tbuckley/cabot-search huggingface dataset:
Mechanisms of endotoxin-induced NO, IL-6, and TNF-α production in activated rat hepatic stellate cells: Role of p38 MAPK
Authors: Chinnasamy Thirunavukkarasu, Simon C. Watkins, Chandrashekhar R. Gandhi
Journal: Hepatology (2006)

Compelling experimental evidence indicates that the interactions between endotoxin and hepatic stellate cells (HSCs) can play a significant role in the pathogenesis of liver disease. Endotoxin-induced release of a multifunctional mediator NO (via inducible NO synthase) and the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin (IL)-6 by HSCs could be an important mechanism of pathological changes in the liver. However, the signaling mechanisms of these effects are poorly understood. In this study, we found that endotoxin causes activation of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated protein kinase [ERK] 1 and 2, p38, and c-Jun NH2-terminal kinase [JNK]) and nuclear factor κB (NF-κB) and production of H2O2 in culture-activated HSCs. However, only p38 and NF-κB were found to be responsible for the synthesis of NO, IL-6, and TNF-α. Exogenous H2O2 caused modest stimulation of TNF-α synthesis, did not affect the synthesis of NO or IL-6, and did not activate NF-κB or MAPKs. Inhibition of p38 and NF-κB activation by SB203580 and pyrrolidine dithiocarbamate, respectively, blocked endotoxin-induced H2O2, NO, TNF-α, and IL-6 synthesis. Inhibition of ERK1/2 and JNK phosphorylation did not alter these effects of endotoxin. Whereas SB203580 inhibited endotoxin-induced NF-κB activation, pyrrolidine dithiocarbamate did not affect p38 phosphorylation in endotoxin-stimulated cells. In conclusion , endotoxin-induced synthesis of NO, TNF-α, and IL-6 in HSCs is mediated by p38 and NF-κB, with involvement of H2O2 in TNF-α production. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Left ventricular pressure-volume relations shift to the left after long-term loss of pericardial restraint.
Authors: J D Hosenpud, N N Yung, M J Morton
Journal: Circulation (1983)

The short-term effect of pericardiectomy is to shift the in vivo left ventricular (LV) pressure-volume curve to the right. We studied nine weight-matched pairs of male guinea pigs 28 to 39 days (mean 35) after complete pericardiectomy or sham thoracotomy to determine the long-term effects of pericardiectomy on LV pressure-volume relations. Hemodynamic and in vitro LV pressure-volume data were collected in matched pairs on the same day, 2 to 3 hr after catheter placement and recovery from anesthesia. Cardiac output was measured by the microsphere reference sample method. Postsurgical weight gain was similar in both groups: 823 +/- 6 (mean +/- SD) to 925 +/- 6 g in the pericardiectomy group and 829 +/- 7 to 927 +/- 7 g in the sham thoracotomy group. We found no difference in LV weight: 1.555 +/- 0.145 g in the pericardiectomy group vs 1.564 +/- 0.148 g in the sham thoracotomy group, nor any difference in heart rate, mean arterial, right atrial, or left ventricular end-diastolic pressures, cardiac outputs, or stroke volumes (p = NS). LV pressure-volume relations, however, were shifted to the left in the pericardiectomy group (p less than .005). At 10 mm Hg, LV volume in the pericardiectomy group (0.85 +/- 0.22 cc) was less than that in the sham thoracotomy group (1.02 +/- 0.15 cc; p less than .025). The LV stress-elastic modulus relationship was not different between groups (p greater than .30). One month after pericardiectomy, LV pressure-volume relations in vitro were shifted to the left without a change in LV weight, LV elastic modulus, or hemodynamics. We speculate that this shift compensates for the lack of pericardial restraint and returns LV volume and hemodynamics to normal in vivo.
Lifestyle factors including less cutaneous sun exposure contribute to starkly lower vitamin D levels in U.K. South Asians compared with the white population
Authors: R. Kift, J.L. Berry, A. Vail, M.T. Durkin, L.E. Rhodes, A.R. Webb
Journal: British Journal of Dermatology (2013)

Long-standing concerns over the vitamin D status of South Asian adults in the U.K. require studies using statistically valid sample sizes to measure annual variation and contributory lifestyle factors.To measure annual variation in the vitamin D status of U.K. South Asians, to determine the associated lifestyle influences, and to compare these with a similar study of white adults.A single-centre, prospective cohort study measuring circulating 25-hydroxyvitamin D [25(OH)D], sunlight exposure levels and lifestyle factors for 1 year in 125 ambulant South Asian adults with sun-reactive skin type V, aged 20-60 years, in Greater Manchester, U.K. (53·5°N).The 25(OH)D levels of South Asians were alarmingly low. In summer, their median 25(OH)D level was 9·0 ng mL(-1) , [interquartile range (IQR) 6·7-13·1], falling to 5·8 ng mL(-1) (IQR 4·0-8·1) in winter. This compared with values in the white population of 26·2 ng mL(-1) (IQR 19·9-31·5) in summer and 18·9 ng mL(-1) IQR (11·6-23·7) in winter. Median daily dietary vitamin D was lower in South Asians (1·32 μg vs. 3·26 μg for white subjects) and was compounded by low supplement use. Despite similar times spent outdoors, ultraviolet (UV) dosimeters recorded lower personal UV exposure among South Asians, indicating sun avoidance when outside, while sun exposure diaries recorded lower amounts of skin surface exposure.The majority of South Asians never reached sufficiency in vitamin D status. Lifestyle differences, with lower oral intake, sun exposure and rates of cutaneous production due to darker skin, indicate that standard advice on obtaining sufficient vitamin D needs modification for the South Asian community in the U.K.
Hugh Sutherland Dodd
Authors: R. Firth, J. Doran
Journal: BMJ (2009)

At the age of 16, Hugh Sutherland Dodd won a scholarship to Magdalen College, Oxford, to read Classics. Completing national service, he went up to Oxford but his studies were interrupted by the death of his father. On returning to Oxford he made the difficult transition to medicine. He gained his second …
Idiopathic Short Stature
Authors: Mary M. Lee
Journal: New England Journal of Medicine (2006)

A healthy, active 12-year-old boy is in the first percentile for height (133.0 cm [52.4 in.]; −2.25 SD) and the third percentile for weight (29 kg [64 lb]). His physical examination is unremarkable, with normal proportions and no signs of puberty. His bone age is 10 years. His midparental height is 164.5 cm (64.8 in.), and his predicted height is 163.8 cm (64.5 in.). Is growth hormone therapy indicated?
The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans.
Authors: D J Rader, W A Mann, W Cain, H G Kraft, D Usher, L A Zech, J M Hoeg, J Davignon, P Lupien, M Grossman
Journal: Journal of Clinical Investigation (1995)

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein which is similar in structure to low density lipoproteins (LDL). The role of the LDL receptor in the catabolism of Lp(a) has been controversial. We therefore investigated the in vivo catabolism of Lp(a) and LDL in five unrelated patients with homozygous familial hypercholesterolemia (FH) who have little or no LDL receptor activity. Purified 125I-Lp(a) and 131I-LDL were simultaneously injected into the homozygous FH patients, their heterozygous FH parents when available, and control subjects. The disappearance of plasma radioactivity was followed over time. As expected, the fractional catabolic rates (FCR) of 131I-LDL were markedly decreased in the homozygous FH patients (mean LDL FCR 0.190 d-1) and somewhat decreased in the heterozygous FH parents (mean LDL FCR 0.294 d-1) compared with controls (mean LDL FCR 0.401 d-1). In contrast, the catabolism of 125I-Lp(a) was not significantly different in the homozygous FH patients (mean FCR 0.251 d-1), heterozygous FH parents (mean FCR 0.254 d-1), and control subjects (mean FCR 0.287 d-1). In summary, absence of a functional LDL receptor does not result in delayed catabolism of Lp(a), indicating that the LDL receptor is not a physiologically important route of Lp(a) catabolism in humans.
India lifts controls on drug prices
Authors: G Nandan
Journal: BMJ (1994)

India will lift price controls on half of its drugs and allow foreign pharmaceutical firms to enter the country more easily under a new drug policy announced last week. The 1994 drug policy, part of India's three year programme of economic liberalisation, reduces the number of drugs under price control from 142 to 73.

The government has also decided to give “automatic approval” to foreign technology agreements on all products except those produced by recombinant DNA technology.

The policy has evoked a largely positive reaction from sections of the pharmaceutical industry that regard it as a major step towards deregulating …
The number needed not to treat
Authors: D. Spence
Journal: BMJ (2011)

After finishing training for general practice I applied for an academic position for a year. I wrote a proposal on an observation I had made, that individual doctors generate much of their own workload. But as we say in Glasgow, “What’s for you won’t go by you,” and I wasn’t interviewed. My observation still holds true, however.

Doctors are aware of the NNT (number needed to treat), the number of patients who need to be treated for one to benefit from the intervention. (Remember that the NNT may be for …
How Far Does the Proctosigmoidoscope Reach?
Authors: Santhat Nivatvongs, David S. Fryd
Journal: New England Journal of Medicine (1980)

FEW studies have been undertaken to determine how far the proctosigmoidoscope can be inserted.1 2 3 Many practitioners erroneously believe that proctosigmoidoscopy is successful only if the proctosigmoidoscope is inserted to its maximum, standard length of 25 cm. An attempt to insert the entire instrument often causes substantial pain and discomfort to the patients.We evaluated the depth of insertion of the proctosigmoidoscope in 1000 patients, when the rectal wall was not stretched and the patients were not caused pain. We found that the average possible depth of insertion was greater in male than in female patients; that in young men 16 . . .
Does Race Predispose to Angiotensin-Associated Angioneurotic Edema?
Authors: Nancy J. Brown
Journal: Annals of Internal Medicine (1993)

Letters15 December 1993Does Race Predispose to Angiotensin-Associated Angioneurotic Edema?Nancy J. Brown, MD and John H. Nadeau, MDNancy J. Brown, MDSearch for more papers by this author and John H. Nadeau, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-119-12-199312150-00020 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Since the report by Wilkin and colleagues [1] of angioneurotic edema in two patients receiving captopril, many other cases associated with angiotensin- onverting enzyme (ACE) inhibitor therapy have been recognized; the incidence has been estimated to be 0.1% to 0.2% [2]. We have recently observed a higher-than-expected incidence in black patients. We examined the literature on ACE inhibitor-associated angioneurotic edema to determine whether others had noted such a trend. We reviewed 38 articles reporting cases of ACE inhibitor-associated angioneurotic edema since 1980. In 18 articles, patient race was reported for at least one case. Fifty-two of 67 ...References1. Wilkin JK, Hammond JL, Kirkendall WM. The captopril-induced eruption. Arch Dermatol. 1980; 116:902-5. Google Scholar2. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. Ann Intern Med. 1992; 117:234-42. Google Scholar3. Cooper WD, Sheldon D, Brown D, Kimber GR, Isitt VL, Currie WJ. Post-marketing surveillance of enalapril:experience in 11,710 hypertensive patients in general practice. J R Coll Gen Pract. 1987; 37: 346-9. Google Scholar4. Cameron HA, Higgins TJ. Clinical exposure with lisinopril. Observations on safety and tolerability. J Hum Hypertens. 1989; 3:177-86. Google Scholar Author, Article, and Disclosure InformationAuthors: Nancy J. Brown, MD; John H. Nadeau, MD PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAngiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factorsEthnicity and adverse drug reactionsACE Inhibitor—Versus Angiotensin II Blocker–Induced Cough and AngioedemaPathologyAngiotensin-converting enzyme (ACE) inhibitors and angio-oedemaAngiotensin–converting enzyme (ACE) inhibitors and angio–oedemaHigher incidence of discontinuation of angiotensin converting enzyme inhibitors due to cough in black subjectsBlack Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema*Adverse Effects of the Angiotensin-Converting Enzyme InhibitorsThe incidence of ACE inhibitor-associated angioneurotic oedema 15 December 1993Volume 119, Issue 12Page: 1224KeywordsACE inhibitor therapyACE inhibitorsAngiotensin converting enzymeEdemaEnzymesHispanic peopleRacial and ethnic issues ePublished: 15 August 2000 Issue Published: 15 December 1993 Copyright & PermissionsCopyright © 1993 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Toward a major risk factor for atopic eczema: Meta-analysis of filaggrin polymorphism data
Authors: Hansjörg Baurecht, Alan D. Irvine, Natalija Novak, Thomas Illig, Bettina Bühler, Johannes Ring, Stefan Wagenpfeil, Stephan Weidinger
Journal: Journal of Allergy and Clinical Immunology (2007)
Support Patterns from Different Outgroups Provide a Strong Phylogenetic Signal
Authors: A. Schneider, G. M. Cannarozzi
Journal: Molecular Biology and Evolution (2009)

It is known that the accuracy of phylogenetic reconstruction decreases when more distant outgroups are used. We quantify this phenomenon with a novel scoring method, the outgroup score pOG. This score expresses if the support for a particular branch of a tree decreases with increasingly distant outgroups. Large-scale simulations confirmed that the outgroup support follows this expectation and that the pOG score captures this pattern. The score often identifies the correct topology even when the primary reconstruction methods fail, particularly in the presence of model violations. In simulations of problematic phylogenetic scenarios such as rate variation among lineages (which can lead to long-branch attraction artifacts) and quartet-based reconstruction, the pOG analysis outperformed the primary reconstruction methods. Because the pOG method does not make any assumptions about the evolutionary model (besides the decreasing support from increasingly distant outgroups), it can detect cases of violations not treated by a specific model or too strong to be fully corrected. When used as an optimization criterion in the construction of a tree of 23 mammals, the outgroup signal confirmed many well-accepted mammalian orders and superorders. It supports Atlantogenata, a clade of Afrotheria and Xenarthra, and suggests an Artiodactyla-Chiroptera clade.
Abstract 341: Imatinib induces expression of Bim and apoptosis in chronic myelogenous leukemia cells via p38/H2AX pathway
Authors: Min Xiong, Tianhui Niu, Yaqiong Dong, Chengrong Lu
Journal: Cancer Research (2014)

Abstract H2AX is a novel human tumor suppressor protein and plays an important role in apoptosis of cancer cells. Increasing published data indicate that H2AX phosphorylation (Ser139) contributes to its regulation of cancer cell apoptosis. Thus, charactering the mechanisms and signaling pathways involved in H2AX phosphorylation (Ser139) will certainly provide better understanding on H2AX function in cancer cells. Our previous report showed that caspase-3/Mst1 pathway regulates phosphorylation of H2AX at Ser139 in chronic myelogenous leukemia (CML) cells. Recently we found another pathway which regulates H2AX phosphorylation (Ser139) in CML cells. When the CML cells were subjected to imatinib treatment, MAPK family member ERK1/2 activity was inhibited, but p38 activity was increased, another member JNK1/2 had no response. Then we used p38 inhibitor SB202190 and siRNA against p38 to block p38 activation and observed that H2AX phosphorylation and apoptosis of CML cells was concurrently inhibited. Our results also showed that inhibition of MSK1/MSK2 did not affect H2AX phosphorylation (Ser139), although the p38 and ERK1/2 downstream MSK1/MSK2 could be activated by imatinib in CML cells. Overall, these data confirmed that p38 signaling pathway is also required for H2AX phosphorylation (Ser139) in CML cells. Our further evidences indicated that inhibition of H2AX phosphorylation (Ser139) regulated by p38 during apoptotic induction with imatinib suppressed the expression of apoptosis-related gene Bim. Taken together, these data demonstrated that p38/H2AX pathway regulates Bim expression and subsequent apoptosis in CML cells. Citation Format: Min Xiong, Tianhui Niu, Yaqiong Dong, Chengrong Lu. Imatinib induces expression of Bim and apoptosis in chronic myelogenous leukemia cells via p38/H2AX pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 341. doi:10.1158/1538-7445.AM2014-341
Globin Lentiviral Vector Insertions Can Perturb the Expression of Endogenous Genes in β-thalassemic Hematopoietic Cells
Authors: Phillip W Hargrove, Steven Kepes, Hideki Hanawa, John C Obenauer, Deiqing Pei, Cheng Cheng, John T Gray, Geoffrey Neale, Derek A Persons
Journal: Molecular Therapy (2008)

Although hematopoietic cell gene therapy using retroviral vectors has recently achieved success in clinical trials, safety issues regarding vector insertional mutagenesis have emerged. Vector insertion, resulting in transcriptional activation of proto-oncogenes, played a role in the development of lymphoid leukemia in an X-linked severe combined immunodeficiency trial, and caused myeloid clonal dominance in a trial for chronic granulomatous disease. These events have raised the question of whether gene therapy for other disorders such as β-thalassemia and sickle cell disease may hold a similar risk. In this study, we prospectively evaluated whether γ-globin lentiviral vectors containing enhancer elements from the β-globin locus control region could alter the expression of genes near the vector insertion. We studied this question in primary, clonal murine β-thalassemic erythroid cells, where globin regulatory elements are highly active. We found an overall incidence of perturbed expression in 28% of the transduced clones, with 11% of all genes contained within a 600-kilobase region surrounding the vector-insertion site demonstrating altered expression. This rate was higher than that observed for a lentiviral vector containing a viral long-terminal repeat (LTR). This is the first direct evidence that lentiviral vectors can cause insertional dysregulation of cellular genes at a frequent rate. Although hematopoietic cell gene therapy using retroviral vectors has recently achieved success in clinical trials, safety issues regarding vector insertional mutagenesis have emerged. Vector insertion, resulting in transcriptional activation of proto-oncogenes, played a role in the development of lymphoid leukemia in an X-linked severe combined immunodeficiency trial, and caused myeloid clonal dominance in a trial for chronic granulomatous disease. These events have raised the question of whether gene therapy for other disorders such as β-thalassemia and sickle cell disease may hold a similar risk. In this study, we prospectively evaluated whether γ-globin lentiviral vectors containing enhancer elements from the β-globin locus control region could alter the expression of genes near the vector insertion. We studied this question in primary, clonal murine β-thalassemic erythroid cells, where globin regulatory elements are highly active. We found an overall incidence of perturbed expression in 28% of the transduced clones, with 11% of all genes contained within a 600-kilobase region surrounding the vector-insertion site demonstrating altered expression. This rate was higher than that observed for a lentiviral vector containing a viral long-terminal repeat (LTR). This is the first direct evidence that lentiviral vectors can cause insertional dysregulation of cellular genes at a frequent rate.
Regulation of Obesity-Related Insulin Resistance with Gut Anti-inflammatory Agents
Authors: Helen Luck, Sue Tsai, Jason Chung, Xavier Clemente-Casares, Magar Ghazarian, Xavier S. Revelo, Helena Lei, Cynthia T. Luk, Sally Yu Shi, Anuradha Surendra, Julia K. Copeland, Jennifer Ahn, David Prescott, Brittany A. Rasmussen, Melissa Hui Yen Chng, Edgar G. Engleman, Stephen E. Girardin, Tony K.T. Lam, Kenneth Croitoru, Shannon Dunn, Dana J. Philpott, David S. Guttman, Minna Woo, Shawn Winer, Daniel A. Winer
Journal: Cell Metabolism (2015)
A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease
Authors: Davide Bagnara, Matthew S. Kaufman, Carlo Calissano, Sonia Marsilio, Piers E. M. Patten, Rita Simone, Philip Chum, Xiao-Jie Yan, Steven L. Allen, Jonathan E. Kolitz, Sivasubramanian Baskar, Christoph Rader, Hakan Mellstedt, Hodjattallah Rabbani, Annette Lee, Peter K. Gregersen, Kanti R. Rai, Nicholas Chiorazzi
Journal: Blood (2011)
Mental disorders in children conceived after fertility treatment
Authors: M. Davies
Journal: BMJ (2013)

High quality follow-up studies are needed of specific treatments and outcomes 

With more than 5 million people born after assisted reproductive technologies (ART) the transition from experimental to routine treatment is well under way. However, with innovation continuing apace, the consequences for the resulting offspring are still not fully understood.

Many outcomes related to growth and development take years to appear. Studies have reported an increased risk of structural abnormalities in babies born after these technologies\_ENREF\_2,1 2 3 but the full range of developmental milestones and capacities needs to be investigated. Some jurisdictions require that outcomes of ART treatments are reported to centralised government registries, but outcomes are confined to events in pregnancy and possibly shortly thereafter. Population registries, and their linkage, are therefore an invaluable resource of reliable, robust measures of association between ART exposures and longer term disease outcomes. Two recently published studies have moved beyond considering structural anomalies and have examined mental disorders in children born after ART treatment using linked registries.4 5

The recent BMJ study from Denmark by Bay and colleagues used national registries to link numerous infertility treatments to cognitive …
James Ramsay Philp
Authors: E. Philp, A. Dillon
Journal: BMJ (2009)

James Ramsay Philp graduated from Beath High School as school captain and vice captain of cricket in 1954. As an undergraduate, he was a Thomas Cowan scholar and was awarded the Jamieson prize in anatomy and the Gunning Victoria jubilee prize in bacteriology. He was house officer at Edinburgh Royal Infirmary during 1961-2 and was appointed lecturer in bacteriology at Edinburgh University in 1962-3. He moved to Aberdeen in1964 as a research fellow in radiobiology and was awarded an MD with commendation for research into treating thyrotoxicosis with ionising radiation. This work demonstrated the intrinsic impossibility of achieving a chronologically predictable radiation partial thyroidectomy and led logically to the establishment, for the first time, of a computer based register for the lifelong follow up of all patients treated with radioiodine (and later surgery) for hyperthyroidism. This register was later expanded to include all such …