tbuckley/cabot-search huggingface dataset:
Subcellular site of superoxide dismutase expression differentially controls AP-1 activity and injury in mouse liver following ischemia/reperfusion
Authors: Weihong Zhou, Yulong Zhang, Micaela S. Hosch, Amie Lang, Ralf M. Zwacka, John F. Engelhardt
Journal: Hepatology (2001)

Acute damage following ischemia and reperfusion (I/R) in the liver is in part caused by the generation of reactive oxygen species, such as superoxides, during the reperfusion event. Gene therapy directed at attenuating mitochondrial superoxide production following warm I/R injury in the liver has demonstrated great promise in reducing acute hepatocellular damage. In the present study, we have compared the therapeutic effects of ectopic expression of mitochondrial (MnSOD) and cytoplasmic (Cu/ZnSOD) superoxide dismutase using recombinant adenoviral vectors for reducing I/R damage in the liver. Consistent with previous observations, recombinant adenoviral delivery of MnSOD to the liver significantly attenuated both acute liver damage and AP–1 activation following I/R injury to the livers of mice. However, ectopic expression of Cu/ZnSOD diminished neither I/R–induced elevations in serum alanine transaminase (ALT) nor AP–1 activation. Interestingly, baseline activation of AP–1 before I/R–induced injury was seen in livers infected with recombinant Ad.Cu/ZnSOD, but not Ad.MnSOD or Ad.LacZ, vectors. The level of Cu/ZnSOD–induced AP–1 activation was significantly reduced by ablation of Kupffer cells or by coexpression of catalase, suggesting that increased H 2 O 2 production facilitated by Cu/ZnSOD in hepatocytes and/or Kupffer cells may be responsible for AP–1 activation. In vitro reconstitution studies using hepatocyte and macrophage cell lines demonstrated that Cu/ZnSOD overexpression induces AP–1 in both cell types, and that secretion of a Cu/ZnSOD–induced macrophage factor is capable of elevating AP–1 in hepatocytes. In summary, our findings demonstrate that subcellular sites of superoxide production in the liver can differentially affect the outcome of I/R injury in the liver and selectively influence AP–1 activation.
Renal Vein Ligation
Authors: Dominic A. DeLaurentis
Journal: JAMA (1970)

<h3>To the Editor.—</h3> Certain comments should be made concerning the case report by E. R. Jennings, MD, and M. A. Glucksman, MD, in the recent LETTERS section ofThe Journal(<b>213</b>:1905, 1970). <i>Left</i>renal vein division and ligation has been done with no serious consequences for portal renal shunts,<sup>1-3</sup>splenorenal shunts,<sup>4</sup>and as an aid in abdominal aortic surgery.<sup>5</sup>Anatomically, this is possible because the left renal vein, in contradistinction to the right renal vein, has a number of tributaries through which collateral venous drainage is possible. The inferior phrenic and suprarenal tributaries enter from above; from below, and to the side come gonadal (spermatic and ovarian), capsular, lumbar, and ascending lumbar veins. Also communication is made with the azygos and hemiazygos veins (usually through the lumbars) and with the extensive set of internal and external vertebral plexuses by way of the intervertebral and lumbar veins.
Sub-minimal inhibitory concentrations of cefmetazole enhance serum bactericidal activity in vitro by amplifying poly-C9 deposition.
Authors: J E Schweinle, M Nishiyasu
Journal: Journal of Clinical Investigation (1992)

Serum-resistant organisms grown in sub-minimal inhibitory concentrations (subMICs) of antibiotics in vitro may be rendered sensitive to complement-mediated, serum bactericidal activity. We measured 125I-C3 and 125I-C9 deposition on genetically serum resistant Salmonella montevideo SH5770 (SH5770) that was rendered serum sensitive by growth in sub-MICs of cefmetazole (CMZ), a parenteral, second generation, cephamycin-group antibiotic. Three times as much C3 and over six times as much C9 bound to SH5770 grown in one-fourth the MIC of CMZ compared to broth-grown bacteria. SDS-PAGE analysis and autoradiography showed that neither the ratio of C3b:iC3b (approximately 1:2.5) nor the nature of the C3-bacterial bond was changed by growing the organisms in CMZ. Large amounts of complement membrane attack complexes containing poly-C9 were seen only on CMZ-grown SH5770 by SDS-PAGE and autoradiography. Poly-C9 was also detected only on CMZ-grown bacteria by indirect immunofluorescence and ELISA using a murine monoclonal antibody directed against a neoantigen of poly-C9. Bacterial hydrophobicity increased after growth in CMZ, and transmission electron micrographs of CMZ-grown SH5770 showed cell wall disruption and blebbing. These results indicate that growth in subMICs of CMZ increases bacterial hydrophobic domains available for interacting with the membrane attack complex, C5b-9, allowing formation and stable insertion of bactericidal complexes containing poly-C9.
15 LANDSCAPE OF SOMATIC MUTATION IN HEPATOCELLULAR CARCINOMA
Authors: C. Guichard, S. Imbeaud, G. Amaddeo, I. Ben Maad, E. Letouze, L. Pelletier, M. Letexier, P. Bioulac-Sage, J. Calderaro, J. Zucman-Rossi
Journal: Journal of Hepatology (2012)
Fatty Acid Composition of Serum Lipid Fractions in Type 2 Diabetic Patients With Microalbuminuria
Authors: Magda S. Perassolo, Jussara C. Almeida, Ronivan L. Prá, Vanessa D. Mello, Ana L. Maia, Cileide C. Moulin, Joíza L. Camargo, Themis Zelmanovitz, Mirela J. Azevedo, Jorge L. Gross
Journal: Diabetes Care (2003)

OBJECTIVE—To determine the fatty acid composition of serum phospholipid, triglyceride, and cholesterol ester fractions and to analyze the lipid profile of microalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A case-control study was conducted with 72 patients: 37 were normoalbuminuric (urinary albumin excretion rate [UAER] &amp;lt;20 μg/min), and 35 were microalbuminuric (UAER 20–200 μg/min). After 4 weeks of a standardized diet, the fatty acid composition of phospholipid, triglyceride, and cholesterol ester fractions was determined by gas chromatography. Total cholesterol and triglycerides were measured by enzymatic-colorimetric methods; cholesterol HDL by double precipitation with heparin, MnCl2, and dextran sulfate; and apolipoprotein B by immunoturbidimetry. RESULTS—Microalbuminuric patients showed a lower proportion of polyunsaturated fatty acids (24.8 ± 11.0%), especially of the n-6 family (21.7 ± 10.5%), in triglyceride fraction than normoalbuminuric patients (34.1 ± 11.3%, P = 0.001 and 31.4 ± 11.5%, P &amp;lt; 0.001, respectively). Patients with microalbuminuria also presented higher levels of saturated fatty acids in triglyceride fraction (43.4 ± 18.0% vs. 34.7 ± 13.1%, P = 0.022). In the logistic regression analysis, only the proportion of polyunsaturated fatty acids in triglyceride fraction remained significantly associated with microalbuminuria (odds ratio [OR] 0.92, 95% CI 0.85–0.98, P = 0.019). Total cholesterol, HDL cholesterol, triglyceride, and apolipoprotein B levels were similar in normo- and microalbuminuric patients. CONCLUSION—Microalbuminuria in type 2 diabetic patients is associated with low polyunsaturated fatty acid contents in serum triglyceride fraction. This association may represent a risk factor for cardiovascular disease and may contribute to the progression of renal disease.
Referrals to hospital by general practitioners: a study of compliance and communication.
Authors: K. J. McGlade, T. Bradley, G. J. Murphy, G. P. Lundy
Journal: BMJ (1988)

To determine the extent of non-attendance at first hospital appointments 269 hospital referrals made in one practice over 14 weeks were analysed retrospectively. Non-attendance was more likely among patients referred to outpatient departments than to casualty or for admission. Fifteen per cent (41/269) of all patients and 20% (33/167) of outpatients failed to keep their initial appointments. Prolonged waiting times from referral to appointment were significantly related to non-attendance. Twenty weeks after the last referral had been made no communication had been received by the practice for 24% (61/252) of all referral letters received by the hospital. Minimum delays to appointments and improved communication between hospitals and general practitioners would help general practitioners to make appropriate referrals and improve compliance.
RAS Blockade for Every Diabetic Patient: Pro and Con
Authors: Luis M. Ruilope, Anna Solini
Journal: Diabetes Care (2011)

The first part of this manuscript offers an overview of clinical data supporting the use of renin-angiotensin system (RAS) inhibitors in every patient with type 1 or type 2 diabetes, based on the known role of the RAS in blood pressure regulation and organ protection. In the second part, a possible, relevant role of drugs other than RAS-active compounds in treating hypertension and preventing cardiovascular disease in type 2 diabetic patients is underlined, paying particular attention to calcium-channel blockers, either alone or, better, in combination with ACE inhibitors.

The guidelines of the European Society of Hypertension and the European Society of Cardiology recognize that the first monotherapy to be given to a diabetic patient with elevated blood pressure is an RAS suppressor, either an ACE inhibitor or an angiotensin receptor blocker (ARB) when micro- or macroalbuminuria are present (1). They also recognize that in order to lower blood pressure, all effective and well tolerated drugs can be used. Having admitted the possibility of non-RAS suppression therapies as first line, the guidelines continue by saying that the great majority of diabetic patients will sooner or later present hypertension and that most of them will require combination therapy. In this case, they specify that a blocker of the RAS should be a regular component of the combination and the one preferred when monotherapy is sufficient. In summary, an RAS blocker should be used when an elevation of blood pressure, even within the high normal range, is detected.

The recent reappraisal of European Society of Hypertension Guidelines (2) confirms that initiation of therapy in the high normal range is reserved for diabetic patients with some degree of target organ damage (TOD), in particular microalbuminuria.

Are the guidelines wrong? Probably not, because RAS suppression has three different aspects:

1.  Capacity to control blood pressure alone …
A CASE ILLUSTRATING PLASTIC SURGERY OF THE EYELIDS.
Authors: CASSIUS D. WESCOTT
Journal: JAMA (1902)

During my service at the Presbyterian Hospital in the summer of 1900, Miss Sarah McB., aged 38, presented herself for the correction of deformities of the eyelids resulting from burns, which she had received six months before by falling into a grate fire in a fainting fit. As shown in photograph No. 1, the soft parts had suffered severely on both sides of her face, a portion of the right wing of the nose had been lost, and there was complete ectropion of the upper lid of the right eye and almost complete eversion of the lower lid of the left eye. The brow just over the nose was so deeply burned that a portion of the external surface of the frontal bone had necrosed and come away during the dressing of the burns. The new skin which had formed in this region and over the right eye was extremely
Abstract IA5: Epigenetic genome control by heterochromatin machinery and non-coding RNAs
Authors: Shiv Grewal
Journal: Cancer Research (2012)

Abstract Heterochromatin assembly involving posttranslational modifications of histones is critical for various chromosomal processes including the regulation of gene expression and the maintenance of genomic integrity. Defective heterochromatin formation has been linked to cancer. Our previous work has shown that non-coding RNAs and the RNAi machinery, involved in the processing of non-coding RNAs, play prominent roles in the assembly of heterochromatin structures. Indeed, the loss of factors involved in RNAi such as Argonaute, Dicer and RNA-dependent RNA polymerase cause severe defects in centromeric heterochromatin formation, leading to missegregation of chromosomes during cell division. An Argonaute-containing RNAi effector complex named RITS has been identified that facilitates the loading of a conserved histone methyltransferase Clr4/Suv39h, which is essential for heterochromatin assembly. We have recently discovered an unexpected role for heterochromatin factors in the RNA quality control. Heterochromatin factors localize broadly across the genome and collaborate with RNAi machinery to suppress potentially deleterious RNAs, the uncontrolled accumulation of which can cause DNA damage and modify epigenetic genomic profiles. I will present our recent findings showing that non-coding RNAs and heterochromatin play important roles in dynamic regulation of genomes, which has important implications for human health and disease. Citation Format: Shiv Grewal. Epigenetic genome control by heterochromatin machinery and non-coding RNAs [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA5.
Gonadotropin-Releasing Hormone Agonists for Endometriosis
Authors: David L. Olive
Journal: New England Journal of Medicine (2008)

A 36-year-old woman with a presumptive diagnosis of endometriosis presents with long-standing pelvic pain that is not relieved by means of oral contraceptives or medroxyprogesterone. Treatment with a gonadotropin-releasing hormone agonist is recommended. Gonadotropin-releasing hormone agonists profoundly suppress gonadotropin secretion and sex-steroid production. Side effects include loss of bone mineral density and memory impairment.
Doctors win South African registration battle
Authors: P. Sidley
Journal: BMJ (1998)

A group of doctors born and trained outside South Africa have won their High Court case against the South African Medical and Dental Council to have limitations on their registration as doctors scrapped so that they may go into private practice.

The case arose out of the fact that foreign born and trained doctors from several countries (excluding the British Isles and Belgium) do not have their qualifications recognised automatically by the council (29 August, p 557). These doctors can work only …
The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells
Authors: Jens Voortman, Agnieszka Chęcińska, Giuseppe Giaccone
Journal: Molecular Cancer (2007)

Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms.
Pilot scheme shows that giving naloxone to families of drug users would save lives
Authors: R. Hurley
Journal: BMJ (2011)

A1 BMJ

A pilot scheme has shown that providing family and friends with training and the drug naloxone seems to reduce deaths from overdose among heroin users and other opioids misusers, says the English National Treatment Agency for Substance Misuse, a special health authority of the NHS.

During the pilot scheme 20 users overdosed, and carers gave naloxone to 18. All the users survived. Family members, partners, or other drug users are often first to find a user who has overdosed.

“If they can be trained in how to manage such an emergency and keep the victim alive while waiting for the ambulance, potentially hundreds of lives could be saved in the UK every …
Book Review Teaching Medical Professionalism Edited by Richard L. Cruess, Sylvia R. Cruess, and Yvonne Steinert. 310 pp., illustrated. New York, Cambridge University Press, 2009. $90 (cloth); $49 (paper). 978-0-521-88104-3 (cloth); 978-0-521-70742-8 (paper).
Authors: Kayhan Parsi
Journal: New England Journal of Medicine (2009)
Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection
Authors: Christine I Wooddell, David B Rozema, Markus Hossbach, Matthias John, Holly L Hamilton, Qili Chu, Julia O Hegge, Jason J Klein, Darren H Wakefield, Claudia E Oropeza, Jochen Deckert, Ingo Roehl, Kerstin Jahn-Hofmann, Philipp Hadwiger, Hans-Peter Vornlocher, Alan McLachlan, David L Lewis
Journal: Molecular Therapy (2013)

RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible to knock down expression of viral RNAs including the pregenomic RNA from which the replicative intermediates are derived, thus reducing viral load, and the viral proteins that result in disease and impact the immune system's ability to eliminate the virus. We previously described the use of polymer-based Dynamic PolyConjugate (DPC) for the targeted delivery of siRNAs to hepatocytes. Here, we first show in proof-of-concept studies that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine-conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol-conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, we show that a single coinjection of NAG-MLP with potent chol-siRNAs targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. These results suggest that coinjection of NAG-MLP and chol-siHBVs holds great promise as a new therapeutic for patients chronically infected with HBV.
Reasons for striking off paediatric gastroenterologist may have been "inadequate," GMC admits
Authors: C. Dyer
Journal: BMJ (2012)

The General Medical Council has admitted at the High Court that its reasons for finding the paediatric gastroenterologisto John Walker-Smith guilty of serious professional misconduct over a Lancet paper that sparked a worldwide scare over the measles, mumps, and rubella (MMR) vaccine may have been “inadequate.”

But the GMC’s counsel, Joanna Glynn QC, told Mr Justice Mitting on the fourth day of a five day hearing: “In spite of inadequate reasons, it is quite clear on overwhelming evidence that the charges are made out.”

The judge, who is hearing Professor Walker-Smith’s appeal against the …
AN UNUSUAL CASE OF PERFORATED DUODENAL ULCER
Authors: Harry L. Schurmeier
Journal: JAMA (1924)

The unusual features of this case were the type and radiation of pain, the lack of abdominal symptoms, the chronicity of the pain, and the rarity of a right-sided subphrenic abscess as a result of a pathologic condition of the stomach. <h3>REPORT OF CASE</h3> A man, aged 48, married, a watchmaker, suddenly experienced excruciating pain in the anterior portion of the right shoulder and arm, May 19, 1923. Examination showed a somewhat tender abdomen, which it was difficult to palpate, as he held himself rigid owing to the intensity of pain in the shoulder. He was sent to the hospital and a study of the case instituted, but he returned home in spite of recommendations to the contrary. He was up and about for four or five days, during which time his chief complaint was of intense pain in the anterior portion of the right shoulder and arm. I did
Citrullination and autoimmune disease: 8th Bertine Koperberg meeting
Authors: E R Vossenaar
Journal: Annals of the Rheumatic Diseases (2005)

Citrullination, the process in which citrulline-containing proteins are formed, seems to have a role in several autoimmune diseases.1,2 Although citrulline is a common metabolite present throughout the human body, it is a non-standard amino acid, which means that it cannot be incorporated into proteins during protein synthesis. Citrulline-containing proteins can only be generated through post-translational modification of arginine residues, a reaction that is catalysed by peptidylarginine deiminase (PAD) enzymes.3

At the 8th Bertine Koperberg meeting in Nijmegen, The Netherlands, held in March 2005, the way in which citrullination might be involved in the autoimmune diseases rheumatoid arthritis (RA) and multiple sclerosis (MS) was discussed.

Ger Pruijn (Nijmegen, The Netherlands) gave an excellent overview of the enzymes responsible for citrullination. Five, highly conserved isotypes of PAD enzymes exist in all mammalian species (PAD1–PAD4 and PAD6). The main difference between the isotypes is their tissue-specific expression. For RA and MS, PAD2 and PAD4 are the most interesting enzymes as both of them are expressed in the synovium and central nervous system (CNS). All PAD enzymes require high calcium levels for activity (about 10−5 mol/l). Because the intracellular calcium concentration in healthy cells is much lower (∼10−7 mol/l), the enzymes are only activated during events that lead to high calcium levels, like cell death, or late in the differentiation of skin cells (PAD1 and PAD3), as was explained by Michel Simon (Toulouse, France). Citrullination thus is believed to have an important role in several physiological processes, including the normal development of the myelin sheath and epidermis.

The effect of citrullination on protein function was also discussed. Whereas arginine is a positively charged amino acid, citrulline is uncharged, and citrullination of proteins thus leads to a loss of net positive charge. As a result, the target proteins adopt an …