tbuckley/cabot-search huggingface dataset:
Proximal and progressive: adenomas in HNPCC
Authors: D T Bishop
Journal: Gut (2002)

Characteristics of hereditary non-polyposis colorectal cancer adenomas

In this issue of Gut , Rijcken and colleagues1 compare adenomas found in hereditary non-polyposis colorectal cancer (HNPCC) patients with those found in patients without a family history of colorectal cancer [see 382 ] . HNPCC is an autosomal dominant syndrome associated with an increased risk of cancer at a number of anatomical sites but most noticeably of the bowel and endometrium. Some of the HNPCC adenomas examined in this study were derived from patients in families with known germline mutations in a DNA mismatch repair (MMR) gene (this topic has been reviewed recently in Gut by Wheeler and colleagues2 ). Colorectal carcinoma in patients with germline MMR mutations exhibit failure of DNA MMR as a result of loss of expression of both copies of the MMR gene. Failure of DNA repair implies that particular DNA sequences, if mutated somatically, are less likely to be corrected.2

There are three notable features of carcinomas arising as a result of HNPCC: (i) an excess of proximal lesions, (ii) an excess of mucinous and undifferentiated lesions, and (iii) evidence of rapid progression rates for some lesions. …
“Westernizing” Women's Risks? Breast Cancer in Lower-Income Countries
Authors: Peggy Porter
Journal: New England Journal of Medicine (2008)

Interview with Peggy Porter on the increased rate of breast cancer in lower-income countries. (07:03)Download Recent media reports have highlighted the increasing incidence of breast cancer in low- and middle-income countries. Although the disease continues to be most prominent in affluent countries, the risks of both breast cancer and death due to breast cancer are clearly increasing worldwide (see maps). Some 45% of the more than 1 million new cases of breast cancer diagnosed each year, and more than 55% of breast-cancer–related deaths, occur in low- and middle-income countries.1 Such countries now face the challenge of effectively detecting and treating a disease that previously was considered too uncommon to merit the allocation of precious health . . .
Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure
Authors: Josep Rodés-Cabau, Eric Horlick, Reda Ibrahim, Asim N. Cheema, Marino Labinaz, Najaf Nadeem, Mark Osten, Mélanie Côté, Josep Ramon Marsal, Donald Rivest, Alier Marrero, Christine Houde
Journal: JAMA (2015)

The occurrence of new-onset migraine attacks is a complication of transcatheter atrial septal defect (ASD) closure. It has been suggested that clopidogrel may reduce migraine attacks after ASD closure.To assess the efficacy of clopidogrel, used in addition to taking aspirin, for the prevention of migraine attacks following ASD closure.Randomized, double-blind clinical trial performed in 6 university hospitals in Canada. Participants were 171 patients with an indication for ASD closure and no history of migraine.Patients were randomized (1:1) to receive dual antiplatelet therapy (aspirin + clopidogrel [the clopidogrel group], n = 84) vs single antiplatelet therapy (aspirin + placebo [the placebo group], n = 87) for 3 months following transcatheter ASD closure. The first patient was enrolled in December 2008, and the last follow-up was completed in February 2015.The primary efficacy outcome was the monthly number of migraine days within the 3 months following ASD closure in the entire study population. The incidence and severity of new-onset migraine attacks, as evaluated by the Migraine Disability Assessment questionnaire, were prespecified secondary end points. A zero-inflated Poisson regression model was used for data analysis.The mean (SD) age of the participants was 49 (15) years and 62% (106) were women. Patients in the clopidogrel group had a reduced mean (SD) number of monthly migraine days within the 3 months following the procedure (0.4 [95% CI, 0.07 to 0.69] days) vs the placebo group (1.4 [95% CI, 0.54 to 2.26] days; difference, -1.02 days [95% CI, -1.94 to -0.10 days]; incident risk ratio [IRR], 0.61 [95% CI, 0.41 to 0.91]; P = .04) and a lower incidence of migraine attacks following ASD closure (9.5% for the clopidogrel group vs 21.8% for the placebo group; difference, -12.3% [95% CI, -23% to -1.6%]; odds ratio [OR], 0.38 [95% CI, 0.15 to 0.89]; P = .03). Among patients with migraines, those in the clopidogrel group had less-severe migraine attacks (zero patients with moderately or severely disabling migraine attacks vs 37% [7 patients] in the placebo group; difference, -36.8% [95% CI, -58.5% to -15.2%]; P = .046). There were no between-group differences in the rate of patients with at least 1 adverse event (16.7% [14 patients] in the clopidogrel group vs 21.8% [19 patients] in the placebo group; difference, -5.2% [95% CI, -17% to 6.6%]; P = .44).Among patients who underwent transcatheter ASD closure, the use of clopidogrel and aspirin, compared with aspirin alone, resulted in a lower monthly frequency of migraine attacks over 3 months. Further studies are needed to assess generalizability and durability of this effect.clinicaltrials.gov Identifier: NCT00799045.
Age-Associated Characteristics of Murine Hematopoietic Stem Cells
Authors: Kazuhiro Sudo, Hideo Ema, Yohei Morita, Hiromitsu Nakauchi
Journal: The Journal of Experimental Medicine (2000)

Little is known of age-associated functional changes in hematopoietic stem cells (HSCs). We studied aging HSCs at the clonal level by isolating CD34−/lowc-Kit+Sca-1+ lineage marker–negative (CD34−KSL) cells from the bone marrow of C57BL/6 mice. A population of CD34−KSL cells gradually expanded as age increased. Regardless of age, these cells formed in vitro colonies with stem cell factor and interleukin (IL)-3 but not with IL-3 alone. They did not form day 12 colony-forming unit (CFU)-S, indicating that they are primitive cells with myeloid differentiation potential. An in vivo limiting dilution assay revealed that numbers of multilineage repopulating cells increased twofold from 2 to 18 mo of age within a population of CD34−KSL cells as well as among unseparated bone marrow cells. In addition, we detected another compartment of repopulating cells, which differed from HSCs, among CD34−KSL cells of 18-mo-old mice. These repopulating cells showed less differentiation potential toward lymphoid cells but retained self-renewal potential, as suggested by secondary transplantation. We propose that HSCs gradually accumulate with age, accompanied by cells with less lymphoid differentiation potential, as a result of repeated self-renewal of HSCs.
The Chlamydia Protease CPAF Regulates Host and Bacterial Proteins to Maintain Pathogen Vacuole Integrity and Promote Virulence
Authors: Ine Jorgensen, Maria M. Bednar, Vishar Amin, Beckley K. Davis, Jenny P.Y. Ting, Dewey G. McCafferty, Raphael H. Valdivia
Journal: Cell Host & Microbe (2011)
Partitioning of dead space ‐ a method and reference values in the awake human
Authors: E. Åström, L. Niklason, B Drefeldt, M Bajc, B Jonson
Journal: European Respiratory Journal (2000)

Although dead space is often increased in disease, it is not frequently measured in the clinic. This may reflect that an adequate method as well as reference values are missing. Healthy males and females, n=38, age 20-61 yrs, were connected to a pneumotachograph and a fast CO2 analyser after radial artery catheterization. The physiological dead space was partitioned into airway and alveolar dead space using a delineation principle denoted the pre-interface expirate. Physiological dead space was 201+/-41 mL in males and 150+/-34 mL in females. Dead space values were depending upon parameters reflecting lung size (predicted total lung capacity), breathing pattern and age. After multiple correlation the variation decreased and differences between males and females disappeared. The residual SD was then for physiological dead space 18.9 mL. The clinical use of the new method for determination of dead space can be based upon reference values, with a more narrow range than previous data.
Assessment of thoracoabdominal bands to detect respiratory effort-related arousal
Authors: J.F. Masa, J. Corral, M.J. Martín, J.A. Riesco, A. Sojo, M. Hernández, N.J. Douglas
Journal: European Respiratory Journal (2003)

It would be helpful to be able to identify respiratory effort-related arousal (RERA) without needing to measure oesophageal pressure. Thoracoabdominal movements yield an indirect flow measurement from which reduction of amplitude and alteration of the inspiratory flow curve can be detected. The aim of this study was to evaluate the accuracy of using the shape and amplitude of signals from thoracoabdominal bands (inductance plethysmography) to detect RERAs. Altogether, 94 subjects suspected of having sleep apnoea but with an apnoea/hypopnoea index ≤10 in full polysomnography with oesophageal pressure were studied. A routine polysomnographical analysis was carried out. The polysomnographies were then reanalysed at random to determine which of the identified arousals were due to RERA, as determined either by oesophageal pressure or by induction bands without an oesophageal pressure signal. Altogether, 14,617 arousals were analysed. The sensitivity and specificity to find RERA (arousal by arousal) from bands versus oesophageal pressure were both 94%. The average difference of RERA index between oesophageal pressure and bands was −0.6. The correlation between RERA index determined by oesophageal pressure and bands was 0.98. To evaluate the intra and interobserver agreement, 1183 arousals were additionally analysed. The intraobserver agreement was 91% for RERAs by oesophageal pressure and 80% by bands. The interobserver agreement was 89% by oesophageal pressure and 85% by bands. The thoracoabdominal bands can be used to identify respiratory effort-related arousal (obstructive events not detected by thermistor) with similar efficacy to oesophageal pressure measurement. Since bands are routinely used in most polysomnographies, they can be used as the usual method to detect respiratory effort-related arousal, using a thermistor to evaluate apnoeas and hypopnoeas or as a complement to other methods, such as nasal cannula, which can detect apnoeas, hypopnoeas and respiratory effort-related arousal.
Detection of left ventricular thrombus by two-dimensional echocardiography: sensitivity, specificity, and causes of uncertainty.
Authors: J R Stratton, G W Lighty, A S Pearlman, J L Ritchie
Journal: Circulation (1982)

To define the sensitivity, specificity and predictive accuracy of two-dimensional echocardiographic detection of left ventricular thrombus, the echocardiograms of 78 patients who had independent proof of the presence or absence of a left ventricular thrombus were interpreted without knowledge of any clinical data. The presence of thrombus was established by autopsy in four patients, by aneurysmectomy in three, and by indium-111 platelet imaging in 15; the absence of thrombus was proved by autopsy in 55 patients and by aneurysmectomy in one patient. The characteristics of true-positive and false-positive echocardiograms, interobserver variability, and clinical features associated with proved thrombus were also defined. The echocardiogram was positive for thrombus in 22 patients, equivocal in seven and negative in 49. For detection of thrombus, a positive or equivocal echocardiogram had a sensitivity of 95% (21 of 22), a specificity of 86% (48 of 56), and a predictive value of 72% (21 of 29); the predictive value of a negative study was 98% (48 of 49). Considering positive and equivocal studies separately, the predictive value of a positive study was 86% (19 of 22), while that of an equivocal study was only 29% (two of seven). Compared with patients who had no thrombus, patients with proved thrombus had a higher prevalence of electrocardiographic transmural anterior infarction (86% vs 13%), left ventricular aneurysm (73% vs 5%), and clinical systemic emboli (36% vs 7%) (all p less than 0.05). These clinical features help to identify a subset of patients most likely to have left ventricular thrombi who may benefit from echocardiography. Two-dimensional echocardiography is highly sensitive in detecting left ventricular thrombus, but false-positive studies are relatively common. Several echocardiographic criteria derived from analysis of the true and false positives in this study may help minimize diagnostic errors.
Reply to S. Gupta et al
Authors: Steven Joffe, Franklin G. Miller
Journal: Journal of Clinical Oncology (2015)

We thank Gupta et al for their thoughtful response to our recent article in the Journal of Clinical Oncology, in which we argued against the view that the control arms of cancer clinical trials in low-resource countries must reflect the highest international standard of care. Gupta et al add the important qualification that standards of care may vary even within nations, with privileged individuals able to access treatments that remain out of reach for most patients in the country. They note, and we agree, that this within-country variation may complicate decisions about which treatments must be included within the control arm of a trial. Gupta et al also argue that some treatments have “conferred unprecedented benefits,” and should therefore be incorporated into the control arms of clinical trials, regardless of their local availability. Other treatments, they argue, confer only modest benefits and may therefore ethically be excluded from trials. The primary justification for basing the control arm of a trial on the local rather than highest international standard of care, however, is that doing so maximizes the likelihood that the trial’s results will be relevant to the communities in which it is conducted. Accepting the position of Gupta et al threatens to undermine the commitment to conducting locally relevant clinical trials. Investigators best improve outcomes for patients in disadvantaged countries when they demonstrate directly that a feasible intervention offers greater benefit than the local standard of care.
Patellofemoral osteoarthritis is prevalent and associated with worse symptoms and function after hamstring tendon autograft ACL reconstruction
Authors: Adam G Culvenor, Courtney C H Lai, Belinda J Gabbe, Michael Makdissi, Natalie J Collins, Bill Vicenzino, Hayden G Morris, Kay M Crossley
Journal: British Journal of Sports Medicine (2013)

<h3>Objectives</h3> To evaluate the compartmental distribution of knee osteoarthritis (OA) after anterior cruciate ligament reconstruction (ACLR), to determine if patellofemoral or tibiofemoral OA is more strongly associated with knee symptoms and function, and to evaluate the contribution of associated injuries and surgical delay to the development of OA. <h3>Methods</h3> This cross-sectional study recruited 70 participants who underwent hamstring tendon (HT) ACLR 5–10 years previously. Radiographic OA was assessed according to the Osteoarthritis Research Society International (OARSI) criteria. Knee symptoms were assessed with the Knee Injury and Osteoarthritis Outcome Score (KOOS) and Anterior Knee Pain Scale (AKPS), while function was assessed with three lower limb tasks (hop-for-distance, one-leg rise and side-hop). Multivariate and binary logistic regression analyses were performed to assess the relationship between OA and symptomatic/functional outcomes and associated injuries/surgical delay, respectively. <h3>Results</h3> Radiographic OA was observed in the patellofemoral (47%) and tibiofemoral joints (31%). Pain, symptoms and quality of life on the KOOS and the AKPS were associated with severity of patellofemoral OA (standardised regression coefficient (β)=−0.3 to −0.5, p=0.001–0.042), whereas only the KOOS-pain subscale was associated with tibiofemoral OA (β=−0.3, p=0.037). For each functional task, greater patellofemoral OA severity was associated with worse performance, independent of tibiofemoral OA severity (β=−0.3 to −0.4, p=0.001–0.026). Medial meniscal and patellofemoral chondral lesions at surgery were associated with tibiofemoral and patellofemoral OA development at follow-up, respectively, while a longer surgery delay was associated with patellofemoral OA. <h3>Conclusions</h3> Patellofemoral OA is common following HT ACLR and is associated with worse knee-related symptoms, including anterior knee pain, and decreased functional performance.
Low Doses of Ouabain Protect from Serum Deprivation–Triggered Apoptosis and Stimulate Kidney Cell Proliferation via Activation of NF-κB
Authors: Juan Li, Sergey Zelenin, Anita Aperia, Oleg Aizman
Journal: Journal of the American Society of Nephrology (2006)

It now generally is agreed that Na,K-ATPase, in addition to its role in the maintenance of Na+ and K+ gradients across the cell membrane, plays a role in communicating information from the extracellular environment to intracellular signaling pathways. It was reported recently that interaction between ouabain-bound Na,K-ATPase and the 1,4,5-trisphosphate receptor (IP3R) triggers slow calcium oscillations and activation of NF-κB. Here it is demonstrated that this signaling pathway can serve to prevent cell death and promote cell growth. Rat renal proximal tubular cells in primary culture first were grown in the presence of 10% serum and then exposed to 0.2% serum for 24 h to induce apoptosis. Serum starvation increased the apoptotic index from 1.21 ± 0.26 to 14.01 ± 1.17%. Ouabain in concentrations that did not inhibit Na,K-ATPase activity (1 to 10 nM) completely abolished the apoptotic effect of serum starvation. Ouabain protection from apoptosis was not observed when release of calcium from intracellular stores via the IP3R was prevented. It was shown that the NH2 terminal tail of the Na,K-ATPase α subunit plays a key role in ouabain-triggered calcium oscillations. It was found that ouabain did not protect from apoptosis in serum-deprived cells that expressed a mutant Na,K-ATPase α subunit with deletion of the NH2 terminal tail. Ouabain exposure (10 nM for 24 h) significantly increased translocation of NF-κB from cytoplasm to nucleus. Helenalin, an inhibitor of NF-κB, abolished the antiapoptotic effect of ouabain. Ouabain (0.1 to 10 nM) also was found to stimulate proliferation and increase the viability of kidney cells. These effects were abolished when release of calcium via the IP3R was prevented.
Overexpression of Cellular Iron Import Proteins Is Associated with Malignant Progression of Esophageal Adenocarcinoma
Authors: Jessica Boult, Keith Roberts, Matthew J. Brookes, Sharon Hughes, Jonathan P. Bury, Simon S. Cross, Gregory J. Anderson, Robert Spychal, Tariq Iqbal, Chris Tselepis
Journal: Clinical Cancer Research (2008)

There is growing evidence that iron is important in esophageal adenocarcinoma, a cancer whose incidence is rising faster than any other in the Western world. However, how iron mediates carcinogenesis at the molecular level remains unclear. In this study, we investigated the expression of iron transport proteins involved in cellular iron import, export, and storage in the premalignant lesion Barrett's metaplasia and esophageal adenocarcinoma.Perls' staining was used to examine iron deposition in tissue. mRNA expression in samples of Barrett's metaplasia matched with esophageal adenocarcinoma and samples of Barrett's metaplasia without evidence of adenocarcinoma were examined by real-time PCR. Semiquantitative immunohistochemistry was used to examine cellular localization and protein levels. The effect of iron loading on cellular proliferation and iron transporter expression was determined in esophageal cell lines OE33 and SEG-1 using a bromodeoxyuridine assay and real-time PCR, respectively.In the progression of Barrett's metaplasia to adenocarcinoma, there was overexpression of divalent metal transporter 1 (DMT1), transferrin receptor 1, duodenal cytochrome b, ferroportin, and H-ferritin, and these changes were associated with increased iron deposition. Overexpression of DMT1 was further associated with metastatic adenocarcinoma. Iron loading OE33 and SEG-1 cells caused increased cellular proliferation, which was associated with increased H-ferritin and decreased transferrin receptor 1 and DMT1 expression.Progression to adenocarcinoma is associated with increased expression of iron import proteins. These events culminate in increased intracellular iron and cellular proliferation. This may represent a novel mechanism of esophageal carcinogenesis.
Two cases of red cell aldolase deficiency associated with hereditary hemolytic anemia in a japanese family
Authors: Shiro Miwa, Hisaichi Fujii, Kenzaburo Tani, Keisuke Takahashi, Susumu Takegawa, Noboru Fujinami, Minoru Sakurai, Masako Kubo, Yasuo Tanimoto, Tomoaki Kato, Noboru Matsumoto
Journal: American Journal of Hematology (1981)

Abstract Two cases of red cell aldolase deficiency associated with congenital nonspherocytic hemolytic anemia are reported. The proband is a fourteen‐month‐old Japanese boy. Consanguineous marriage was not proven but probable in this family, as the parents were born in the same small island. The proband had moderate to mild anemia aggravated by upper respiratory infections, 1 cm hepatomegaly and 2.5 cm splenomegaly, but was unremarkable in other respects and has thus far not shown mental or growth retardation. He did not have dysmorphic features. The red cell aldolase activity was 6% of the normal mean. The enzyme was unstable with respect to heat, and Km for fructose 1,6‐diphosphate (F‐1,6‐DP) was high. The parents and other heterozygotes showed intermediate activity between that of the proband and that of normal subjects. Red cell F‐1,6‐DP concentration in this case was remarkably increased. Red cell glucose consumption, and lactate formation, as well as hexose monophosphate shunt activity, were decreased as compared with a comparable reticulocyte‐rich hereditary spherocytosis patient. Hexose monophosphate shunt activity was assumed to be decreased due to inhibition of glucose 6‐phosphate dehydrogenase by a high concentration of F‐1,6‐DP in his red cells. As a result of family study, another homozygous aldolase deficiency case associated with hemolytic anemia was found. He is 13 years old and a nephew of the proband's paternal grandmother. His hemolytic anemia also is moderate to mild and aggravated by upper respiratory infections. He does not seem to have mental or growth retardation, nor does he possess dysmorphic features.