around 4,800 years ago. We assessed selection in 15 pearl millet DNA sequences homologous to flowering time genes and showed that these genes underwent selection more frequently than expected. We highlighted significant signatures of selection in six pearl millet flowering time genes associated with domestication or improvement of pearl millet. Moreover, higher deviations from neutrality were found for circadian clock–associated genes. Our study provides new insights into the domestication process of pearl millet and shows that a category of genes of the flowering pathway were preferentially selected during pearl millet domestication.
Luminal P2Y2 Receptor-Mediated Inhibition of Na+ Absorption in Isolated Perfused Mouse CCD
Authors: Heiko Lehrmann, Jo[Combining Diaeresis]rg Thomas, Sung Joon Kim, Christoph Jacobi, Jens Leipziger
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Extracellular nucleotides regulate renal transport. A luminal P2Y2 receptor in mouse cortical collecting duct (CCD) principal cells has been demonstrated elsewhere. Herein the effects of adenosine triphosphate (ATP) and uridine triphosphate (UTP) on electrogenic Na+ absorption in perfused CCD of mice kept on a low-NaCl diet were investigated. Simultaneously, transepithelial voltage (Vte), transepithelial resistance (Rte), and fura-2 [Ca2+]i fluorescence were measured. Baseline parameters were Vte, −16.5 ± 1.2 mV; Rte, 80.8 ± 7.1 Ω cm2; and equivalent short-circuit current (Isc), −261.0 ± 25.1 μA/cm2 (n = 45). Amiloride (10 μM) almost completely inhibited Isc to −3.9 ± 3.8 μA/cm2 (n = 10). Luminal ATP (100 μM) reduced Vte from −16.5 ± 2.1 to −12.5 ± 1.93 and increased Rte from 113.1 ± 16.2 to 123.8 ± 16.7 Ω cm2, which resulted in a 31.7% inhibition of amiloride-sensitive Isc (n = 12). Similarly, luminal UTP reversibly reduced Vte from −22.0 ± 2.1 to −13.6 ± 2.1 mV and increased Rte from 48.4 ± 5.3 to 59.2 ± 7.1 Ω cm2, which resulted in 49.1% inhibition of Na+ absorption (n = 6). In parallel, luminal ATP and UTP elevated [Ca2+]i in CCD, increasing the fura-2 ratio by 2.7 ± 0.7 and 4.0 ± 1.2, respectively. Basolateral ATP and UTP (100 μM) also inhibited amiloride-sensitive Isc by 21.8 (n = 14) and 20.1% (n = 8), respectively. Inhibition of luminal nucleotide-induced [Ca2+]i increase by Ca2+ store depletion with cyclopiazonic acid (3 μM) did not affect nucleotide-mediated inhibition of Na+ transport (n = 7). No evidence indicated the activation of a luminal Ca2+-activated Cl− conductance, a phenomenon previously shown in M-1 CCD cells (J Physiol 524: 77–99, 2000). In essence, these data indicate that luminal ATP and UTP, most likely via P2Y2 receptors, mediate inhibition of amiloride-sensitive Isc in perfused mouse CCD. This inhibition appears to occurs independently of an increase of cytosolic Ca2+.
Management of travellers' diarrhoea
Authors: D. R Hill, E. T Ryan
Journal: BMJ (2008)

Travellers' diarrhoea is one of the most common illnesses in people who travel internationally, and depending on destination affects 20-60% of the more than 800 million travellers each year. In most cases the diarrhoea occurs in people who travel to areas with poor food and water hygiene.1 This review examines the approach to the prevention and treatment of diarrhoea in travellers. Much of the evidence base for travellers' diarrhoea has been established over the past 30 years, with a strong body of randomised trials and consensus opinion in support of recommendations. The use of antibiotics for self treatment or chemoprophylaxis, however, remains debatable. #### Sources and selection criteria We identified articles through an electronic search of PubMed and the Cochrane library using the term "travelers' diarrhea" alone and in combination with "treatment", "etiology", and "prevention". Additional studies were sourced from the retrieved articles. We also reviewed our extensive collection of articles on the subject, as well as current national guidelines in travel medicine. #### Summary points
The Role of Homeobox Genes in Vascular Remodeling and Angiogenesis
Authors: David H. Gorski, Kenneth Walsh
Journal: Circulation Research (2000)

Homeodomain-containing transcription factors are critical in the regulation of cell proliferation, differentiation, and migration, and they play an important role in organogenesis and pattern formation during embryogenesis. There is evidence that some of them are oncogenes or tumor suppressors. The cardiovascular system undergoes extensive remodeling during embryogenesis and disease states such as atherosclerosis and tumor-induced angiogenesis, and homeobox genes may play an important role in regulating these processes. Recently, homeobox genes have been detected in both vascular smooth muscle and endothelial cells, and they are implicated in pathological processes such as arterial restenosis after balloon angioplasty and tumor-induced angiogenesis. The cellular function of some of these genes is beginning to be elucidated. Therefore, we briefly review what is currently known about the involvement of homeobox transcription factors in both physiological and pathological vascular remodeling and angiogenesis.