tbuckley/cabot-search huggingface dataset:
Methotrexate Hepatotoxicity in Psoriasis--Comparison of Different Dose Regimens
Authors: M. G. C. Dahl, M. M. Gregory, P. J. Scheuer
Journal: BMJ (1972)

Liver histological appearances were studied in 44 patients treated for psoriasis with methotrexate. Cirrhosis was found in six and hepatic fibrosis in another 11. Of these 17 patients 12 had received methotrexate by a regimen of frequent small dosage, two had been treated by a regimen of intermittent large dosage, while three had been treated at different times by both methods. The prevalence of cirrhosis and fibrosis was significantly greater in patients treated by frequent small dosage than in those treated by intermittent large dosage, though the dose level (mg/month) was similar in both groups. Hepatic fibrosis, sometimes preceding cirrhosis, seems to develop invariably if treatment with small frequent dosage is sufficiently prolonged. In the few circumstances in which this drug is indicated for psoriasis intermittent large dosage is the treatment regimen of choice.
Advanced Glycation End Products Stimulate an Enhanced Neutrophil Respiratory Burst Mediated Through the Activation of Cytosolic Phospholipase A <sub>2</sub> and Generation of Arachidonic Acid
Authors: Richard K.M. Wong, Andrew I. Pettit, Paulene A. Quinn, Sonja C. Jennings, Joan E. Davies, Leong L. Ng
Journal: Circulation (2003)

Background— Advanced glycation end products (AGEs) enhance NADPH oxidase, and hence respiratory burst activity, of stimulated neutrophils. They are thus potentially vasculopathic, especially in diabetes, uremia, and aging, in which AGEs classically accumulate. We investigated the underlying mechanisms. Methods and Results— Neutrophils prelabeled with [ 3 H]arachidonic acid display increased [ 3 H]arachidonate release on exposure to AGE-albumin over exposure to albumin alone (by 151±16%, P &lt;0.01). Arachidonic acid (AA) itself seems to mediate the AGE-augmented neutrophil respiratory burst (ascertained by chemiluminescence). Inhibitors of the cyclooxygenase pathway (indomethacin) and lipoxygenase pathway (MK-886) do not impair this AGE effect, excluding a contribution from AA metabolites. Cytosolic phospholipase A 2 (cPLA 2 ) controls AA generation. Its inhibition by methyl arachidonyl fluorophosphonate abrogates the AGE-enhanced activated neutrophil respiratory burst, and it is demonstrably stimulated in AGE-exposed neutrophils, as evidenced by isoform gel-shift and an increasingly membrane-translocated state in Western blots of neutrophil subfractions. Inhibition of other PLA 2 isoforms, secretory PLA 2 and calcium-independent PLA 2 , by manoalide and haloenol-lactone suicide substrate, respectively, does not affect this effect of AGEs relative to inhibitor-treated controls. The thiol antioxidant NAC reduces activation of cPLA 2 (assessed by isoform gel-shift and membrane translocation), production of AA in AGE-albumin–exposed neutrophils (H 3 release reduced to 104±17%, P =0.94 compared with albumin-exposed neutrophils), and the AGE-augmented neutrophil respiratory burst. Conclusions— AGE augmentation of the activated neutrophil respiratory burst requires AA generation, through which neutrophil NADPH oxidase may be upregulated, enhancing reactive oxygen species output. AA is generated by cPLA 2 , which may be stimulated through an AGE-activated redox-sensitive pathway.
Cell may lose 'killer instinct'
Authors: Phil Gunby
Journal: JAMA (1983)

Since discovery of the leukocyte subpopulation called "natural killer (NK) cells," researchers have been studying what these "lymphocytes that act like phagocytes" do. Now, Salt Lake City investigators have clues as to what may happen in the<i>absence</i>of NK cells. The team, from the University of Utah College of Medicine and Latter-Day Saints Hospital, assayed for NK cell activity in 16 patients with idiopathic, dilated (congestive) cardiomyopathy. This disorder, while not well understood, is believed to involve immunologic and viral factors. The activity of the patients' mononuclear lymphocytes was assayed with a cell line commonly used as a "target" for NK cells. Results showed that NK cell activity was virtually absent in eight of the 16 patients. When those eight patients were retested six months later, NK cell activity had returned to normal in one—the only one among the eight who had quickly recovered from the cardiomyopathy. This could
EG-17 * SUV420-MEDIATED HETEROCHROMATIN CHANGES IN PEDIATRIC BRAIN CANCERS
Authors: T. E. Van Meter, J. Terry, N. Rockwell, S. Goggin, P. Nethala, A. Khan
Journal: Neuro-Oncology (2014)

Silencing mechanisms play a role in genomic stability by maintaining condensed, non-active regions of the genome. SUV420 enzymes contain a SET domain conferring methyltransferase activity toward histones. The Histone H4 lysine 20 trimethylation (H4K20me3) mark maintained by SUV420H2 is associated with heterochromatin formation and gene silencing, whereas the dimethylated mark (H4K20me2) is associated with DNA repair. In studies of epigenetic factors in large patient cohorts with ependymoma, it was found that SUV420H2 expression was lost or diminished in patients with reciprocal increases in prognostic markers such as hTERT. To better understand the normal function of Suv4-20H1/H2 enzyme in neural progenitors, and pathological changes in cancers, a variety of differentiation paradigms were used. The NT2D1 neurally restricted cell line, and BGO1V and H9 human embryonic stem cells (ESCs), and differentiated progeny, were used alongside tumors to better understand enzyme targets and functional outcomes (e.g.,lineage, differentiation, regional chromatin modifications). Lineage stages were verified with stage-specific markers by immunofluorescence and qPCR. Suv4-20 H1 and H2 were present in ESCs and neural progenitors and decreased thereafter. RNAi knockdown of SUV420 enzymes led to decreased H4K20 methylation in cancer cells. DNA methylation microarrays and ChIP-PCR suggest 1) that SUV420 is not regulated by DNA methylation in ependymomas; 2) that active chromatin marks such as H3K4 dimethylation are enriched near the transcriptional start site in the SUV420H2 gene, and 3) that hTERT is hyper-methylated at specific CpG islands and histones in a tumor sub-group-specific manner. This data supports the hypothesis that Suv4-20H2 is highly active in progenitor cells and functionally lost in some brain cancers. These studies begin to elucidate coincident mechanisms of gene silencing active in neural progenitors that may be altered in a subset of pediatric brain cancers.
Concomitant alterations in intragastric pH and ascorbic acid concentration in patients with Helicobacter pylori gastritis and associated iron deficiency anaemia
Authors: B Annibale
Journal: Gut (2003)

Seroepidemiological and clinical studies suggest that Helicobacter pylori may cause iron deficiency anaemia (IDA) in the absence of peptic lesions by undefined mechanisms, which still remain to be fully elucidated. Gastric acidity and ascorbic acid (AA) promote iron absorption. AA is lowered in the presence of H pylori infection. H pylori can cause atrophic body gastritis with achlorhydria, decreased iron absorption, and consequent IDA. Whether alterations in intragastric acidity and AA concentrations play a role in IDA developing in patients with H pylori gastritis remains to be determined.To evaluate gastric juice pH and gastric juice and plasma AA in patients with H pylori infection and unexplained IDA, compared with controls with IDA and a healthy stomach or with controls with H pylori infection and no IDA.Patients with IDA and H pylori gastritis were characterised by concomitant increased intragastric pH (median value 7) and decreased intragastric AA (median value 4.4 micro g/ml) compared with controls with a healthy stomach (median pH 2; median intragastric AA 17.5 micro g/ml) and with H pylori positive controls without IDA (median pH 2.1; median intragastric AA 7.06 micro g/ml). Intragastric AA was inversely related to pH (r=-0.40, p=0.0059) and corporal degree of gastritis (r=-0.53, p=0.0039). Plasma AA concentrations were lower in all infected groups than in healthy controls.Patients with unexplained IDA and H pylori gastritis present concomitant changes in intragastric pH and AA that may justify impaired alimentary iron absorption and consequent IDA.
Nuclear factor high-mobility group box1 mediating the activation of toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice
Authors: Liang Li, Lei Chen, Liang Hu, Yuan Liu, Han-Yong Sun, Jing Tang, Yu-Jie Hou, Yan-Xin Chang, Qian-Qian Tu, Gen-Sheng Feng, Feng Shen, Meng-Chao Wu, Hong-Yang Wang
Journal: Hepatology (2011)

One of the challenges surrounding nonalcoholic fatty liver disease (NAFLD) is to discover the mechanisms that underlie the initiation of it. The aim of the present study was to elucidate the effects of Toll-like receptor 4 (TLR4) signaling in liver parenchymal cells during the early stage of NAFLD. Male TLR4-wildtype, TLR4-knockout, TLR2-knockout, MyD88-knockout, and TRIF-knockout mice were fed a normal diet or high-fat diet (HFD). Liver steatosis, alanine aminotransferase levels, nuclear translocation of nuclear factor kappa B (NF-κB) (p65), macrophage accumulation, and neutrophil infiltration were assessed. Using Kupffer cell depletion or bone marrow transplantation, we examined the potential role of Kupffer cells and myeloid infiltrating cells during the initiation of NAFLD. Immunohistochemistry and western blotting were implemented to determine the release of high-mobility group box1 (HMGB1). The neutral-antibody against HMGB1 was used to block the activity of free HMGB1. Here we report that the activation of TLR4 signaling in hepatocytes, accompanied with the relocation of P65 in nucleus, was proven to play an important role during the initiation of NAFLD. Importantly, HMGB1 releasing from hepatocytes in response to free fatty acid (FFA) infusion was first reported as the key molecule for the TLR4/MyD88 activation and cytokines expression in vitro and in vivo. Treatment with neutralizing antibody to HMGB1 protects against FFA-induced tumor necrosis factor alpha and interleukin-6 production.Our study supports the notion that TLR4/MyD88 signaling in liver parenchymal cells plays a pivotal role during the early progression of HFD-induced NAFLD, in which free HMGB1 served as a positive component mediating TLR4 activation.
Misstatements of the Antivivisectionists Again.
Authors: W. W. Keen
Journal: JAMA (1901)

San Francisco, July 8, 1901. On January 21, 1901, I sent a reply to James M. Brown, president of the American Humane Association, in response to. a letter from him challenging me to produce proof of inaccuracy in the references to a number of certain alleged experiments and of garbling of the reports of the same. My reply was published inThe Journalof the American Medical Association and the<i>Philadelphia Medical Journal</i>of Feb. 23, 1901. In reply I received a letter from Mr. Brown saying that he expected to spend the month of February in California, and could not give attention to my letter until his return. Mr. Brown seems to have been detained in California much longer than expected, for up to the present moment—nearly six months—I have received no further reply whatever. Indirectly, however, a certain reply has been published in the form of an anonymous
MMP16 Mediates a Proteolytic Switch to Promote Cell–Cell Adhesion, Collagen Alignment, and Lymphatic Invasion in Melanoma
Authors: Olga Tatti, Erika Gucciardo, Pirita Pekkonen, Tanja Holopainen, Riku Louhimo, Pauliina Repo, Pilvi Maliniemi, Jouko Lohi, Ville Rantanen, Sampsa Hautaniemi, Kari Alitalo, Annamari Ranki, Päivi M. Ojala, Jorma Keski-Oja, Kaisa Lehti
Journal: Cancer Research (2015)

Abstract Lymphatic invasion and accumulation of continuous collagen bundles around tumor cells are associated with poor melanoma prognosis, but the underlying mechanisms and molecular determinants have remained unclear. We show here that a copy-number gain or overexpression of the membrane-type matrix metalloproteinase MMP16 (MT3-MMP) is associated with poor clinical outcome, collagen bundle assembly around tumor cell nests, and lymphatic invasion. In cultured WM852 melanoma cells derived from human melanoma metastasis, silencing of MMP16 resulted in cell-surface accumulation of the MMP16 substrate MMP14 (MT1-MMP) as well as L1CAM cell adhesion molecule, identified here as a novel MMP16 substrate. When limiting the activities of these trans-membrane protein substrates toward pericellular collagen degradation, cell junction disassembly, and blood endothelial transmigration, MMP16 supported nodular-type growth of adhesive collagen-surrounded melanoma cell nests, coincidentally steering cell collectives into lymphatic vessels. These results uncover a novel mechanism in melanoma pathogenesis, whereby restricted collagen infiltration and limited mesenchymal invasion are unexpectedly associated with the properties of the most aggressive tumors, revealing MMP16 as a putative indicator of adverse melanoma prognosis. Cancer Res; 75(10); 2083–94. ©2015 AACR.
A WARNING AGAINST OPERATIONS FOR VARICOCELE ON APPLICANTS FOR ENLISTMENT, REGISTRANTS FOR THE SELECTIVE DRAFT, AND SOLDIERS
Authors: John Colt Bloodgood
Journal: JAMA (1918)

To the Editor:  —Until recently, varicocele disqualified for military service, and many applicants for enlistment in the Army and Navy and for admission to West Point and Annapolis subjected themselves voluntarily to this operation. Now that varicocele does not disqualify, officers and especially enlisted men who complain of discomfort in the groin and testicles during their physical training may be referred to the base hospitals in the various training camps and cantonments, and subjected to an unnecessary operation for varicocele.  The evidence against operation for varicocele, except in selected cases, is based on these facts: The majority of men suffering with this lesion show, after long observation, that the condition as a rule spontaneously disappears. Varicocele is observed most frequently after puberty and before the age of 21, and as a rule it disappears at about the age of 25, and, with few exceptions, before 30.  Those persons who have
In overweight or obese patients with atrial fibrillation, a weight reduction program reduced symptoms
Authors: D. George Wyse
Journal: Annals of Internal Medicine (2014)

Source Citation Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA. 2013;310:2050-60. 24240932
Mass immunization in the control of infectious disease.
Authors: D. Thomson
Journal: BMJ (1966)

In 1518, when the Royal College of Physicians was founded, plague was rife, and the resulting sense of emergency partly explains why a new organization of physicians was set up. Henry VIII often consulted the College, and in 1529, being excluded from London by a fresh outbreak, the King asked for advice on measures to be taken to control the infection.Arising from this the Privy Council instituted the registration of cases and issued Bills ôf Mortality.Dr. Gavin Milroy (1 805-86), the founder of these lectures, was keenly interested in the great infections of his time.This interest was roused by his experiences when Super- intendent Medical Inspector yph of the General Board of Health and on his several trips overseas.Notable among those
Induction and function of vascular adhesion protein-1 at sites of inflammation.
Authors: M Salmi, K Kalimo, S Jalkanen
Journal: The Journal of Experimental Medicine (1993)

Emigration of leukocytes from the blood into the tissues is critical in controlling lymphocyte patrolling in different lymphatic organs and in leukocyte accumulation at sites of inflammation. During the first stage of the extravasation process, leukocytes bind to the endothelial lining of vessels. At the molecular level, several adhesion molecules on leukocytes and endothelial cells function as receptor-ligand pairs in mediating this dynamic interaction. Recently, we have identified a novel human endothelial cell molecule, vascular adhesion protein 1 (VAP-1), that mediates lymphocyte binding (Salmi, M., and S. Jalkanen. 1992. Science [Wash. DC] 257:1407). VAP-1 was initially characterized by mAb 1B2 which inhibits lymphocyte adhesion to high endothelial venules (HEV) and to purified VAP-1 protein. Here we report the location and function of VAP-1 in normal and inflamed tissues in humans. VAP-1 is abundant in HEV of lymphatic organs belonging to the peripheral lymph node system, but considerably less is expressed in vessels of mucosa-associated lymphatic tissues. A subset of venules in most normal nonlymphatic tissues like skin, brain, kidney, liver, and heart is also VAP-1 positive. In addition to vessels, VAP-1 is distributed on a few other cell types, most notably in dendritic-like cells of germinal centers. At sites of inflammation, such as in inflammatory bowel diseases and chronic dermatoses, expression of VAP-1 is clearly increased. The induced VAP-1 is functional, since mAb 1B2 inhibits lymphocyte binding to inflamed lamina propria venules by approximately 60%. Thus VAP-1 is an endothelial adhesion molecule that under normal conditions is expressed mainly in HEV of lymphatic tissues. However, expression of functional VAP-1 in vivo is upregulated during an inflammatory reaction at other sites as well. Inducibility of VAP-1 suggests that it may play a significant role, not only in recirculation of lymphocytes, but also in controlling entry of leukocytes into sites of inflammation.
Mammography Screening in Women Under Age 50 Years
Authors: James C. Maher
Journal: JAMA (1988)

To the Editor.—  The importance of the recent article by Eddy et al 1 to health planners cannot be overestimated.  However, I believe their statistical conclusions are a little optimistic. From the data presented, 100 women in 10 000 will undergo breast biopsies due to false-positive results of mammography. Nowhere do I see calculated into the life expectancy any mortality from the thousands of biopsies or any cost estimation for the complications of biopsy, such as anesthesia complications, infection, or allergic reactions to antibiotic or analgesic medications. Certainly with so many procedures taking place, these human and economic costs will be substantial.  This article provides great food for thought for health planners who must decide where medical dollars can be expended best. I certainly hope that organizations such as the American Cancer Society take into account a cost-benefit analysis in making their recommendations. If not, the liability issues involved in
A second NHS trust turns to the army for help with staffing
Authors: C. Dyer
Journal: BMJ (2012)

A hospital trust that has been forced to close its accident and emergency department at night because of a shortage of middle grade doctors has asked the army whether it can provide doctors to help plug the gap temporarily.

Mid Yorkshire Hospitals NHS Trust is following the example of Mid Staffordshire Foundation NHS Trust, where two army doctors at consultant level and five nurses from the army and air force spent two months in the accident and emergency unit at Stafford Hospital from October to December last year ( BMJ 2011;343:d7566, doi:10.1136/bmj.d7566).

The Mid …
Adipokine resistin promotes in vitro angiogenesis of human endothelial cells
Authors: H MU, R OHASHI, S YAN, H CHAI, H YANG, P LIN, Q YAO, C CHEN
Journal: Cardiovascular Research (2006)

Resistin may be associated with obesity and cardiovascular diseases. However, it is unknown whether resistin directly contributes to angiogenesis. In the present study, we evaluated the effects of resistin on angiogenic potential, including endothelial cell proliferation, migration, and capillary-like tube formation.Human coronary artery endothelial cells (HCAECs) were treated with resistin. Cell proliferation was evaluated by [3H]thymidine incorporation and MTS assays. Cell migration was assessed by a modified Boyden chamber assay. Capillary-like tube formation was studied with a Matrigel model. Several gene expression levels were determined by real-time PCR. Activation of mitogen-activated protein kinases (MAPKs) was determined by Bio-Plex luminex analyzer. Basic fibroblast growth factor (bFGF) was used as a control. Human umbilical vein endothelial cells (HUVECs) and human lung microvascular endothelial cells (HMVEC-L) were also included.Resistin induced both endothelial proliferation and migration in a dose- and time-dependent manner with the maximal effect at 40 ng/ml. Both resistin-induced cell proliferation and migration could be effectively blocked by a resistin-neutralization antibody. In addition, resistin promoted capillary-like tube formation of HCAECs on Matrigel. Resistin also significantly upregulated the mRNA expression of vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2) and matrix metalloproteinases (MMP-1 and MMP-2) at both mRNA and protein levels. Furthermore, transient phosphorylation of ERK1/2 and p38 was observed after the addition of resistin to HCAECs. The resistin-induced cell proliferation and migration were both completely blocked by specific ERK1/2 and p38 inhibitors.Resistin induces human endothelial cell proliferation and migration, promotes capillary-like tube formation, upregulates the expression of VEGFRs and MMPs, and activates ERK1/2 and p38 pathways. Thus, resistin may play an important role in angiogenesis-associated vascular disorders.
Design of an improved set of oligonucleotide primers for genotyping MeCP2tm1.1BirdKO mice by PCR
Authors: Julie Miralvès, Eddy Magdeleine, Etienne Joly
Journal: Molecular Neurodegeneration (2007)

Abstract Background The strain of MeCP2 tm1.1Bird mice is a broadly used model for Rett syndrome. Because males carrying the invalidated MeCP2 locus are sterile, this strain has to be maintained in a heterozygous state. All animals therefore have to be genotyped at every generation to discriminate those carrying the invalidated allele (+/- females and y/- males) from those that do not. This is conveniently carried out by PCR on tail genomic DNA but because the primer pairs described initially for this purpose yield very similar size DNA bands on the WT and the KO alleles, this requires to carry out two independent PCR reactions on tail DNA preparations from all animals. Results After cloning and sequencing the PCR fragment amplified on the KO allele, we tested several sets of primers that were designed to yield PCR fragments of different sizes on the KO and WT alleles. Conclusion We have thus identified a set of three primers that allows for efficient genotyping of the animals by a single PCR reaction. Furthermore, using of this set of primers also resolves a recurrent problem related to the tendency of one of the initial primers to give rise to a non specific band because of its capacity to anneal at both ends of a repeated genomic element which we have identified as MurvyLTR.