tbuckley/cabot-search huggingface dataset:
Imaging of the Prostate
Authors: Derek Fawcett
Journal: Journal of the Royal Society of Medicine (2003)

Though well illustrated, Imaging of the Prostate is not a coffee-table book. It is a serious attempt to bring together matters that, I suspect, are ill-understood by urologists and radiologists alike. In urology, transrectal ultrasound is used mainly as a guide for biopsy placement, MRI or CT being requested for staging of prostate cancer before definitive treatment. Many urologists take the view that neither ultrasound nor MRI can exclude prostatic cancer, and contributors to this book seem to agree. The work is excellently illustrated and the radiological anatomy is well described (although the terms inner and outer gland are not used in the UK). The sections on benign conditions are comprehensive and useful. There is also a section on therapy. Essentially this is a work by radiologists for radiologists, but urologists who perform a large number of prostatic biopsies and ultrasounds will find it a useful source of reference when something odd is seen on a routine biopsy scan. I suspect it will also be a good addition to the radiologist's library.
Evidence-Based Treatment of Delirium in Patients With Cancer
Authors: William Breitbart, Yesne Alici
Journal: Journal of Clinical Oncology (2012)

Delirium is the most common neuropsychiatric complication seen in patients with cancer, and it is associated with significant morbidity and mortality. Increased health care costs, prolonged hospital stays, and long-term cognitive decline are other well-recognized adverse outcomes of delirium. Improved recognition of delirium and early treatment are important in diminishing such morbidity. There has been an increasing number of studies published in the literature over the last 10 years regarding delirium treatment as well as prevention. Antipsychotics, cholinesterase inhibitors, and alpha-2 agonists are the three groups of medications that have been studied in randomized controlled trials in different patient populations. In patients with cancer, the evidence is most clearly supportive of short-term, low-dose use of antipsychotics for controlling the symptoms of delirium, with close monitoring for possible adverse effects, especially in older patients with multiple medical comorbidities. Nonpharmacologic interventions also appear to have a beneficial role in the treatment of patients with cancer who have or are at risk for delirium. This article presents evidence-based recommendations based on the results of pharmacologic and nonpharmacologic studies of the treatment and prevention of delirium.
Sildenafil Inhibits β-Adrenergic–Stimulated Cardiac Contractility in Humans
Authors: Barry A. Borlaug, Vojtech Melenovsky, Tricia Marhin, Patricia Fitzgerald, David A. Kass
Journal: Circulation (2005)

Background— Sildenafil inhibits phosphodiesterase 5 (PDE5A) to elevate intracellular cGMP and to induce vasodilation. This effect has led to its use for treating erectile dysfunction. Although its influence on rest heart function has appeared minimal, recent animal studies suggest that sildenafil can have potent effects on hearts stimulated by β-adrenergic or pressure overloads. We therefore tested whether sildenafil blunts dobutamine-stimulated cardiac function in humans. Methods and Results— Thirty-five healthy volunteers underwent a randomized, double-blind, placebo-controlled study in which cardiac function was assessed in response to dobutamine before and after oral sildenafil (100 mg, n=19) or placebo (n=16). Echo Doppler and noninvasive blood pressure data yielded load-independent contractility indexes (maximal power index and end-systolic elastance), ejection fraction, and measures of diastolic function. In the initial dobutamine test, systolic and diastolic function improved similarly in both treatment groups (eg, peak power index rose 80±28% in the placebo group and 82±31% in the sildenafil group; P =NS). However, in subjects who then received sildenafil, their second dobutamine response was significantly blunted, with peak power, ejection fraction, and end-systolic elastance changes reduced by 32±34%, 66±64%, and 56±63%, respectively (each P &lt;0.001 versus the initial response). This contrasted to the placebo group, which displayed similar functional responses with both dobutamine tests. Sildenafil treatment did not significantly alter diastolic changes induced by dobutamine compared with results with placebo. Conclusions— PDE5A inhibition by sildenafil blunts systolic responses to β-adrenergic stimulation. This finding supports activity of PDE5A in the human heart and its role in modifying stimulated cardiac function.
In vitro assessment of drug delivery through an endotracheal tube using a dry powder inhaler delivery system.
Authors: M. L. Everard, S. G. Devadason, P. N. Le Souef
Journal: Thorax (1996)

BACKGROUND: Jet nubulisers and metered dose inhalers are widely used to deliver aerosolised drugs to the lungs of intubated patients in adult intensive care units. Drug delivery using these systems has been shown to be inefficient and both forms of delivery have the potential to induce paradoxical bronchoconstriction in patients with reactive airways disease. METHODS: Experiments were carried out to determine whether it was possible to deliver drug from a dry powder delivery system through an endotracheal tube. A 200 micrograms budesonide Turbohaler was enclosed in a chamber which allowed it to be inserted into a ventilator circuit. Experiments were performed with a multistage liquid impinger in which drug was drawn through the Turbohaler and endotracheal tube at 60 l/min providing an index of the maximum drug delivery achievable via this route. A second series of experiments was performed in which the Turbohaler was placed in a ventilator circuit using a Servo 900C volume cycled ventilator. Drug delivered from the Turbohaler during the inspiratory phase was collected on a filter placed between the end of a 9 mm endotracheal tube and a model lung. A tidal volume of 500 ml and inspiratory time of 0.5 seconds was used. Budesonide was assayed using an ultraviolet spectrophotometric assay. RESULTS: Thirty percent of the nominal dose passed through the endotracheal tube and was collected in the multistage liquid impinger. Mean drug delivery to the filter in the ventilator circuit was 20%. CONCLUSIONS: This in vitro study indicates that drugs from dry powder inhalers (in this case the Turbohaler) can be satisfactorily delivered through endotracheal tubes and that clinical evaluation of this technique is now indicated.
Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age
Authors: Bakhtawar K. Mahmoodi, Jan-Leendert P. Brouwer, Nic J.G.M. Veeger, Jan van der Meer
Journal: Circulation (2008)

Whether hereditary protein S, protein C, or antithrombin deficiency is associated with arterial thromboembolism (ATE) and whether history of venous thromboembolism in these subjects predisposes them to subsequent ATE have yet to be determined.On the basis of pedigree analysis, we enrolled a total of 552 subjects (52% women; mean age, 46+/-17 years), belonging to 84 different kindreds, in this retrospective family cohort study. Detailed information on previous episodes of venous thromboembolism, ATE, anticoagulant use, and atherosclerosis risk factors was collected. Primary study outcome was objectively verified symptomatic ATE. Of 552 subjects, 308 had protein S (35%), protein C (39%), or antithrombin (26%) deficiency. Overall, annual incidences of ATE were 0.34% (95% confidence interval [CI], 0.23 to 0.49) in deficient versus 0.17% (95% CI, 0.09 to 0.28) in nondeficient subjects; the hazard ratio was 2.3 (95% CI, 1.2 to 4.5). Because the risk hazards varied over lifetime, we performed a time-dependent analysis. After adjusting for atherosclerosis risk factors and clustering within families, we found that deficient subjects had a 4.7-fold (95% CI, 1.5 to 14.2; P=0.007) higher risk for ATE before 55 years of age versus 1.1 (95% CI, 0.5 to 2.6) thereafter compared with nondeficient family members. For separate deficiencies, the risks were 4.6- (95% CI, 1.1 to 18.3), 6.9- (95% CI, 2.1 to 22.2), and 1.1- (95% CI, 0.1 to 10.9) fold higher in protein S-, protein C-, and antithrombin-deficient subjects, respectively, before 55 years of age. History of venous thromboembolism was not related to subsequent ATE (hazard ratio, 1.1; 95% CI, 0.5 to 2.2).Compared with nondeficient family members, subjects with protein S or protein C deficiency but not antithrombin deficiency have a higher risk for ATE before 55 years of age that is independent of prior venous thromboembolism.
110 URINARY METABOLIC PROFILE DISCRIMINATES HEPATOCELLULAR CARCINOMA BETTER THAN SERUM ALPHA FETOPROTEIN IN WEST AFRICANS
Authors: N.G. Ladep, A. Dona, M.J.W. McPhail, M.I. Shariff, M.M. Crossey, A. Wijeyesekera, E.N. Okeke, E. Banwat, M. Lemoine, R. Njie, D. Garside, S.A. Khan, A.V. Thillainayagam, M. Thursz, E.C. Holmes, S.D. Taylor-Robinson
Journal: Journal of Hepatology (2013)
Death-associated protein kinase 1 promotes growth of p53-mutant cancers
Authors: Jing Zhao, Dekuang Zhao, Graham M. Poage, Abhijit Mazumdar, Yun Zhang, Jamal L. Hill, Zachary C. Hartman, Michelle I. Savage, Gordon B. Mills, Powel H. Brown
Journal: Journal of Clinical Investigation (2015)

Estrogen receptor–negative (ER-negative) breast cancers are extremely aggressive and associated with poor prognosis. In particular, effective treatment strategies are limited for patients diagnosed with triple receptor–negative breast cancer (TNBC), which also carries the worst prognosis of all forms of breast cancer; therefore, extensive studies have focused on the identification of molecularly targeted therapies for this tumor subtype. Here, we sought to identify molecular targets that are capable of suppressing tumorigenesis in TNBCs. Specifically, we found that death-associated protein kinase 1 (DAPK1) is essential for growth of p53-mutant cancers, which account for over 80% of TNBCs. Depletion or inhibition of DAPK1 suppressed growth of p53-mutant but not p53-WT breast cancer cells. Moreover, DAPK1 inhibition limited growth of other p53-mutant cancers, including pancreatic and ovarian cancers. DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR pathway. Our studies demonstrated that high DAPK1 expression causes increased cancer cell growth and enhanced signaling through the mTOR/S6K pathway; evaluation of multiple breast cancer patient data sets revealed that high DAPK1 expression associates with worse outcomes in individuals with p53-mutant cancers. Together, our data support targeting DAPK1 as a potential therapeutic strategy for p53-mutant cancers.
Effects of acutely impaired regional function on remote myocardial wall motion and blood flow in the canine left ventricle studied by coronary occlusion and hypoxic perfusion
Authors: S. Ohtsuka, M. Kakihana, T. Doi, Y. Sugishita, I. Ito
Journal: Cardiovascular Research (1990)

The aim was to examine whether regional myocardial dysfunction has a significant effect on the wall motion and blood flow in remote non-ischaemic regions.Two different severities of regional dysfunction were produced by occluding the left anterior descending coronary artery and perfusing it with a hypoxic solution. Haemodynamic variables were otherwise identical in the two conditions. The relationship of regional dysfunction in the left anterior descending artery region to regional wall motion and regional myocardial blood flow in the left circumflex artery region were examined.22 anaesthetised mongrel dogs, 9-16 kg, were used for the studies: 14 for the regional wall motion studies, and eight for the regional myocardial blood flow studies.Segment shortening in the left anterior descending artery region was impaired differently in the two conditions: arterial occlusion caused a bulge, while hypoxic perfusion caused only mild hypokinesis. Segment shortening and the myocardial blood flow in the left circumflex artery region were augmented similarly in the two conditions. Left ventricular end diastolic pressure and end diastolic segment length in the left circumflex region were increased and aortic pressure was slightly decreased by left anterior descending artery occlusion and hypoxic perfusion, but there was no significant difference between the two conditions. Heart rate was not affected.The augmentation of wall motion and blood flow of the remote myocardium does not depend on the magnitude of acutely induced regional dysfunction per se. The augmented wall motion in the remote region is unlikely to be due to mechanical unloading of the remote myocardium due to an intraventricular regional interaction, but rather to the Frank-Starling mechanism and left ventricular afterload reduction following acute ischaemia.
What Do We Do with Missing Data? Some Options for Analysis of Incomplete Data
Authors: Trivellore E. Raghunathan
Journal: Annual Review of Public Health (2004)

Missing data are a pervasive problem in many public health investigations. The standard approach is to restrict the analysis to subjects with complete data on the variables involved in the analysis. Estimates from such analysis can be biased, especially if the subjects who are included in the analysis are systematically different from those who were excluded in terms of one or more key variables. Severity of bias in the estimates is illustrated through a simulation study in a logistic regression setting. This article reviews three approaches for analyzing incomplete data. The first approach involves weighting subjects who are included in the analysis to compensate for those who were excluded because of missing values. The second approach is based on multiple imputation where missing values are replaced by two or more plausible values. The final approach is based on constructing the likelihood based on the incomplete observed data. The same logistic regression example is used to illustrate the basic concepts and methodology. Some software packages for analyzing incomplete data are described.
HPV DNA Testing in Cervical Cancer Screening
Authors: Mark Schiffman, Rolando Herrero, Allan Hildesheim, Mark E. Sherman, Maria Bratti, Sholom Wacholder, Mario Alfaro, Martha Hutchinson, Jorge Morales, Mitchell D. Greenberg, Attila T. Lorincz
Journal: JAMA (2000)

Human papillomaviruses (HPVs) are known to cause most cervical cancer worldwide, but the utility of HPV DNA testing in cervical cancer prevention has not been determined.To provide comprehensive data on the screening performance of HPV testing for the most common carcinogenic types, at different levels of analytic sensitivity.Laboratory analysis conducted during 1993-1995, using 3 cytologic techniques and cervicography, followed by colposcopic examination of women with any abnormal cervical finding, to detect all high-grade intraepithelial lesions and cancer (reference standard of clinically significant disease). The HPV testing was performed subsequently with masking regarding clinical findings.Guanacaste Province, Costa Rica, a region with a high age-adjusted incidence of cervical cancer.Of 11742 randomly selected women, 8554 nonpregnant, sexually active women without hysterectomies underwent initial HPV DNA testing using the original Hybrid Capture Tube test; a stratified subsample of 1119 specimens was retested using the more analytically sensitive second generation assay, the Hybrid Capture II test.Receiver operating characteristic analysis of detection of cervical high-grade intraepithelial lesions and cancer by HPV DNA testing based on different cut points of positivity.An analytic sensitivity of 1.0 pg/mL using the second generation assay would have permitted detection of 88.4% of 138 high-grade lesions and cancers (all 12 cancers were HPV-positive), with colposcopic referral of 12.3% of women. Papanicolaou testing using atypical squamous cells of undetermined significance as a cut point for referral resulted in 77.7% sensitivity and 94.2% specificity, with 6.9% referred. Specificity of the second generation assay for positivity for high-grade lesions and cancer was 89.0%, with 33.8% of remaining HPV DNA-positive subjects having low-grade or equivocal microscopically evident lesions. The higher detection threshold of 10 pg/mL used with the original assay had a sensitivity of 74.8% and a specificity of 93.4%. Lower levels of detection with the second generation assay (<1 pg/mL) proved clinically nonspecific without gains in diagnostic sensitivity.In this study population, a cut point of 1.0 pg/mL using the second generation assay permitted sensitive detection of cervical high-grade lesions and cancer, yielding an apparently optimal trade-off between high sensitivity and reasonable specificity for this test. The test will perform best in settings in which sensitive detection of high-grade lesions and cancer is paramount. Because HPV prevalence varies by population, HPV testing positive predictive value for detection of high-grade lesions and cancer will vary accordingly, with implications for utility relative to other cervical cancer screening methods.
Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment.
Authors: B F Haynes, C S Heinly
Journal: The Journal of Experimental Medicine (1995)

To determine events that transpire during the earliest stages of human T cell development, we have studied fetal tissues before (7 wk), during (8.2 wk), and after (9.5 wk to birth) colonization of the fetal thymic rudiment with hematopoietic stem cells. Calculation of the approximate volumes of the 7- and 8.2-wk thymuses revealed a 35-fold increase in thymic volumes during this time, with 7-wk thymus height of 160 microM and volume of 0.008 mm3, and 8.2-wk thymus height of 1044 microM and volume of 0.296 mm3. Human thymocytes in the 8.2-wk thymus were CD4+ CD8 alpha+ and cytoplasmic CD3 epsilon+ cCD3 delta+ CD8 beta- and CD3 zetta-. Only 5% of 8-wk thymocytes were T cell receptor (TCR)-beta+, &amp;lt; 0.1% were TCR-gamma+, and none reacted with monoclonal antibodies against TCR-delta. During the first 16 wk of gestation, we observed developmentally regulated expression of CD2 and CD8 beta (appearing at 9.5 wk), CD1a,b, and c molecules (CD1b, then CD1c, then CD1a), TCR molecules (TCR-beta, then TCR-delta), CD45RA and CD45RO isoforms, CD28 (10 wk), CD3 zeta (12-13 wk), and CD6 (12,75 wk). Whereas CD2 was not expressed at the time of initiation of thymic lymphopoiesis, a second CD58 ligand, CD48, was expressed at 8.2 wk, suggesting a role for CD48 early in thymic development. Taken together, these data define sequential phenotypic and morphologic changes that occur in human thymus coincident with thymus colonization by hematopoietic stem cells and provide insight into the molecules that are involved in the earliest stages of human T cell development.
CIN85 drives B cell responses by linking BCR signals to the canonical NF-κB pathway
Authors: Kohei Kometani, Takayuki Yamada, Yoshiteru Sasaki, Tadashi Yokosuka, Takashi Saito, Klaus Rajewsky, Masamichi Ishiai, Masaki Hikida, Tomohiro Kurosaki
Journal: The Journal of Experimental Medicine (2011)

CIN85, an adaptor protein which binds the C-terminal domain of tyrosine phosphorylated Cbl and Cbl-b, has been thought to be involved in the internalization and subsequent degradation of receptors. However, its physiological function remains unclear. To determine its role in B cells, we used Mb1-cre to generate mice with a B cell–specific deletion of CIN85. These mice had impaired T cell–independent type II antibody responses in vivo and diminished IKK-β activation and cellular responses to B cell receptor (BCR) cross-linking in vitro. Introduction of a constitutively active IKK-β construct corrected the defective antibody responses as well as cellular responses in the mutant mice. Together, our results suggest that CIN85 links the BCR to IKK-β activation, thereby contributing to T cell–independent immune responses.
Increased expression of IRF4 and ETS1 in CD4<sup>+</sup> cells from patients with intermittent allergic rhinitis
Authors: S. Bruhn, F. Barrenäs, R. Mobini, B. A. Andersson, S. Chavali, B. S. Egan, E. Hovig, G. K. Sandve, M. A. Langston, G. Rogers, H. Wang, M. Benson
Journal: Allergy (2011)

To cite this article: Bruhn S, Barrenäs F, Mobini R, Andersson BA, Chavali S, Egan BS, Hovig E, Sandve GK, Langston MA, Rogers G, Wang H, Benson M. Increased expression of IRF4 and ETS1 in CD4 + cells from patients with intermittent allergic rhinitis. Allergy 2012; 67 : 33–40. Abstract Background: The transcription factor (TF) IRF4 is involved in the regulation of Th1, Th2, Th9, and Th17 cells, and animal studies have indicated an important role in allergy. However, IRF4 and its target genes have not been examined in human allergy. Methods: IRF4 and its target genes were examined in allergen‐challenged CD4 + cells from patients with IAR, using combined gene expression microarrays and chromatin immunoprecipitation chips (ChIP‐chips), computational target prediction, and RNAi knockdowns. Results: IRF4 increased in allergen‐challenged CD4 + cells from patients with IAR, and functional studies supported its role in Th2 cell activation. IRF4 ChIP‐chip showed that IRF4 regulated a large number of genes relevant to Th cell differentiation. However, neither Th1 nor Th2 cytokines were the direct targets of IRF4. To examine whether IRF4 induced Th2 cytokines via one or more downstream TFs, we combined gene expression microarrays, ChIP‐chips, and computational target prediction and found a putative intermediary TF, namely ETS1 in allergen‐challenged CD4 + cells from allergic patients. ETS1 increased significantly in allergen‐challenged CD4 + cells from patients compared to controls. Gene expression microarrays before and after ETS1 RNAi knockdown showed that ETS1 induced Th2 cytokines as well as disease‐related pathways. Conclusions: Increased expression of IRF4 in allergen‐challenged CD4 + cells from patients with intermittent allergic rhinitis leads to activation of a complex transcriptional program, including Th2 cytokines.
Evaluating an Educational Intervention to Improve the Treatment of Asthma in Four European Countries
Authors: CATHARINA C. M. VENINGA, PER LAGERL ØV, ROLF WAHLSTRÖM, MARIA MUSKOVA, PETRA DENIG, JOHANNES BERKHOF, MICHAEL M. KOCHEN, FLORA M. HAAIJER-RUSKAMP
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

In the international Drug Education Project, a new educational program for peer groups of doctors was developed and tested to improve the treatment of asthma patients in The Netherlands, Norway, Sweden, and Slovakia. Individualized feedback on prescribing and the underlying decision strategy was presented and discussed within the group of doctors, in relation to existing guidelines. In a parallel, randomized controlled design the effect on competence and actual prescribing was tested. Results were related to national guidelines. In general, the program improved the doctors' attitudes as well as some of their prescribing behavior. The proportion of patients treated with inhaled corticosteroids significantly improved in The Netherlands (effect size 1.27), and the proportion of oral corticosteroid use for exacerbation treatment increased both in The Netherlands and in Norway (effect sizes 1.99 and 0.87, respectively). Overall attitudes of Dutch and Norwegian doctors also improved significantly (effect sizes 1.06 and 0.87, respectively), as did both knowledge (effect size 1.06) and attitudes (effect size 1.49) concerning exacerbation treatment in Slovakia. In Sweden no significant improvements could be measured. Conclusively, improvements in asthma treatment are possible with an educational program based on self-learning in small peer groups, although effects in one health care setting may not occur in another health care setting. Possible explaining factors may be different attitudes to and experiences with guidelines as well as with continuing medical education programs, and differences in the opportunities for change, including prevailing trends in prescribing behavior.