tbuckley/cabot-search huggingface dataset:
Are relatives of patients with multiple HNPCC spectrum tumours at increased risk of cancer?
Authors: S R Brown, P J Finan, D T Bishop
Journal: Gut (1998)

Background —Relatives of patients with early onset colorectal cancer, a feature of hereditary non-polyposis colorectal cancer (HNPCC), are at increased risk of colorectal cancer. Aims —To investigate risk in relatives of patients with multiple primary cancers, another feature of HNPCC. Methods —Details were obtained on patients from one region who had developed colorectal cancer and a separate primary from the HNPCC tumour spectrum (colorectal, stomach, urinary, ovary, endometrial). Overall, 157 patients had second primaries occurring between 1990 and 1995 and 128 completed family histories were obtained by structured interview (study group). A comparison group of 444 patients with a single colorectal cancer were similarly interviewed. Results —Fifteen families (13%) from the study group were suggestive of HNPCC compared with three (0.7%, p&lt;0.0001) from the comparison group. Overall risk of colorectal cancer in close relatives of the study group was 3.4 times the general population rate compared with 1.8 times for the comparison group. Bowel cancer risk was even higher for relatives of bowel/ovary and bowel/endometrial subgroups, but was similar to the comparison group for the bowel/bowel subgroup. Finally, extracolonic HNPCC associated cancers were seen twice as frequently as expected in the general population in relatives of the study group. Conclusion —This study highlights the importance of taking a family history in patients with multiple primary cancers and indicates the risk of malignancy in their relatives.
Cost-Effectiveness of Colonoscopy in Screening for Colorectal Cancer
Authors: Amnon Sonnenberg
Journal: Annals of Internal Medicine (2000)

Background: Fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy are used to screen patients for colorectal cancer. Objective: To compare the cost-effectiveness of fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy. Design: The cost-effectiveness of the three screening strategies was compared by using computer models of a Markov process. In the model, a hypothetical population of 100 000 persons 50 years of age undergoes annual fecal occult blood testing, sigmoidoscopy every 5 years, or colonoscopy every 10 years. Positive results on fecal occult blood testing or adenomatous polyps found during sigmoidoscopy are worked up by using colonoscopy. After polypectomy, colonoscopy is repeated every 3 years until no polyps are found. Data Sources: Transition rates were estimated from U.S. vital statistics and cancer statistics and from published data on the sensitivity, specificity, and efficacy of various screening techniques. Costs of screening and cancer care were estimated from Medicare reimbursement data. Target Population: Persons 50 years of age in the general population. Time Horizon: The study population was followed annually until death. Perspective: Third-party payer. Outcome Measure: Incremental cost-effectiveness ratio. Results of Base-Case Analysis: Compared with colonoscopy, annual screening with fecal occult blood testing costs less but saves fewer life-years. A screening strategy based on flexible sigmoidoscopy every 5 or 10 years is less cost-effective than the other two screening methods. Results of Sensitivity Analysis: Screening with fecal occult blood testing is more sensitive to changes in compliance rates, and it becomes easily dominated by colonoscopy under most conditions assuming less than perfect compliance. Other assumptions about the sensitivity and specificity of fecal occult blood testing, screening frequency, efficacy of colonoscopy in preventing cancer, and polyp incidence have a lesser influence on the differences in cost-effectiveness between colonoscopy and fecal occult blood testing. Conclusions: Colonoscopy represents a cost-effective means of screening for colorectal cancer because it reduces mortality at relatively low incremental costs. Low compliance rates render colonoscopy every 10 years the most cost-effective primary screening strategy for colorectal cancer.
Chemokine Receptor CCR5 and CXCR4 Expression in HIV-Associated Kidney Disease
Authors: FRANK EITNER, YAN CUI, KELLY L. HUDKINS, MICHAEL B. STOKES, STEPHAN SEGERER, MATTHIAS MACK, PAUL L. LEWIS, A. ANDREW ABRAHAM, DETLEF SCHLO[Combining Diaeresis]NDORFF, GLORIA GALLO, PAUL L. KIMMEL, CHARLES E. ALPERS
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The chemokine receptors CCR5 and CXCR4 have been identified as essential coreceptors for entry of HIV-1 strains into susceptible cells. Direct infection of renal parenchymal cells has been implicated in the pathogenesis of HIV-associated renal disease, although data are conflicting. The localization of CCR5 and CXCR4 in kidneys with HIV-associated renal disease is unknown. Formalin-fixed, paraffin-embedded renal biopsies from patients with HIV-associated nephropathy (HIVAN) ( n = 13), HIV-associated immune complex glomerulonephritis ( n = 3), HIV-associated thrombotic microangiopathy ( n = 1), and HIV-negative patients with collapsing glomerulopathy ( n = 8) were analyzed in this study. Cellular sites of expression of CCR5 and CXCR4 were identified by immunohistochemistry and by in situ hybridization. The presence of HIV-1 was detected by immunohistochemistry and by in situ hybridization. Expression of both chemokine receptors CCR5 and CXCR4 was undetectable in intrinsic glomerular, tubular, and renovascular cells in all analyzed cases. In the presence of tubulointerstitial inflammation, CCR5 and CXCR4 expression was localized to infiltrating mononuclear leukocytes. HIV-1 protein was undetectable by immunohistochemistry in all cases of HIV-associated renal disease. HIV-1 RNA was identified in one case of HIVAN but was restricted to infiltrating leukocytes. HIV-1 RNA was not detected in intrinsic renal cells in all analyzed cases. Identifying the cellular expression of HIV-coreceptors CCR5 and CXCR4 may help to clarify which tissues are permissive for direct HIV infection. These data do not support a role of productive HIV-1 infection of renal parenchymal cells in the pathogenesis of HIV-associated renal disease.
Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension
Authors: M.M. Hoeper, C. Faulenbach, H. Golpon, J. Winkler, T. Welte, J. Niedermeyer
Journal: European Respiratory Journal (2004)

It has been proposed that targeted treatments should be combined for patients with idiopathic pulmonary arterial hypertension (IPAH) responding insufficiently to monotherapy. This study followed the clinical course of nine patients with severe IPAH, in whom the endothelin receptor antagonist bosentan caused transient clinical improvement, eventually followed by a decline in exercise tolerance, who received adjunct treatment with the phospodiesterase-5-inhibitor sildenafil. Measurements included the 6-min walk distance (6MWD) and cardiopulmonary exercise testing (CPET). The 6MWD at baseline was 346±66 m and improved to 403±80 m 3 months after introduction of bosentan treatment. However, this effect was not sustained and, after an interval of 11±5 months, the walk distance had declined to 277±80 m. At this point, sildenafil was added to bosentan. Three months later, the 6MWD had increased to 392±61 m and the patients remained stable throughout the median follow-up of 9 months (range 6–12). Measurement of the maximum oxygen uptake during CPET confirmed these results. The combination of bosentan and sildenafil was well tolerated by all patients. These preliminary data suggest that combining bosentan and sildenafil may be safe and effective in patients with idiopathic pulmonary arterial hypertension.
Management of hypersensitivity reactions to iodinated contrast media
Authors: K. Brockow, C. Christiansen, G. Kanny, O. Clément, A. Barbaud, A. Bircher, P. DeWachter, J.‐L. Guéant, R.‐M. Rodriguez Guéant, C. Mouton‐Faivre, J. Ring, A. Romano, J. Sainte‐Laudy, P. Demoly, W. J. Pichler
Journal: Allergy (2005)

All iodinated contrast media (CM) are known to cause both immediate (≤1 h) and nonimmediate (&gt;1 h) hypersensitivity reactions. Although for most immediate reactions an allergic hypersensitivity cannot be demonstrated, recent studies indicate that the severe immediate reactions may be IgE‐mediated, while most of the nonimmediate exanthematous skin reactions, appear to be T‐cell mediated. Patients who experience such hypersensitivity reactions are therefore advised to undergo an allergologic evaluation. Several investigators have found skin testing to be useful in confirming a CM allergy, especially in patients with nonimmediate skin eruptions. If a patient with confirmed allergy to a CM needs a new CM exposure, a skin test negative CM should be chosen and premedication may be tried. However, none of these precautional measures is a guarantee against a repeat reaction. More research focusing on pathomechanisms, diagnostic testing and premedication is therefore clearly needed in order to prevent CM‐induced hypersensitivity reactions in the future.
A Sequence-Based Model Accounts Largely for the Relationship of Intron Positions to Protein Structural Features
Authors: Danny W. De Kee, Vivek Gopalan, Arlin Stoltzfus
Journal: Molecular Biology and Evolution (2007)

Claims of intron-structure correlations have played a major role in debates surrounding split gene origins. In the formative (as opposed to disruptive or “insertional”) model of split gene origins, introns represent the scars of chimaeric gene assembly. When analyzed retrospectively, formative introns should tend to fall between modular units, if such units exist, or at least to exhibit a preference for sites favorable to chimaera formation. However, there is another possible source of preferences: under a disruptive model of split gene origins, fortuitous intron-structure correlations may arise because the gain of introns is biased with respect to flanking nucleotide sequences. To investigate the extent to which a sequence-biased intron gain model may account for the present-day distribution of introns, data on over 10,000 introns in eukaryotic protein-coding genes were integrated with structural data from a set of 1,851 nonredundant protein chains. The positions of introns with respect to secondary structures, solvent accessibility, and so-called “modules” were evaluated relative to the expectations of a null model, a disruptive model based on amino acid frequencies at splice junctions, and a formative model defined relative to these. The null model can be excluded for most structural features and is highly improbable when intron sites are grouped by reading frame phase. Phase-dependent correlations with secondary structure and side-chain surface accessibility are particularly strong. However, these phase-dependent correlations are explained largely by the sequence-based disruptive model.
Responses of atherosclerotic human coronary arteries in vivo to the endothelium-dependent vasodilator substance P.
Authors: D C Crossman, S W Larkin, M R Dashwood, G J Davies, M Yacoub, A Maseri
Journal: Circulation (1991)

The effects of the endothelium-dependent vasodilator substance P (SP) on atherosclerotic human coronary arteries was studied.[125I]-SP binding to luminal cells was shown to be preserved in the atherosclerotic epicardial coronary arteries of four patients. No binding to medial smooth muscle cells was demonstrated. Intracoronary infusions of SP were undertaken in patients with coronary artery disease. SP was infused for 2-minute periods starting at a dose of 2.8 pmol/min rising by doubling increments to 22.4 pmol/min. Analysis of the epicardial coronary artery diameter, using a computerized analysis system (CAAS) of the angiograms, was performed at the end of each infusion. Analysis of seven smooth vessel segments from seven coronary vessels, which were stenosed at more proximal sites, was performed. Significant dose-dependent dilatation was seen (p = 0.04), which was maximal at 5.6 pmol/min SP. No additional dilatation was produced with 2 mg intracoronary isosorbide dinitrate (ISDN). Two of these seven patients showed no response to SP, and only one of these appeared to sustain dilatation with ISDN (2 mg intracoronary). In a second group of six patients with discrete coronary stenoses, analysis at the site of the stenosed segments appeared to reveal dilatation in response to SP in only one instance. One other stenotic segment dilated with isosorbide dinitrate but failed to dilate with SP; the remaining four were fixed. The segment immediately proximal to the stenosis preserved a dose-dependent vasodilator response.These findings demonstrate that the endothelium-dependent vasodilator substance P can still produce epicardial vasodilatation in vivo in the presence of coronary atherosclerosis.
Incidence and Prediction of Posttraumatic Stress Disorder Symptoms in Severely Injured Accident Victims
Authors: Ulrich Schnyder, Hanspeter Moergeli, Richard Klaghofer, Claus Buddeberg
Journal: American Journal of Psychiatry (2001)

This study was designed to assess the incidence of posttraumatic stress disorder (PTSD) in severely injured accident victims and to predict the presence of PTSD symptoms at a 12-month follow-up.A longitudinal, 1-year follow-up study was carried out with 106 consecutive patients with severe accidental injuries who were admitted to the trauma surgeons' intensive care unit at a university hospital. Patients were interviewed within 1 month and 12 months after the accident. Assessments included an extensive clinical interview, the Impact of Event Scale, the Clinician-Administered PTSD Scale, the Sense of Coherence questionnaire, and the Freiburg Questionnaire of Coping With Illness.A total of 13.4 days (SD=6.6) after the accident, five patients (4.7%) met all criteria for PTSD with the exception of the time criterion. A total of 22 other patients (20.8%) had subsyndromal PTSD. At the 1-year follow-up, two patients (1.9%) had PTSD, and 13 (12.3%) had subsyndromal PTSD. Multiple regression analysis explained 34% of the variance of PTSD symptoms 12 months after the accident. Biographical risk factors, the sense of a death threat, symptoms of intrusion, and problem-oriented coping each contributed significantly to the predictive model.In severely injured accident victims who were healthy before experiencing trauma, the incidence of PTSD was low. One-third of the variance of PTSD symptoms at 1-year follow-up could be predicted by mainly psychosocial variables.
Multicenter, Phase II Trial of Sunitinib in Previously Treated, Advanced Non–Small-Cell Lung Cancer
Authors: Mark A. Socinski, Silvia Novello, Julie R. Brahmer, Rafael Rosell, Jose M. Sanchez, Chandra P. Belani, Ramaswamy Govindan, James N. Atkins, Heidi H. Gillenwater, Cinta Pallares, Lesley Tye, Paulina Selaru, Richard C. Chao, Giorgio V. Scagliotti
Journal: Journal of Clinical Oncology (2008)

Aberrant vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) signaling have been shown to play a role in non-small-cell lung cancer (NSCLC) pathogenesis and are associated with decreased survival. We evaluated the clinical activity and tolerability of sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor that blocks the activity of receptors for VEGF and PDGF, as well as related tyrosine kinases in patients with previously treated, advanced NSCLC.
The HAS-BLED Score Has Better Prediction Accuracy for Major Bleeding Than CHADS2 or CHA2DS2-VASc Scores in Anticoagulated Patients With Atrial Fibrillation
Authors: Vanessa Roldán, Francisco Marín, Sergio Manzano-Fernández, Pilar Gallego, Juan Antonio Vílchez, Mariano Valdés, Vicente Vicente, Gregory Y.H. Lip
Journal: Journal of the American College of Cardiology (2013)
STUDIES ON X-RAY EFFECTS
Authors: Waro Nakahara
Journal: The Journal of Experimental Medicine (1923)

Cancer cells implanted in a skin region previously exposed to an erythema dose of x-rays show a series of degenerative changes in every way comparable to the frequently described stages of cancer cell degeneration following x-ray treatment. The findings contrast strongly with the survival and growth of grafts implanted in unexposed regions in the same animal. Since the changes are the same whether the cancer cells have been directly exposed in situ or merely implanted in the previously exposed skin, it follows that it is impossible to establish microscopically a direct injury from the x-raying as the principal factor in the therapeutic action of x-rays on cancer.
Major incidents in England
Authors: S. Hardy
Journal: BMJ (2015)

Why aren’t we learning from them?

Reporting the results of every intervention is becoming the norm in medicine and provides an excellent basis for medical advancement and quality control. But major incidents have so far escaped this scrutiny. In England, agencies are not mandated to record or report major incidents. Reports that do exist are unstructured and unregulated, and it is difficult to derive useful information from them. Our understanding of major incidents and how best to respond to them is therefore limited.

A major incident is one that overwhelms capacity or, in the NHS’s words, “any event that cannot be managed within routine service arrangements.”1 As recent media attention on emergency departments in England has shown, routine service arrangements are easily strained. With increasing threats from global terrorism and natural disasters,2 major incidents are becoming a more familiar part of our everyday lives. A recent Dutch study examined reports from five consecutive national disasters and noted that, despite changes in protocol, legislation, organisation, and funding, the same mistakes were being made each time.3

Why is it so difficult to learn from major incidents? I was on duty in …
Confusion of Wide Thrombolytic Time Window for Acute Pulmonary Embolism: Mass Spectrographic Analysis for Thrombus Proteins
Authors: Lemin Wang, Zhu Gong, Jinfa Jiang, Wenjun Xu, Qianglin Duan, Jiangning Liu, Chuan Qin
Journal: American Journal of Respiratory and Critical Care Medicine (2011)
Small airways function declines after allogeneic haematopoietic stem cell transplantation
Authors: S. Lahzami, R.E. Schoeffel, V. Pechey, C. Reid, M. Greenwood, C.M. Salome, N. Berend, G.G. King
Journal: European Respiratory Journal (2011)

Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) affects peripheral airways. Detection of BO is presently delayed by the low sensitivity of spirometry. We examined the relationship between peripheral airway function and time since HSCT, and compared it with spirometry and clinical indices in 33 clinically stable allogeneic HSCT recipients. The following measurements were performed: lung function, exhaled nitric oxide, forced oscillatory respiratory system resistance and reactance, acinar (S acin ) and conductive airways ventilation heterogeneity and lung clearance index (LCI) measured by multiple breath nitrogen washout. 22 patients underwent repeat visits from which short-term changes were examined. Median time post HSCT was 12 months. Eight patients were clinically diagnosed as having BO. In multivariate analysis, time since HSCT was predicted by S acin and forced expiratory volume in 1 s % predicted. 20 patients had abnormal S acin with normal spirometry, whereas none had airflow obstruction with normal S acin . S acin and LCI were the only measures to change significantly between two visits, with both worsening. Change in S acin was the only parameter to correlate with change in chronic graft- versus -host disease grade. In conclusion, peripheral airways ventilation heterogeneity worsens with time after HSCT. S acin may be more sensitive than spirometry in detecting BO at an early stage, which needs confirmation in a prospective study.
Pioglitazone improves insulin secretory capacity and prevents the loss of β-cell mass in obese diabetic db/db mice: possible protection of β cells from oxidative stress
Authors: Hitoshi Ishida, Makoto Takizawa, Sachihiko Ozawa, Yoko Nakamichi, Shinya Yamaguchi, Hidenori Katsuta, Toshiaki Tanaka, Masahiro Maruyama, Hiroshi Katahira, Katsuhiko Yoshimoto, Eiji Itagaki, Shinya Nagamatsu
Journal: Metabolism (2004)
Independent HHsearch, Needleman-Wunsch-Based, and Motif Analyses Reveal the Overall Hierarchy for Most of the G Protein-Coupled Receptor Families
Authors: K. J. V. Nordstrom, M. Sallman Almen, M. M. Edstam, R. Fredriksson, H. B. Schioth
Journal: Molecular Biology and Evolution (2011)

Several families of G protein-coupled receptors (GPCRs) show no significant sequence similarities to each other, and it has been debated which of them share a common origin. We developed and performed integrated and independent HHsearch, Needleman--Wunsch-based and motif analyses on more than 6,600 unique GPCRs from 12 species. Moreover, we mined the evolutionary important Trichoplax adhaerens, Nematostella vectensis, Thalassiosira pseudonana, and Strongylocentrotus purpuratus genomes, revealing remarkably rich vertebrate-like GPCR repertoires already in the early Metazoan species. We found strong evidence that the Adhesion and Frizzled families are children to the cyclic AMP (cAMP) family with HHsearch homology probabilities of 99.8% and 99.4%, respectively, also supported by the Needleman--Wunsch analysis and several motifs. We also found that the large Rhodopsin family is likely a child of the cAMP family with an HHsearch homology probability of 99.4% and conserved motifs. Therefore, we suggest that the Adhesion and Frizzled families originated from the cAMP family in an event close to that which gave rise to the Rhodopsin family. We also found convincing evidence that the Rhodopsin family is parent to the important sensory families; Taste 2 and Vomeronasal type 1 as well as the Nematode chemoreceptor families. The insect odorant, gustatory, and Trehalose receptors, frequently referred to as GPCRs, form a separate cluster without relationship to the other families, and we propose, based on these and others' results, that these families are ligand-gated ion channels rather than GPCRs. Overall, we suggest common descent of at least 97% of the GPCRs sequences found in humans.