tbuckley/cabot-search huggingface dataset:
Correlation of Factor VIIa Values With Factor VII Gene Polymorphism, Fasting and Postprandial Triglyceride Levels, and Subclinical Carotid Atherosclerosis
Authors: Habib M. Ghaddar, Aaron R. Folsom, Nena Aleksic, Leonard B. Hearne, Lloyd E. Chambless, James H. Morrissey, Kenneth K. Wu
Journal: Circulation (1998)

Background —Factor VII plays a pivotal role in coagulation. Factor VIIc levels were reported to be a risk factor for fatal coronary heart disease (CHD). Factor VIIc and VIIag levels were noted to be positively associated with plasma triglyceride (TG) levels and influenced by a VII gene polymorphism. The purpose of this study is to determine whether these associations are related to activated factor VII (factor VIIa). Methods and Results —Fasting and 3.5-hour postprandial samples from 216 cases with subclinical atherosclerosis and 341 matched controls selected from the ARIC cohort were assayed for levels of factors VIIa, VIIc, and VIIag and TG, and factor VII codon 353 gene polymorphism. The level of factor VIIa was higher in Arg/Arg than in Arg/Gln+Gln/Gln genotypes, and the difference was in accord with that of factors VIIag and VIIc. However, the factor VIIa difference was statistically insignificant. Factor VIIa values were not correlated with fasting or 3.5-hour postprandial TG levels, nor were they associated with subclinical atherosclerosis. Conclusions —Factor VIIa levels, like factor VIIag and VIIc levels, are influenced by factor VII gene codon 353 polymorphism. However, unlike factor VIIag or VIIc, factor VIIa is not influenced by TG levels; none of these is associated with subclinical atherosclerosis.
Outcome of community-acquired pneumonia: influence of age, residence status and antimicrobial treatment
Authors: H. Kothe, T. Bauer, R. Marre, N. Suttorp, T. Welte, K. Dalhoff
Journal: European Respiratory Journal (2008)

Community-acquired pneumonia remains a major cause of mortality in developed countries. There is much discrepancy in the literature regarding factors influencing the outcome in the elderly population. Data were derived from a multicentre prospective study initiated by the German Competence Network for Community-Acquired Pneumonia. Patients with community-acquired pneumonia (n = 2,647; 1,298 aged < 65 yrs and 1,349 aged > or = 65 yrs) were evaluated, of whom 72.3% were hospitalised and 27.7% treated in the community. Clinical history, residence status, course of disease and antimicrobial treatment were prospectively documented. Microbiological investigations included cultures and PCR of respiratory samples and blood cultures. Factors related to mortality were included in multivariate analyses. The overall 30-day mortality was 6.3%. Elderly patients exhibited a significantly higher mortality rate that was independently associated with the following: age; residence status; confusion, urea, respiratory frequency and blood pressure (CURB) score; comorbid conditions; and failure of initial therapy. Increasing age remained predictive of death in the elderly. Nursing home residents showed a four-fold increased mortality rate and an increased rate of gram-negative bacillary infections compared with patients dwelling in the community. The CURB score and cerebrovascular disease were confirmed as independent predictors of death in this subgroup. Age and residence status are independent risk factors for mortality after controlling for comorbid conditions and disease severity. Failure of initial therapy was the only modifiable prognostic factor.
Class 1 (unique) tumor antigens of human melanoma. Identification of a 90,000 dalton cell surface glycoprotein by autologous antibody.
Authors: F X Real, M J Mattes, A N Houghton, H F Oettgen, K O Lloyd, L J Old
Journal: The Journal of Experimental Medicine (1984)

Analysis of the humoral immune response of patients with melanoma has identified a small group of individuals with antibody to cell surface antigens that are restricted to autologous melanoma cells. These antigens, referred to as Class I or unique tumor antigens, are demonstrated by reactions between serum and cultured melanoma cells from the same patient and absorption tests with autologous and allogeneic normal and malignant cells to determine antibody specificity. Five Class 1 melanoma antigens have been defined to date, but insight into the nature of these antigens has been limited because antibodies identifying these antigens lacked detectable immunoprecipitating activity. We have now defined a Class 1 melanoma antigen (designated FD) that is immunoprecipitated by autologous antibody. FD antigen is identified by an IgG antibody present in the sera of patient FD, and peak titers of this antibody in tests with cultured autologous melanoma cells are in the range of 1:2048. By absorption tests, FD antigen could not be detected on any other cell type, including 33 allogeneic melanomas. Prolonged culture of FD melanoma cells resulted in decreased expression of FD antigen, but sublines could be obtained with stable antigen expression. FD antigen is trypsin and heat sensitive, neuraminidase resistant, and is shed in the culture medium. Immunoprecipitation of 125I-labeled cell membrane preparations revealed a 90,000 dalton component of pI 5.5. Serum immunoprecipitating activity could be absorbed by autologous melanoma cells but not by autologous B cells or allogeneic cell lines. A component of the same molecular mass could be precipitated from lysates of cells metabolically labeled with [3H]mannose. The membrane form of the FD antigen binds strongly to Con A-Sepharose and can be eluted with methyl-alpha-D-mannoside. The identification of a precipitating Class I antigenic system of melanoma facilitates efforts to generate monoclonal antibodies to this tumor antigen and to clone its coding sequence.
Synergistic Effects of Acyclic Retinoid and OSI-461 on Growth Inhibition and Gene Expression in Human Hepatoma Cells
Authors: Masahito Shimizu, Masumi Suzui, Atsuko Deguchi, Jin T. E. Lim, Danhua Xiao, Julia H. Hayes, Kyriakos P. Papadopoulos, I. Bernard Weinstein
Journal: Clinical Cancer Research (2004)

Abstract Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 μmol/L acyclic retinoid and 0.01 μmol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21CIP1 protein and mRNA, and stimulated p21CIP1 promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor β and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21CIP1 and retinoic acid receptor β expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.
MicroRNA Expression Signatures in Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Hushan Yang, Jian Gu, Kenneth K. Wang, Wei Zhang, Jinliang Xing, Zhinan Chen, Jaffer A. Ajani, Xifeng Wu
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Esophageal adenocarcinoma is a highly aggressive malignancy that frequently develops from Barrett's esophagus, a premalignant pathologic change occurring in the lower end of the esophagus. Identifying Barrett's esophagus patients at high risk of malignant transformation is essential to the prevention of esophageal adenocarcinoma. Although microRNA (miRNA) expression signatures have been associated with the etiology and prognosis of several types of cancers, their roles in the development of esophageal adenocarcinoma have not been extensively evaluated. Experimental Design: In this study, we analyzed the expression patterns of 470 human miRNAs using Agilent miRNA microarray in 32 disease/normal-paired tissues from 16 patients diagnosed with Barrett's esophagus of either low- or high-grade dysplasia, or esophageal adenocarcinoma. Results: Using unsupervised hierarchical clustering and class comparison analyses, we found that miRNA expression profiles in tissues of Barrett's esophagus with high-grade dysplasia were significantly different from their corresponding normal tissues. Similar findings were observed for esophageal adenocarcinoma, but not for Barrett's esophagus with low-grade dysplasia. The expression patterns of selected miRNAs were further validated using quantitative reverse transcription real-time PCR in an independent set of 75 pairs of disease/normal tissues. Finally, we identified several miRNAs that were involved in the progressions from low grade-dysplasia Barrett's esophagus to esophageal adenocarcinoma. Conclusions: We showed that miRNAs were involved in the development and progression of esophageal adenocarcinoma. The identified significant miRNAs that may become potential targets for early detection, chemoprevention, and treatment of esophageal cancer. (Clin Cancer Res 2009;15(18):5744–52)
The biomechanical link between skin and joint disease in psoriasis and psoriatic arthritis: what every dermatologist needs to know
Authors: D. McGonagle, A. L. Tan, M. Benjamin
Journal: Annals of the Rheumatic Diseases (2007)

In this issue of the Annals of the Rheumatic Diseases , Gisondi et al ( see page 26 ) present an ultrasonography study showing that otherwise asymptomatic patients with psoriasis often have evidence for subclinical disease involving the enthesis (ie, the site of insertion of a tendon, ligament or joint capsule to bone).1 The authors suggest that this may represent a useful approach for the future prediction of which patients with psoriasis will eventually develop an associated arthropathy. While the value of such a strategy in otherwise healthy patients with a common disease such as psoriasis is debatable, it is clear that, if validated and reproduced, the present findings could have far reaching consequences for understanding the link between skin and joints in psoriasis. In particular it further challenges the concept that the primary link between skin and joint disease is related to common autoimmune mechanisms affecting the skin and synovial membrane. Given that entheses are sites of particularly high joint stressing, it further supports the alternative emerging view that the link could be a biomechanical one.

In the study, the authors used an ultrasound-based approach to examine five asymptomatic entheses in the region of the knee and heel (insertion of the quadriceps tendon, both ends of the patellar ligament, the insertion of the Achilles tendon and the calcaneal attachment of the plantar aponeurosis) in subjects with psoriasis, using the previously reported system from the Glasgow group: the Glasgow Ultrasound Enthesitis Scoring System (GUESS).2 An enthesis is composed of both soft tissue components (ligament, tendon and their associated fibrocartilages) and hard tissue components (calcified fibrocartilage, immediately adjacent bone (the “subchondral bone plate”) and the underlying trabecular network).3 While magnetic resonance imaging (MRI) is well suited to depicting the adjacent osteitis that may accompany enthesitis, ultrasound is probably the imaging …
Calcium Restores a Normal Proliferation Phenotype in Human Polycystic Kidney Disease Epithelial Cells
Authors: Tamio Yamaguchi, Scott J Hempson, Gail A Reif, Anne-Marie Hedge, Darren P Wallace
Journal: Journal of the American Society of Nephrology (2005)

Polycystic kidney disease (PKD) is a lethal disorder characterized by progressive expansion of renal cysts. Genetic mutations associated with PKD are thought to disrupt intracellular Ca2+ regulation, leading to abnormal proliferation of tubule epithelial cells. cAMP stimulates the B-Raf/MEK/extracellular signal-regulated kinase (B-Raf/MEK/ERK) pathway and accelerates the proliferation of cells that are cultured from PKD cysts. By contrast, cAMP inhibits the proliferation of cells from normal human kidneys (NHK) and M-1 mouse collecting duct cells. Previously, it was found that a sustained reduction of intracellular Ca2+ levels in NHK and M-1 cells that were treated with Ca2+ entry blockers allowed cAMP activation of the B-Raf/MEK/ERK pathway, switching the cells to a cAMP-growth stimulated phenotype. In this study, primary cultures of cyst epithelial cells from autosomal dominant (ADPKD) and recessive (ARPKD) PKD kidneys were used to determine whether controlled addition of Ca2+ could reverse the aberrant mitogenic response to cAMP. Steady-state intracellular Ca2+ levels were found to be 20 nM lower in cyst-derived ADPKD cells (57 +/- 2 nM) compared with NHK cells (77 +/- 2 nM). Treatment of ADPKD cells or ARPKD cells with either Bay K8644, a Ca2+ channel activator, or A23187, a Ca2+ ionophore, caused sustained increases in intracellular Ca2+ levels and completely reversed the mitogenic response to cAMP. Elevation of intracellular Ca2+ levels in ADPKD cells increased Akt activity and blocked cAMP-dependent B-Raf and ERK activation. Thus, increases in [Ca2+]i are able to restore the normal anti-mitogenic response to cAMP in cells that are derived from two genetically distinct forms of PKD.
Another far more ancient tongue
Authors: John Bradshaw
Journal: Behavioral and Brain Sciences (1995)

Abstract Language started evolving early, before gesture; commonalities of generativity between language and praxis have been over-emphasized. Language did not drive hominid brain evolution, evolving multifactorially and interactively. More than communication, it permits a cognitive modelling of reality and hierarchical data management. As the interactive sum of various cognitive and linguistic systems, and of brain structures each semi-independently evolved, it is not part of a single, general-purpose cognitive processor, nor is it a separately-evolved quasi-independent module.
Bordetella bronchiseptica pneumonia in a patient with AIDS.
Authors: J de la Fuente, C Albo, A Rodriguez, B Sopena, C Martinez
Journal: Thorax (1994)

Bordetella bronchiseptica is recognised as a respiratory tract pathogen in many mammalian species, but has rarely been implicated in human infection. A case is reported of pneumonia caused by B bronchiseptica in a patient suffering from acquired immunodeficiency syndrome (AIDS).
Back to the future: how good are doctors at gazing in the crystal ball?
Authors: Rob Stepney
Journal: BMJ (2006)

Twenty years ago, in a study commissioned by the Bristol-Myers company, 227 of the world's leading clinical scientists were asked to predict the state of medicine in the early 21st century.1 The success of the 1986 predictions, or lack of it, may tell us the likely value of current attempts to foresee the speed and nature of medical advance: sometimes you have to look back to look forwards. 

#### Six of the best (among the 227 clinical scientists interviewed)

The scientists interviewed came from 10 countries (13 were from the United Kingdom), but most were based in the United States, so the US is usually the reality against which I test their predictions—but the conclusions should be widely applicable.⇓ 



Predictions that a million people in the US would have AIDS by now were right, but predictions for an effective vaccine and curative treatment were wrong 



Back in 1986, all the buzz was in biological response modifiers. We were going to dissect out elements of the immune response, amplify them, and set them to work on tumours with devastating effect. Of course, it came to very little: interleukins, interferons, and even tumour necrosis factor proved sadly ineffective against common solid tumours and were unexpectedly toxic when given in pharmacological doses. In the mid-1980s there was great, if misplaced, faith in these agents. Despite this, future rates of cure were predicted accurately. 

The pollsters told the specialists they interviewed that “the average cure rate for cancer patients of all types” was about 50%. They then asked what it would be in the year 2000. Estimates ranged from no change to 90% , …
<i>PIK3CA</i> Mutations Correlate with Hormone Receptors, Node Metastasis, and ERBB2, and Are Mutually Exclusive with PTEN Loss in Human Breast Carcinoma
Authors: Lao H. Saal, Karolina Holm, Matthew Maurer, Lorenzo Memeo, Tao Su, Xiaomei Wang, Jennifer S. Yu, Per-Olof Malmström, Mahesh Mansukhani, Jens Enoksson, Hanina Hibshoosh, Åke Borg, Ramon Parsons
Journal: Cancer Research (2005)

Abstract Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit α of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate (PIP3) is critical for tumorigenesis in a significant fraction of breast cancers and that loss of PIP3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications.
OC-032 A New Validated whole Gut Transit Time (WGTT) Measurement using Magnetic Resonance Imaging (Mri-Wgtt) Technique
Authors: C Lam, G Chaddock, C Hoad, C Costigan, E Cox, L Marciani, P Gowland, R Spiller
Journal: Gut (2013)

<h3>Introduction</h3> Disorders of gut transit are very common in gastroenterology clinics. Objective assessment may be useful for targeting and monitoring treatment. Current scintigraphic or radio-opaque marker techniques involve undesirable ionising radiation. <h3>Aims</h3> To validate a new MRI method for measuring WGTT against the current gold standard in which 20 radio-opaque markers (ROMs) are ingested per day on 3 consecutive days and the number retained assessed from a single abdominal x-ray on day 4. To assess reproducibility of MRI-WGTT. <h3>Methods</h3> 20 healthy volunteers (HV) ages 21–70 (12 males and 8 females) participated in the study involving 2 visits a week apart (test-retest). On each visit, each HV underwent 2 tests: (A) MRI-WGTT test for which HV swallow 5 pills, each filled with a MRI contrast agent diluted with water, 24 hours before undergoing MRI scans which precisely locate the pills in the colon. Transit of the markers was assessed by scoring each pill from its position in the colon (7 = small bowel, 6 = lower ascending 5 = upper AC, 4 = right transverse (TC), 3 = left TC, 2 = descending, 1 = rectosigmoid, 0 = expelled) and calculating an average score (Transit score TS) using an algorithm which gives a weighting inversely related to the distance from the median. (B) ROM test: the number of ROM was counted and multiplied by 1.2 to give a WGTT in hours. Spearman’s correlation was used to assess the correlation between the two measurements and intra-class correlation coefficient (ICC) was used to assess the variability of each test when repeated twice. <h3>Results</h3> The MRI images provided excellent 3D spatial resolution, allowing the gut to be viewed from all angles, hence allowing accurate location of the pills within the colon especially the sigmoid region (Figure 1). WGTT using ROM was median (SD), 27.6 (20.8) and TS was 0.9 (0.8). WGTT using ROM and TS were well correlated, Spearman’s r = 0.85, p &lt; 0.01. Using this we converted TS to MRI-WGTT in hours. Mean calculated MRI-WGTT was 27.6 (24.7) hours. The mean absolute difference in the MRI-WGTT on 2 separate visits was 15.3 hours (SD, 15.8) with an ICC of 0.62 (p &lt; 0.01). The mean absolute difference in the WGTT for ROMS on 2 separate visits was 11.3 hours (SD, 9.7) with and ICC of 0.69 (p &lt; 0.01). <h3>Conclusion</h3> MRI-WGTT correlated well with the gold standard ROM WGTT but was more convenient, involving only one day of marker ingestion and no exposure to ionising radiation. This technique could be implemented easily in most NHS hospitals. Funded by: Medical Research Council and NIHR UK. <h3>Disclosure of Interest</h3> None Declared
Maintenance of intragastric pH &gt; 4 with famotidine in duodenal ulcer patients: factors influencing drug requirements.
Authors: J C Delchier, F Roudot-Thoraval, L Stanescu, M C Deharvengt, L Elouaer Blanc
Journal: Gut (1994)

The gastrojet, a closed loop pH feedback infusion pump capable of maintaining intragastric pH at a target value by infusing H2 blockers at variable rates, was used to assess factors influencing the quantity of famotidine required to maintain intragastric pH above 4 for 24 hours in 34 fed patients with duodenal ulcers. The following factors were considered: sex, age, duration of the disease, previous bleeding, previous poor response to H2 blockers (ulcer unhealed at six weeks, or recurrence within three months during maintenance treatment), activity of the ulcer disease, smoking habits, cirrhosis. The patients had taken no antisecretory drugs for the 15 days before the study. Two standardised meals were given during the study period (from 1000 to 1000). Fifty ml of famotidine (4 mg/ml) was loaded into infusion bags and the pump was programmed to deliver the drug intravenously at 11 rates varying from 0 to 40 microliters/min. The target pH was 4. Mean famotidine use was 111 mg (range 33 to 200), the 23 hour median pH was 5.3, and the mean time during which pH was above 4 was 75.4%. There was a negative correlation (p &lt; 0.001) between famotidine delivery and the inhibition of gastric acidity. Statistical analysis showed that only cirrhosis significantly influenced drug delivery, median pH, and the time during which pH was above 4. Mean drug delivery in the cirrhotic and non-cirrhotic patients was 135 v 97 mg (p &lt; 0.04), 23 hour median pH was 4.7 v 5.6 (p &lt; 0.01), and the mean time at pH &gt; 4 was 65.9 v 81.6% (p &lt; 0.01). There were large interindividual variations in famotidine requirements, but not only cirrhosis was predictive of dose requirement. These results suggest that the appropriate amount of famotidine to treat duodenal ulcer in cirrhotic patients is probably higher than the usually recommended dose.