tbuckley/cabot-search huggingface dataset:
Efficient Gene Regulation by PPARγ and Thiazolidinediones in Skeletal Muscle and Heart
Authors: Raphaël Darteil, Manping Wang, Martine Latta-Mahieu, Anne Caron, Abderrahim Mahfoudi, Bart Staels, Vincent Thuillier
Journal: Molecular Therapy (2002)

We have developed a new gene regulation system for gene therapy. This system consists of two expression cassettes; one expresses the human peroxisome proliferator-activated receptor γ(PPARγ), and the other expresses the therapeutic gene under the control of multiple peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) linked to a basal promoter. Using direct injection of plasmid DNA into skeletal muscle or myocardium of rodents and oral administration of clinically approved PPARγ activators, we demonstrate that reporter gene expression can be induced more than 25-fold. We show that oral administration of PPARγ activator at intervals separated by several months results in repeated pulses of high-level reporter gene expression. We also document a PPARγ activator dose-response effect on reporter gene expression. This is the first report of a gene regulation system that makes use of a human transcription factor and that may be safer than chimeric transcription factors for human gene therapy. We have developed a new gene regulation system for gene therapy. This system consists of two expression cassettes; one expresses the human peroxisome proliferator-activated receptor γ(PPARγ), and the other expresses the therapeutic gene under the control of multiple peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) linked to a basal promoter. Using direct injection of plasmid DNA into skeletal muscle or myocardium of rodents and oral administration of clinically approved PPARγ activators, we demonstrate that reporter gene expression can be induced more than 25-fold. We show that oral administration of PPARγ activator at intervals separated by several months results in repeated pulses of high-level reporter gene expression. We also document a PPARγ activator dose-response effect on reporter gene expression. This is the first report of a gene regulation system that makes use of a human transcription factor and that may be safer than chimeric transcription factors for human gene therapy.
Die Psyche des Rheumakranken aus der Sicht seines Arztes
Authors: R. Schild
Journal: Psychotherapy and Psychosomatics (1972)

Introducing the Neologisme 'Striking psychological pecularity' ('Psychologische Auffälligkeit') we asked two groups of psychological uninhibited doctors (doctors specialized in rheumatology) to describe the psychological pecularities of their daily patients. In a second questionnaire the doctors themselves were asked to judge their feelings in front of so-called 'patients with problems'. The questionnaire about the patients with different rheumatic illnesses, showed a preference of psychological disabilities with an accent on depressiveness and centered around syndromes of the spine. The analysis of the doctors behaviour in front of such patients confirms the necessity of a patient-centered medicine (Balint).
AFAP: variety is the spice of life
Authors: H T LYNCH, P WATSON
Journal: Gut (1998)

See article on page 548 

Familial adenomatous polyposis (FAP) has been known for over 100 years1; Gardner’s syndrome, the familial association of multiple colonic adenomas and early onset colorectal cancer (CRC) with osteomas and multiple cutaneous fibromas or epidermoid cysts has been known for almost 50 years.2 The discovery of the APC gene3 has changed the diagnosis and clinical management of FAP radically. Firstly, it became clear that FAP and Gardner’s syndrome have the same genetic basis. The expression of osteomas and of the cutaneous signs varies greatly among people with the same mutation. Other phenotypic variations have been found to have a genetic basis. For example, congenital hypertrophy of the retinal pigment epithelium is associated with mutations distal to exon 9,4 whereas susceptibility to desmoid tumours is associated with mutations at codons 1444 and 15785 and a profuse number of colonic adenomas, often more than 5000 (compared with the more typical 1000–2000), is associated with mutations between codons 1250 and 1464.6 

A variant called attenuated FAP (AFAP) has been associated with mutations in the 5′ portion of the APC gene.7 AFAP is characterised by the occurrence of often fewer than 100 colonic adenomas (sometimes …
Efficient Gene Transfer Into the Mouse Lung by Fetal Intratracheal Injection of rAAV2/6.2
Authors: Marianne Carlon, Jaan Toelen, Anke Van der Perren, Luk H Vandenberghe, Veerle Reumers, Lourenço Sbragia, Rik Gijsbers, Veerle Baekelandt, Uwe Himmelreich, James M Wilson, Jan Deprest, Zeger Debyser
Journal: Molecular Therapy (2010)

Fetal gene therapy is one of the possible new therapeutic strategies for congenital or perinatal diseases with high mortality or morbidity. We developed a novel delivery strategy to inject directly into the fetal mouse trachea. Intratracheal (i.t.) injection at embryonic day 18 (E18) was more efficient in targeting the fetal lung than conventional intra-amniotic (i.a.) delivery. Viral vectors derived from adeno-associated virus serotype 6.2, with tropism for the airway epithelium and not earlier tested in the fetal mouse lung, were injected into the fetal trachea. Bioluminescence (BL) imaging (BLI) was combined with magnetic resonance (MR) imaging (MRI) for noninvasive and accurate localization of transgene expression in vivo. Histological analysis for β-galactosidase (β-gal) revealed 17.5% of epithelial cells transduced in the conducting airways and 1.5% in the alveolar cells. Stable gene expression was observed up to 1 month after injection. This study demonstrates that direct injection of rAAV2/6.2 in the fetal mouse trachea is superior to i.a. delivery for transducing the lung. Second, as stable gene transfer was detected up to 1 postnatal month, this approach may be useful to evaluate fetal gene therapy for pulmonary diseases such as cystic fibrosis, requiring both substantial numbers of transduced cells as well as prolonged gene expression to obtain a stable phenotypic effect.
Successful Treatment with Foscarnet of an Acyclovir-Resistant Mucocutaneous Infection with Herpes Simplex Virus in a Patient with Acquired Immunodeficiency Syndrome
Authors: P.A. Chatis, C.H. Miller, L.E. Schrager, C.S. Crumpacker
Journal: New England Journal of Medicine (1989)

THE most widely used drug therapy for herpes simplex virus (HSV) is the nucleoside analogue acyclovir.1 2 3 To inhibit the growth of HSV, acyclovir must first be phosphorylated to the monophosphate form by virus–specific thymidine kinase, followed by phosphorylation to the active triphosphate form by cellular enzymes. The activated triphosphate is a potent inhibitor of herpes-specific DNA polymerase.4 Resistance to acyclovir has occurred infrequently, usually in patients with severe immunodeficiency disorders, and resistance is usually associated with loss of viral thymidine kinase activity.5 6 7 8 9 10 Severe mucocutaneous infections due to acyclovir-resistant herpesvirus infections are now occurring with increasing frequency in patients with the . . .
FDA approves "instant" HIV home test
Authors: B. Roehr
Journal: BMJ (2012)

The US Food and Drug Administration has approved the first true over the counter self administered test for HIV. The OraQuick In-Home HIV Test is manufactured by OraSure Technologies.

The test consists of a swab to collect an oral fluid sample from the gums of the mouth, which is then placed in a developer vial to measure antibodies to the virus. The test produces results in 20 to 40 minutes in much the same way as a home pregnancy test.

It has a specificity of 99.98%, resulting in one false positive result in every 5000 tests …
Computer assisted knee arthroplasty is here today
Authors: Graeme Holt, A G Gregori
Journal: BMJ (2005)

Monitoring global health Problems are primarily nationalEditor-Murray et al urge for improved global reporting of health data. 1 They also highlight the difficulty of showing national decision makers that good health data can strongly support decision making.Why is this?A reason may be that data are always subject to interpretation.The article by Murray et al is a case in point.They want to establish "an independent monitoring organisation," arguing that the World Health Organization is not fit to undertake the job because of tension between advocacy, monitoring, and evaluation.But evidence that it is this tension that leads to poor monitoring by WHO is weak, at best.In reality, the problems of global health reporting are primarily national (and subnational).The fact that the sum of deaths claimed by different programmes is greater than the actual number of deaths reflects epidemiological methods and the current limitations in global health reporting, more than any WHO failure.The global burden of disease project was limited by these issues, but it was undertaken as effectively in WHO as in any other organisation.Not only are there problems in capacity, understanding the value of surveillance, and coverage of health services.The reporting of health events can be politically sensitive or even economically damaging.It is therefore likely that political interference will continue (whoever collects the data) until governments can be shown that honesty pays.It is perhaps this failure that needs to be dealt with rather than setting up yet another organisation without a proper analysis of the reasons (and locus) for failures in global health reporting.
Cytokines suppress human islet function irrespective of their effects on nitric oxide generation.
Authors: D L Eizirik, S Sandler, N Welsh, M Cetkovic-Cvrlje, A Nieman, D A Geller, D G Pipeleers, K Bendtzen, C Hellerström
Journal: Journal of Clinical Investigation (1994)

Cytokines have been proposed as inducers of beta-cell damage in human insulin-dependent diabetes mellitus via the generation of nitric oxide (NO). This concept is mostly based on data obtained in rodent pancreatic islets using heterologous cytokine preparations. The present study examined whether exposure of human pancreatic islets to different cytokines induces NO and impairs beta-cell function. Islets from 30 human pancreata were exposed for 6-144 h to the following human recombinant cytokines, alone or in combination: IFN-gamma (1,000 U/ml), TNF-alpha (1,000 U/ml), IL-6 (25 U/ml), and IL-1 beta (50 U/ml). After 48 h, none of the cytokines alone increased islet nitrite production, but IFN-gamma induced a 20% decrease in glucose-induced insulin release. Combinations of cytokines, notably IL-1 beta plus IFN-gamma plus TNF-alpha, induced increased expression of inducible NO synthase mRNA after 6 h and resulted in a fivefold increase in medium nitrite accumulation after 48 h. These cytokines did not impair glucose metabolism or insulin release in response to 16.7 mM glucose, but there was an 80% decrease in islet insulin content. An exposure of 144 h to IL-1 beta plus IFN-gamma plus TNF-alpha increased NO production and decreased both glucose-induced insulin release and insulin content. Inhibitors of NO generation, aminoguanidine or NG-nitro-L-arginine, blocked this cytokine-induced NO generation, but did not prevent the suppressive effect of IL-1 beta plus IFN-gamma plus TNF-alpha on insulin release and content. In conclusion, isolated human islets are more resistant to the suppressive effects of cytokines and NO than isolated rodent islets. Moreover, the present study suggests that NO is not the major mediator of cytokine effects on human islets.
Antibody Fc engineering improves frequency and promotes kinetic boosting of serial killing mediated by NK cells
Authors: Gabrielle Romain, Vladimir Senyukov, Nicolas Rey-Villamizar, Amine Merouane, William Kelton, Ivan Liadi, Ankit Mahendra, Wissam Charab, George Georgiou, Badrinath Roysam, Dean A. Lee, Navin Varadarajan
Journal: Blood (2014)

Key Points Fc-engineered mAb promotes NK cell ADCC via better activation, serial killing, and kinetic boosting at higher target cell densities. Enhanced target killing also increased frequency of NK cell apoptosis, but this effect is donor-dependent.
Treatment of Typhoid Fever.
Authors: W. P. Howle
Journal: JAMA (1895)

Oran, Mo., Jan. 8, 1895. <h3>To the Editor:</h3> —In ourJournalof January 5, I find a report on typhoid fever by Dr. Woodbridge and it reminds me of a report I made to the Southeastern Missouri Medical Association a few days before the Doctor made his report at Hot Springs. I reported a case of typhoid fever treated with<i>hyposulphite soda and Fowler's solution</i>, which gained over a pound a day during treatment. He ate his meals regularly, went to the table and to the privy (fifty yards distant from his hotel) his temperature ranging from 102½ to 105 for fifteen days. He ate largely of green apples, dates, oranges, lemons, anything he wanted (and could get), never complained of any pain, said he felt firstrate all the time, slept well, read the newspapers by day, and was a great Breckinridge man, they both being Kentuckians. I am as
British soldiers are “guinea pigs” for new use of blood clotting agent
Authors: Owen Dyer
Journal: BMJ (2006)

British soldiers in Iraq are being treated for traumatic injury with an unlicensed blood clotting agent that has yet to complete clinical trials.

The drug, NovoSeven, also called recombinant factor VIIa, has been licensed for the treatment of haemophilia since 1999 but is still undergoing phase III trials as treatment for traumatic bleeding. It was first used in a military setting four years ago, on a wounded Israeli soldier, and has since been used by US forces in …
Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension
Authors: P.C.M. van de Kerkhof, S. Segaert, M. Lahfa, T.A. Luger, Z. Karolyi, A. Kaszuba, G. Leigheb, F.M. Camacho, D. Forsea, C. Zang, M.P. Boussuge, L. Paolozzi, J. Wajdula
Journal: British Journal of Dermatology (2008)

Background In previous studies, etanercept 25 mg twice weekly (BIW) or 50 mg BIW significantly reduced disease severity in patients with plaque psoriasis and demonstrated a favourable safety profile. Objectives To assess the efficacy and safety of etanercept 50 mg administered once weekly (QW) compared with placebo in patients with moderate-to-severe plaque psoriasis over 24 weeks. Methods This study was conducted in two parts: (i) a 12-week, double-blind, placebo-controlled phase, in which patients received etanercept 50 mg QW or placebo QW; and (ii) a 12-week, open-label extension phase, in which all patients received etanercept 50 mg QW. Primary endpoint was a 75% or greater improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at week 12. Secondary endpoints included percentage PASI improvement and Physician's Global Assessment (PGA). Results One hundred and forty-two patients were analysed in the double-blind phase; 126 patients entered the open-label phase. At week 12, significantly more patients receiving etanercept 50 mg QW (37·5%) achieved PASI 75 response than patients receiving placebo (2·2%; P < 0·0001). At week 24, 71·1% in the etanercept–etanercept group and 44·4% in the placebo–etanercept group achieved PASI 75. Mean percentage of PASI improvement from baseline was 55·4% with etanercept vs. 9·4% worsening with placebo at week 12 (P < 0·0001), with 77·4% and 57·7% improvement in the etanercept–etanercept and placebo–etanercept groups at week 24. A PGA score of 0–1 (clear–almost clear) was achieved by 64% and 42% in the etanercept–etanercept and placebo–etanercept groups at week 24, respectively. Etanercept 50 mg QW was well tolerated. No deaths, serious infections, opportunistic infections (including tuberculosis), demyelinating disorders, malignancies or new safety signals were reported. Conclusions Nearly three-quarters of patients with moderate-to-severe psoriasis receiving etanercept 50 mg QW achieved significant improvement in disease severity over 24 weeks. This study also showed a favourable tolerability and safety profile with etanercept 50 mg QW.
Office of Health Economics
Authors: J. Cassidy
Journal: BMJ (2011)

Perhaps best known for producing an annual compendium of health statistics encompassing population, morbidity, mortality, UK healthcare expenditure, and NHS costs, the Office of Health Economics is currently carrying out an expert commission on the role of competition in the NHS. The idea is to investigate which health services would benefit from competition and which would be harmed by it.

By collecting evidence it says that it hopes to cut through extreme positions for and against that are unlikely to represent the most socially beneficial outcome.

Chaired by the Oxford economics professor James Malcomson, the commission expects to complete its work and issue a …
Pulmonary Physiological Measurements in Smokers and Nonsmokers
Authors: Nestor M. Hensler, David J. Giron
Journal: JAMA (1963)

The lung function of 163 middle-aged military officers was studied in relation to smoking habits. The 113 habitual cigarette smokers were found to have significantly lower average ventilatory capacities and increased residual volumes as compared with 50 nonsmokers. Although most subjects in both groups were within normal range, there were significantly more smokers who demonstrated abnormal results to tests of maximum voluntary ventilation, timed vital capacity, and residual volume. Habitual smokers also admitted to chronic cough and shortness of breath with greater frequency than did nonsmokers, although the differences were not statistically significant. The authors conclude that these differences cannot be explained on any factor other than that one group smoked and the other group did not.
ADDRESS ON THE PROGRESS OF MEDICAL SCIENCE DURING THE PAST HALF CENTURY.
Authors: JAMES GRANT
Journal: JAMA (1889)

Sir James Grant, M.D., of Ottawa, Canada, upon being called upon, rose and spoke as follows: I beg to return to you my sincere thanks for the invitation extended by a committee of this Association to be present at this meeting of the medical profession of the United States, and it is an additional source of gratification that I am asked to a seat on this platform. I am reminded of the fact that when the Marquis of Lorne was governor of Canada, the Royal Society was invited to lunch at the government house. When the health of the president of the United States was proposed, a sentiment which we Canadians fully appreciate, and which we are delighted to honor next to that of our glorious Queen Victoria, Mark Twain was asked to respond. He thanked his excellency for the compliment and was proud to be the recipient of the
ALTERATIONS IN THE MOUSE CECUM AND ITS FLORA PRODUCED BY ANTIBACTERIAL DRUGS
Authors: Dwayne C. Savage, René Dubos
Journal: The Journal of Experimental Medicine (1968)

Addition of penicillin, Terramycin, or kanamycin to the drinking water of adult mice rapidly induced in them an enlargement of the cecum. In all animals, this occurred within 12 hr after the beginning of drug administration-the effect being most pronounced with penicillin. The cecums remained enlarged and generally continued to increase in size as long as the antibacterial drugs were administered. The increase in wet weight of the cecums was due primarily to an accumulation of water in the lumens during the first 24-48 hr of drug administration. At that time, there were no detectable histological changes in any case, but the bacteriological picture differed from drug to drug. The cecums were free of bacteria in animals receiving penicillin, fusiform-shaped bacteria and bacteroides were present in those receiving Terramycin, and lactobacilli and bacteroides in those receiving kanamycin. After the initial 48 hr, an abundant and complex secondary microflora developed in all treated animals, its composition being characteristic for each type of antibacterial drug. When penicillin was administered for 2 wk, the cecal weights and microbial populations did not return to normal levels for over 14 days after discontinuance of the drug. This recovery period could be shortened to 10 days by giving the mice food contaminated with cecal homogenates prepared from normal animals. A period of 7 or 8 days was required for the cecal weights and microflora to reach normal levels when the administration of penicillin lasted only 24 hr; this period could not be shortened by giving the animals contaminated food. The effects of drugs on the size and bacterial contents of the cecum have been discussed in the light of earlier findings concerning the characteristics of the huge cecums uniformly found in germfree mice. Taken together, these observations support the hypothesis that certain elements of the intestinal microflora-not yet completely identified-play an essential role in maintaining the integrity of the water-transport mechanism in the intestinal epithelium.
STUDIES ON A PARATYPHOID INFECTION IN GUINEA PIGS
Authors: John B. Nelson, Theobald Smith
Journal: The Journal of Experimental Medicine (1927)

The course of a natural outbreak of paratyphoid in a normal guinea pig population is outlined. A description is given of the gross pathology of the disease. The bacteriology of the causal organism is discussed with particular reference to its agglutinative affinities.
[Na+]i handling in the failing human heart
Authors: B Pieske
Journal: Cardiovascular Research (2003)

Proper contractile function of the heart depends on intact excitation-contraction processes and ion homeostasis of the myocytes. The Ca2+ ion activates contraction through its binding to troponin C. However, Ca2+ homeostasis is tightly linked to Na+ regulation because the primary mechanism for Ca2+ efflux in cardiac myocytes is via electrogenic Na+/Ca2+-exchange. While altered Ca2+-homeostasis has been demonstrated in animal models of heart failure and failing human cardiac tissue, the role of dysfunctional Na+ handling processes in altered excitation-contraction coupling remains obscure. Furthermore, altered Na+ handling has been implicated in a wide range of cellular processes, such as regulation of membrane potential, pH, and growth. This review will discuss (1) the evidence for altered [Na+]i homeostasis in the failing human heart, (2) how alterations in the Na+ electrochemical gradient can influence Ca2+ handling, contractile function, and a number of other cellular processes, and (3) the potential defects in Na+ channels and transporters that may underlie altered [Na+]i in the failing human heart.