tbuckley/cabot-search huggingface dataset:
Discussion: Immunology, cellular pathology, genetics
Authors: C Ritchlin
Journal: Annals of the Rheumatic Diseases (2005)

### What is the evidence suggesting that genetic factors are important in the pathogenesis of psoriatic arthritis (PsA)?

Much of the evidence supporting the genetic basis of PsA is derived from twin studies, family based investigations, and population based epidemiologic studies. Concordance rates of PsA in twins are unknown, but monozygotic twins have a threefold increased risk for psoriasis compared with fraternal twins. A population study conducted by Moll and Wright indicated the overall prevalence of PsA among first degree relatives was 5.5% and that the risk for affected first degree relatives (λ1) is 55. This compares to a reported λ1 of 8 for psoriasis. One family study reported that if one sibling had PsA, the corresponding risk for another sibling to develop the disease was 0.10, 0.22, and 0.31 if no parent was affected, the mother was affected, or the father was affected, respectively.

### Which genetic factors have been associated with PsA?

The commonest approaches to identify specific genetic factors include positional cloning studies that involve collections of families with multiple affected individuals or analysing affected sibling pairs so that linkage analysis can be performed. One genome-wide scan in 178 Icelandic patients reported an LOD score of 2.17 on chromosome 16q, whereas conditional on paternal transmission to affected individuals, the LOD score was 4.19. Recent studies of patients with PsA in Newfoundland suggest that variants within the CARD15 locus on chromosome 16q contribute to disease susceptibility.

Another approach for pinpointing genetic factors includes association studies. The strongest associations in PsA and psoriasis have been noted in the genes of the major histocompatibility complex (MHC) region. In particular, the class I human leucocyte …
Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma: Table 1–
Authors: Ioannis Pantazopoulos, Paraskevi Boura, Theodoros Xanthos, Konstantinos Syrigos
Journal: European Respiratory Journal (2012)

Malignant mesothelioma (MM) is an aggressive tumour with poor prognosis whose early diagnosis is difficult. Mesothelin, megakaryocyte potentiating factor (MPF) and osteopontin have attracted attention as biomarkers. The aim of the present review is to provide an overview regarding these candidate biomarkers for MM, and discuss their potential role in today's clinical practice. Mesothelin and MPF have good specificity but sub-optimal sensitivity for detection of MM, being negative both in the sarcomatoid histological sub-type and in almost half of epithelioid mesothelioma, especially in the early stages. Osteopontin is a marker of the duration of asbestos exposure, but lacks specificity for mesothelioma. Several patient characteristics influence the diagnostic accuracy of biomarkers and make the establishment of the “optimal” diagnostic threshold difficult. Mesothelin and MPF have proved useful in assessing response to treatment. Combining different markers together may lead to an improvement in diagnostic accuracy, but there is still need for research in this area. Extensive validation and further research is required to improve the use of serum markers in mesothelioma management. In the near future, their application in clinical practice is probably in monitoring response to therapy, rather than in guiding diagnostic decisions and risk assessment of asbestos-exposed populations.
Comments on 'Early features of acute-on-chronic liver failure: a prospective cohort study'
Authors: D. Gleeson, E. McFarlane, A. Dube, D. A. Elphick
Journal: Gut (2010)

We read with interest the study by Katoonizadeh et al 1 of acute-on-chronic (alcoholic) liver failure (ACLF) and the accompanying Editorial,2 which cites our report3 of liver histology in decompensated alcoholic liver disease (ALD). We found features of alcoholic hepatitis (intralobular neutrophils, Mallory bodies and ballooning) to be more frequent and more severe in patients biopsied within a month of first onset of decompensation, compared with those biopsied before decompensation or later, and argued for a causal relationship. We acknowledge the strengths of the prospective study of Katoonizadeh et al 1 but would interpret their results differently.

Their definition of ACLF1 excludes patients with no prior liver disease and also those without cirrhosis on biopsy. It thus excludes many patients with first presentation …
David Oliver: Who is to blame for older people’s readmission?
Authors: David Oliver
Journal: BMJ (2015)

In July Healthwatch England published Safely Home, a report describing the problems facing older people and their families when they leave hospital. 1 Disturbing personal stories highlight poor coordination between services.Patients often feel stigmatised for problems they don't control-for instance, viewing themselves as "bed blockers," which is a dreadful term-and they are not always properly involved in very personal decisions.Despite considerable efforts to plan hospital discharges well, about 15% of patients aged over 65 in England are readmitted within 28 days. 2Charities including Age UK 3 and the Royal Voluntary Service 4 have highlighted this distressing statistic and have publicised that support at home is often inadequate.
Quinacrine synergistically enhances the antivascular and antitumor efficacy of cediranib in intracranial mouse glioma
Authors: M. R. Lobo, S. C. Green, M. C. Schabel, G. Y. Gillespie, R. L. Woltjer, M. M. Pike
Journal: Neuro-Oncology (2013)

Despite malignant glioma vascularity, anti-angiogenic therapy is largely ineffective. We hypothesize that efficacy of the antiangiogenic agent cediranib is synergistically enhanced in intracranial glioma via combination with the late-stage autophagy inhibitor quinacrine. Relative cerebral blood flow and volume (rCBF, rCBV), vascular permeability (Ktrans), and tumor volume were assessed in intracranial 4C8 mouse glioma using a dual-bolus perfusion MRI approach. Tumor necrosis and tumor mean vessel density (MVD) were assessed immunohistologically. Autophagic vacuole accumulation and apoptosis were assessed via Western blot in 4C8 glioma in vitro. Cediranib or quinacrine treatment alone did not alter tumor growth. Survival was only marginally improved by cediranib and unchanged by quinacrine. In contrast, combined cediranib/quinacrine reduced tumor growth by >2-fold (P < .05) and increased median survival by >2-fold, compared with untreated controls (P < .05). Cediranib or quinacrine treatment alone did not significantly alter mean tumor rCBF or Ktrans compared with untreated controls, while combined cediranib/quinacrine substantially reduced both (P < .05), indicating potent tumor devascularization. MVD and necrosis were unchanged by cediranib or quinacrine treatment. In contrast, MVD was reduced by nearly 2-fold (P < .01), and necrosis increased by 3-fold (P < .05, one-tailed), in cediranib + quinacrine treated vs untreated groups. Autophagic vacuole accumulation was induced by cediranib and quinacrine in vitro. Combined cediranib/quinacrine treatment under hypoxic conditions induced further accumulation and apoptosis. Combined cediranib/quinacrine treatment synergistically increased antivascular/antitumor efficacy in intracranial 4C8 mouse glioma, suggesting a promising and facile treatment strategy for malignant glioma. Modulations in the autophagic pathway may play a role in the increased efficacy.
Stepwise DNA Methylation Changes Are Linked to Escape from Defined Proliferation Barriers and Mammary Epithelial Cell Immortalization
Authors: Petr Novak, Taylor J. Jensen, James C. Garbe, Martha R. Stampfer, Bernard W. Futscher
Journal: Cancer Research (2009)

The timing and progression of DNA methylation changes during carcinogenesis are not completely understood. To develop a timeline of aberrant DNA methylation events during malignant transformation, we analyzed genome-wide DNA methylation patterns in an isogenic human mammary epithelial cell (HMEC) culture model of transformation. To acquire immortality and malignancy, the cultured finite lifespan HMEC must overcome two distinct proliferation barriers. The first barrier, stasis, is mediated by the retinoblastoma protein and can be overcome by loss of p16(INK4A) expression. HMEC that escape stasis and continue to proliferate become genomically unstable before encountering a second more stringent proliferation barrier, telomere dysfunction due to telomere attrition. Rare cells that acquire telomerase expression may escape this barrier, become immortal, and develop further malignant properties. Our analysis of HMEC transitioning from finite lifespan to malignantly transformed showed that aberrant DNA methylation changes occur in a stepwise fashion early in the transformation process. The first aberrant DNA methylation step coincides with overcoming stasis, and results in few to hundreds of changes, depending on how stasis was overcome. A second step coincides with immortalization and results in hundreds of additional DNA methylation changes regardless of the immortalization pathway. A majority of these DNA methylation changes are also found in malignant breast cancer cells. These results show that large-scale epigenetic remodeling occurs in the earliest steps of mammary carcinogenesis, temporally links DNA methylation changes and overcoming cellular proliferation barriers, and provides a bank of potential epigenetic biomarkers that may prove useful in breast cancer risk assessment.
Occupational asthma in aluminium potroom workers related to pre-employment eosinophil count
Authors: B Sorgdrager, TM Pal, AJ de Looff, AE Dubois, JG de Monchy
Journal: European Respiratory Journal (1995)

Occupational asthma still occurs in aluminium potroom workers despite pre-employment medical selection. The purpose of our study was to identify workers with an increased risk of developing "potroom asthma". A nested, case-control study was carried out in two Dutch aluminium producing plants. Pre-employment data of 364 potroom workers (182 cases and 182 controls) were analyzed. Cases were workers unable to work because of work-related respiratory disease, meeting the criteria for potroom asthma. The selected controls were matched for age, year of starting employment and working conditions. Pre-employment eosinophil count was significantly related to the occurrence of potroom asthma, even though the mean number of the eosinophils in cases was within the normal range (< 275 cells.mm-3; 0.28 cells x 10(9).L-1). Hence, 39 of the 45 individuals with blood eosinophil counts in the upper range of normal (> 220 cells.mm-3; 0.22 cells x 10(9).L-1) developed potroom asthma with time. We conclude that workers without respiratory symptoms, with normal lung function and normal bronchial responsiveness before employment developed potroom asthma. Fluoride exposure, combined with an elevated eosinophil count, might induce an immunological or cytotoxic process.
PWE-067 Water Insufflation vs Narrow Band Imaging, Which Modality Produces Reliable Images Of Terminal Ileum at Colonoscopy?: Abstract PWE-067 Table 1
Authors: M H Thoufeeq, N Kumar
Journal: Gut (2013)

<h3>Introduction</h3> Terminal ileal (TI) images are reliable indicators of completeness of colonoscopy<sup>1</sup>. Studies have shown that TI image provide more convincing than caecal images to verify completion of colonoscopy<sup>2</sup>. Acquisitionof TI images after water insufflation (WI) has been found to produce reliable images<sup>3</sup>.We wanted to identify if TI images after WI through the biopsy channel or narrow band images of TI produce more reliable as part of image documentation. <h3>Methods</h3> 4 images of terminal ileum were captured using Olympus colonoscope ®. They were 1 captured with conventional white light endoscopy (WLE), 1 captured with white light endoscopy + water insufflation (WLEWI), 1 captured with narrow band imaging (NBI) and 1 captured with NBI + water insufflation (NBIWI). Without informing that these were TI images, the 4 terminal images were sent to endoscopists by email along with an invitation to participate in a survey using survey monkey® portal. Using the survey the respondents marked each image as follows: not terminal ileum = 1, may be terminal ileum = 2, most likely terminal ileum = 3, definitely terminal ileum = 4. <h3>Results</h3> 36 endoscopists completed our survey. 49% were gastroenterology Specialist registrar, 40% were consultant gastroenterologists and 11% were colorectal surgeons. Most of the respondents (n = 31) were from the UK, 4 were from the United States and 1 was from the rest of the Europe. 19.4% (n = 7) of respondents had colonoscopy experience of 1–2 years, 30.6% (n = 11) had colonoscopy experience of 3–5 years, 19.4% (n = 7) had colonoscopy experience of 5–9 years 30.6% (n = 11) had colonoscopy experience of more than 10 years. Responses in Table 1: <h3>Conclusion</h3> Water insufflation on terminal ileum using the biopsy channel of colonoscope produce more reliable images compared to White light or narrow band images (NBI). Combination of NBI and water insufflation together produced the most reliable images. <h3>Disclosure of Interest</h3> None Declared. <h3>References</h3> Cherian S, Singh P. Is routine ileoscopy useful? An observational study of procedure times, diagnostic yield, and learning curve.<i> Am J Gastroentero</i>l 2004; 99(12):2324–2329. Powell N, Knight H, Dunn J, Saxena V, Mawdsley J, Murray C <i>et al.</i> Images of the terminal ileum are more convincing than cecal images for verifying the extent of colonoscopy. <i>Endoscopy</i> 2011; 43(3):196–201. Baraza W, Brown S, Shorthouse AJ, Tiffin N, Hurlstone DP. Direct photographic documentation of ileal mucosa in routine colonoscopy is not an independent valid or reliable proof of completion: quality assurance issues for the national colorectal cancer-screening programme. <i>Colorectal Dis</i> 2009; 11(1):89–93.
Reporting Randomized, Controlled Trials of Herbal Interventions: An Elaborated CONSORT Statement
Authors: Joel J. Gagnier, Heather Boon, Paula Rochon, David Moher, Joanne Barnes, Claire Bombardier
Journal: Annals of Internal Medicine (2006)

Herbal medicinal products are widely used, vary greatly in content and quality, and are actively tested in randomized, controlled trials (RCTs). The authors' objective was to develop recommendations for reporting RCTs of herbal medicine interventions, based on the need to elaborate on the 22-item CONSORT (Consolidated Standards of Reporting Trials) checklist. Telephone calls were made and a consensus meeting was held with 16 participants in Toronto, Canada, to develop these recommendations. The group agreed on context-specific elaborations of 9 CONSORT checklist items for RCTs of herbal medicines. Item 4, concerning the herbal medicine intervention, required the most extensive elaboration. These recommendations have been developed to improve the reporting of RCTs using herbal medicine interventions.
Long-Term Outcomes in Idiopathic Membranous Nephropathy Using a Restrictive Treatment Strategy
Authors: Jan A.J.G. van den Brand, Peter R. van Dijk, Julia M. Hofstra, Jack F.M. Wetzels
Journal: Journal of the American Society of Nephrology (2013)

Recently published Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend limiting the use of immunosuppressive drugs in idiopathic membranous nephropathy to patients at the highest risk of kidney failure. However, recommendations are based on natural history rather than direct assessment of a restrictive treatment strategy. Here, we describe the long-term outcomes of treating a large cohort of patients with idiopathic membranous nephropathy according to a restrictive treatment policy. We analyzed data for 254 patients who visited our outpatient clinic between 1995 and 2009. All patients were treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Immunosuppressive therapy was recommended in cases of deteriorating renal function or untreatable nephrotic syndrome. Primary outcomes for the present study were renal replacement therapy and death. Secondary outcomes included adverse events during follow-up and remission of proteinuria. In total, 124 patients (49%) received immunosuppressive therapy, which predominantly consisted of cyclophosphamide combined with steroids. Ten-year cumulative incidence rates were 3% for renal replacement therapy and 10% for death. Partial remission rates were 39%, 70%, and 83% after 1, 3, and 5 years, respectively; complete remission rates were 5%, 24%, and 38% at 1, 3, and 5 years, respectively. A serious adverse event occurred in 23% of all patients. The most notable complications were infections (17%), leukopenia (18%), cardiovascular events (13%), and malignancies (8%). In conclusion, the use of a restrictive treatment strategy in this cohort of patients with idiopathic membranous nephropathy yielded favorable outcomes while limiting the number of patients exposed to toxic drugs. These results support current KDIGO guidelines.
Influence of Preoperative Left Ventricular Contractile Reserve on Postoperative Ejection Fraction in Low-Gradient Aortic Stenosis
Authors: Jean-Paul Quere, Jean-Luc Monin, Franck Levy, Hélène Petit, Serge Baleynaud, Christophe Chauvel, Camélia Pop, Patrick Ohlmann, Claude Lelguen, Patrick Dehant, Pascal Gueret, Christophe Tribouilloy
Journal: Circulation (2006)

Dobutamine stress hemodynamics (DSH) has the potential to stratify operative risk in low-gradient aortic stenosis (AS), but little is known about the relation between left ventricle contractile reserve and postoperative left ventricular ejection fraction (LVEF). We sought to assess the value of DSH to predict postoperative improvement in LVEF.Sixty-six consecutive patients with symptomatic severe AS (aortic valve area < or =1 cm2), LVEF < or =40%, and mean pressure gradient < or =40 mm Hg prospectively enrolled in the French multicenter study on low-gradient AS and who survived to aortic valvular replacement (AVR) were included. Preoperative contractile reserve was present in 46 patients (group I; 70%) and absent in 20 patients (group II; 30%). In the overall sample, 58% of patients improved by 2 New York Heart Association (NYHA) classes after AVR. Mean LVEF improved from 29+/-6% to 47+/-11% (P<0.0001). LVEF improved by > or =10 EF units in 38 patients (83%) in group I and in 13 patients (65%) in group II. Mean LVEF improvement was similar in the 2 groups (19+/-10% versus 17+/-11%; P=0.54). On multivariable analysis, multivessel coronary artery disease (P=0.05) and baseline mean transaortic pressure gradient (P=0.01) were related to LVEF improvement, whereas contractile reserve was not.LVEF increases in the majority of patients with low-gradient AS who survive after AVR. Although the absence of contractile reserve on DSH is related to high operative mortality, it does not predict the absence of LVEF recovery in patients surviving to AVR. These data further support the concept that surgery should not be contraindicated on the basis of absence of contractile reserve alone.
Respiratory failure with diffuse patchy lung infiltrates: an unusual presentation of squamous cell carcinoma
Authors: M. Meysman, D. F Schoors, H. Reynaert, M. Noppen, E. Pierre, W. Vincken
Journal: Thorax (1994)

The case history is presented of a patient with squamous cell carcinoma of the lung with diffuse bilateral pulmonary shadowing mimicking bronchioloalveolar cell carcinoma which led to type I respiratory failure.
Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell malignancy. European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom.
Authors: S D Fosså, S B Kaye, G M Mead, M Cullen, R de Wit, I Bodrogi, C J van Groeningen, P H De Mulder, S Stenning, E Lallemand, L De Prijck, L Collette
Journal: Journal of Clinical Oncology (1998)

PURPOSE To determine the effect of r-metHu granulocyte colony-stimulating factor (G-CSF) on the proportion of patients with metastatic poor-prognosis malignant germ cell tumors who receive full dose-intensity combination chemotherapy. PATIENTS AND METHODS In a phase III study patients received six cycles of BEP/EP (etoposide, and cisplatin, plus or minus bleomycin) or six cycles of BOP/VIP-B (bleomycin, vincristine, cisplatin/etoposide, ifosfamide, cisplatin, bleomycin). A subset were secondarily randomized to receive or not receive filgrastim. Filgrastim 5 microg/kg/day was administered subcutaneously on days 3 through 9 after each BOP and on days 6 through 19 after each VIP, BEP, or EP cycle. RESULTS Eighty-five percent of 120 eligible patients randomized to filgrastim received at least six chemotherapy cycles compared with 70% of 130 patients randomized to not receive filgrastim (VCP = .003). Patients in the filgrastim-arm achieved significantly higher dose-intensities. Neutropenic fever occurred in 25 of 128 filgrastim-patients and in 38 of 129 non-filgrastim-patients (P = .052). Twelve and three toxic deaths occurred in the non-filgrastim- and filgrastim-arms, respectively. Nine of the 12 toxic deaths and all of the three toxic deaths were associated with febrile grade 4 neutropenia. Failure-free and overall survival were similar in both arms. CONCLUSION During combination chemotherapy in patients with malignant germ cell tumors, the routine use of filgrastim significantly improved the delivery of the planned treatment schedule without effect on failure-free or overall survival. The use of filgrastim was associated with a clinically important reduction in the number of toxic deaths, confined to the experimental intensified-chemotherapy schedule. This study does not support the routine use of filgrastim during standard chemotherapy with BEP.
Hypertension Management in Patients With Diabetes
Authors: Dan R. Berlowitz, Arlene S. Ash, Elaine C. Hickey, Mark Glickman, Robert Friedman, Boris Kader
Journal: Diabetes Care (2003)

OBJECTIVE—Clinical trials have demonstrated the importance of tight blood pressure control among patients with diabetes. However, little is known regarding the management of hypertension in patients with coexisting diabetes. To examine this issue, we addressed 1) whether hypertensive patients with coexisting diabetes are achieving lower levels of blood pressure than patients without diabetes, 2) whether there are differences in the intensity of antihypertensive medication therapy provided to patients with and without diabetes, and 3) whether diabetes management affects decisions to increase antihypertensive medication therapy. RESEARCH DESIGN AND METHODS—We abstracted medical records to collect detailed information on 2 years of care provided for 800 male veterans with hypertension. We compared patients with and without diabetes on intensity of therapy and blood pressure control. Intensity of therapy was described using a previously validated measure that captures the likelihood of an increase in antihypertensive medications. We also determined whether increases in antihypertensive medications were less likely at those visits in which the diabetes medications were being adjusted. RESULTS—Of the 274 hypertensive patients with diabetes, 73% had a blood pressure ≥140/90 mmHg, compared with 66% in the 526 patients without diabetes (P = 0.04). Diabetic patients also received significantly (P = 0.05) less intensive antihypertensive medication therapy than patients without diabetes. Less intensive therapy in diabetic patients could not be explained by clinicians being distracted by the treatment for diabetes. CONCLUSIONS—There is an urgent need to improve hypertension care and blood pressure control in patients with diabetes. Additional information is required to understand why clinicians are not more aggressive in managing blood pressure when patients also have diabetes.