tbuckley/cabot-search huggingface dataset:
Do statins offer therapeutic potential in inflammatory arthritis?
Authors: I B McInnes
Journal: Annals of the Rheumatic Diseases (2004)

Statins may reduce inflammation and modify vascular risk

Rheumatoid arthritis (RA) is associated with accelerated vascular risk with attendant early mortality (pooled standardised mortality rate 1.7) and excess morbidity.1 Optimal treatment of RA disease activity should therefore reasonably deal with vascular risk modification in addition to the well recognised objectives of treatment—namely, to suppress inflammation, improve function, prevent articular damage, and modify psychosocial implications of disease. Intriguingly, vascular specialists are now exercised with the realisation that inflammation is central to the pathogenesis of atherogenesis. Striking similarities in the atherogenic lesion in the vessel have been drawn with the chronic synovitis characteristic of RA, particularly to plaque structure and the role of extracellular matrix degradation in subsequent rupture. That said, vascular inflammation is not reflected in the same degree of local tissue destruction, nor the sustained substantial increase in the acute phase response as in RA, but rather with a lower grade chronic inflammatory response relying on high sensitivity assays for detection of the persistent inflammatory load. Thus, although not necessarily exemplary of shared aetiology, these parallels suggest that shared interventions may be possible.

HMG-CoA reductase inhibitors (statins) reduce cardiovascular morbidity and mortality by around 25–50% and are widely used in primary and secondary prevention of vascular disease syndromes.2–4 Although operating in part through lipid modulation, recent studies demonstrate broader properties for statins, particularly in altering inflammatory pathways.5 There is considerable current interest, therefore, in the broader clinical uses of statins, in particular in disease states more clearly associated with high grade inflammation.

Many in vitro and animal studies now describe the potential anti-inflammatory effects of statins. After exposure to statins, endothelial cells exhibit increased endothelial nitric oxide synthase and tissue plasminogen activator antigen with reduced plasminogen activator inhibitor 1, tissue factor, and endothelin expression (reviewed by …
A fresh look at interferon-α signaling and treatment outcomes in chronic hepatitis C
Authors: Pantxika Bellecave, Darius Moradpour
Journal: Hepatology (2008)

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The current standard therapy for chronic hepatitis C (CHC) consists of a combination of pegylated IFN alpha (pegIFNα) and ribavirin. It achieves a sustained viral clearance in only 50-60% of patients. To learn more about molecular mechanisms underlying treatment failure, we investigated IFN-induced signaling in paired liver biopsies collected from CHC patients before and after administration of pegIFNα. In patients with a rapid virological response to treatment, pegIFNα induced a strong up-regulation of IFN-stimulated genes (ISGs). As shown previously, nonresponders had high expression levels of ISGs before therapy. Analysis of posttreatment biopsies of these patients revealed that pegIFNα did not induce expression of ISGs above the pretreatment levels. In accordance with ISG expression data, phosphorylation, DNA binding, and nuclear localization of STAT1 indicated that the IFN signaling pathway in nonresponsive patients is preactivated and refractory to further stimulation. Some features characteristic of nonresponders were more accentuated in patients infected with HCV genotypes 1 and 4 compared with genotypes 2 and 3, providing a possible explanation for the poor response of the former group to therapy. Taken together with previous findings, our data support the concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway.
Causal curiosity and the conventionality of culture
Authors: Lori Markson, Gil Diesendruck
Journal: Behavioral and Brain Sciences (2005)

Tomasello et al. argue that cultural cognition derives from humans' unique motivation to share psychological states. We suggest that what underlies this motivation is children's propensity to seek out the underlying causes of behavior. This propensity, combined with children's competence at it, makes them especially skillful at acquiring the intentional, conventional, and reliable forms that constitute culture.
Lentiviral Expression of Retinal Guanylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness
Authors: Melissa L Williams, Jason E Coleman, Shannon E Haire, Tomas S Aleman, Artur V Cideciyan, Izabel Sokal, Krzysztof Palczewski, Samuel G Jacobson, Susan L Semple-Rowland
Journal: PLoS Medicine (2006)

Background Leber congenital amaurosis (LCA) is a genetically heterogeneous group of retinal diseases that cause congenital blindness in infants and children. Mutations in the GUCY2D gene that encodes retinal guanylate cyclase–1 (retGC1) were the first to be linked to this disease group (LCA type 1 [LCA1]) and account for 10%–20% of LCA cases. These mutations disrupt synthesis of cGMP in photoreceptor cells, a key second messenger required for function of these cells. The GUCY1*B chicken, which carries a null mutation in the retGC1 gene, is blind at hatching and serves as an animal model for the study of LCA1 pathology and potential treatments in humans. Methods and Findings A lentivirus-based gene transfer vector carrying the GUCY2D gene was developed and injected into early-stage GUCY1*B embryos to determine if photoreceptor function and sight could be restored to these animals. Like human LCA1, the avian disease shows early-onset blindness, but there is a window of opportunity for intervention. In both diseases there is a period of photoreceptor cell dysfunction that precedes retinal degeneration. Of seven treated animals, six exhibited sight as evidenced by robust optokinetic and volitional visual behaviors. Electroretinographic responses, absent in untreated animals, were partially restored in treated animals. Morphological analyses indicated there was slowing of the retinal degeneration. Conclusions Blindness associated with loss of function of retGC1 in the GUCY1*B avian model of LCA1 can be reversed using viral vector-mediated gene transfer. Furthermore, this reversal can be achieved by restoring function to a relatively low percentage of retinal photoreceptors. These results represent a first step toward development of gene therapies for one of the more common forms of childhood blindness.
Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma
Authors: Kathryn R Taylor, Alan Mackay, Nathalène Truffaux, Yaron S Butterfield, Olena Morozova, Cathy Philippe, David Castel, Catherine S Grasso, Maria Vinci, Diana Carvalho, Angel M Carcaboso, Carmen de Torres, Ofelia Cruz, Jaume Mora, Natacha Entz-Werle, Wendy J Ingram, Michelle Monje, Darren Hargrave, Alex N Bullock, Stéphanie Puget, Stephen Yip, Chris Jones, Jacques Grill
Journal: Nature Genetics (2014)
Primary hepatic cryptococcosis.
Authors: B C Das, I Haynes, R M Weaver, P R Acland
Journal: BMJ (1983)

treated with piperazine.On this occasion he developed a severe exfoliative erythroderma within three hours and was admitted to hospital.The rash cleared over several weeks with the use of topical steroid ointments.Some weeks later with his agreement he was readmitted and challenged with 50 ,sg piperazine hydrate by mouth.This provoked a generalised maculopapular erythema within hours with shivering, anxiety, and a tachycardia of 140 beats/min.Subsequent patch testing showed him to have a contact allergy to 1% ethylenediamine (+ + reaction at 48 and 96 hours) but not to 1% promethazine, 1% mepyramine, 1% diphenhydramine, 0-5% antazoline, and the standard European battery of contact allergens.On further inquiry he identified Tri-Adcortyl cream (Squibb) as a medicament that he had used previously.The constituents of Tri-Adcortyl cream include triamcinolone acetonide, neomycin, gramicidin, nystatin, parabens, and ethylenediamine.
Noninvasive Cardiac Diagnosis
Authors: Alfred F. Parisi, Donald E. Tow, W. Robert Felix, Arthur A. Sasahara
Journal: New England Journal of Medicine (1977)

Clinical ApplicationsCoronary-Artery Disease Acute myocardial infarction. One of the striking developments in the past two years has been the ability to identify acutely infarcted myocardium with radiopharmaceuticals. Using 99mTc stannous pyrophosphate, Bonte, Parkey et al. have shown a high correlation between acute myocardial infarction confirmed by electrocardiography and enzyme studies and the appearance of a radioisotopic "hot spot" in the heart within five days after the acute event.20 , 21 Canine experiments involving coronary-artery ligation indicate that radiopharmaceuticals of this class accumulate in ischemic regions as well as infarcted areas after a threshold reduction in coronary blood flow is reached. . . .
Reversing the natural decline in human fertility. An extended clinical trial of oocyte donation to women of advanced reproductive age
Authors: M. V. Sauer
Journal: JAMA (1992)

To evaluate the effect of age on pregnancy success rates in functionally agonadal women undergoing oocyte donation.A prospective study of 100 consecutive patients using oocyte donation for the treatment of infertility.Women aged 40 years and above requesting oocyte donation (N = 104) were required to undergo medical, reproductive, and psychological screening. Suitable candidates (n = 65) were matched with an oocyte donor whose cycle was synchronized with that of the potential recipient, prior to the donor's undertaking ovarian hyperstimulation and transvaginal ultrasound-directed follicle aspiration. Outcomes were compared with those of two groups undergoing therapy at the same time: (1) women below 40 years of age undergoing oocyte donation for premature ovarian failure (n = 35) and (2) women 40 years of age and above undergoing standard in vitro fertilization and embryo transfer using their own oocytes (n = 57).Embryo implantation and pregnancy rates.The in vitro fertilization program of the University of Southern California and the California Medical Center, Los Angeles.Improved outcomes were observed with regard to fertilization rates in vitro, number of embryos transferred, embryo implantation rate, clinical pregnancy rates, and ongoing or successfully completed pregnancy rates when women undergoing oocyte donation regardless of age were compared with women 40 years of age and above using their own oocytes. No age-related decline in fertility was demonstrable when oocyte donation was used, with a mean age of 44.3 +/- 3.1 years for those successfully conceiving (range, 40 to 52 years). Perinatal outcomes (n = 27) were generally uncomplicated, with a mean gestational age at delivery of 38.4 +/- 2.1 weeks (range, 34 to 42 weeks), although multiple births occurred in 24.1% of cases.The age-related decline in female fertility may be reversed in couples electing to use donated oocytes from a younger woman, and women of advanced reproductive age may conceive, carry, and give birth to infants with success rates similar to those of their younger counterparts using assisted reproductive methods.
An Appraisal of the Role of Biosynthetic Human Insulin in the Future Treatment of Diabetes Mellitus
Authors: John E Gerich
Journal: Diabetes Care (1981)

Although initial laboratory studies using biosynthetic human insulin (BHI) indicate little difference in the intrinsic potency of biosynthetic human and purified pork insulin (PPI) in vitro, certain in vivo observations suggest that BHI may differ pharmacokinetically from pork insulin. If further studies support these suggestions, the use of BHI may be able to provide better glycemic control and more near normal plasma insulin profiles during treatment of insulin-dependent diabetes than can be achieved with presently available insulin preparations. However, BHI appears to offer no advantage over presently available PPI in terms of prevention and treatment of insulin lipodystrophy, insulin allergy, and immune insulin resistance.
Abstract A57: Dual role of the histone methyltransferase PR-SET7/SETD8 in the local regulation of Pol II promoter-proximal pausing
Authors: Priya Kapoor, Paula M. Vertino
Journal: Cancer Research (2013)

Abstract Tumor suppressor gene silencing in cancers is often achieved through epigenetic mechanisms which involve the hypermethylation of promoter-associated CpG islands and a local shift from permissive to repressive histone modifications. Recently, we showed that epigenetic silencing of the tumor suppressor gene TMS1/ASC in human breast cancer cells is accompanied by a local shift from histone H4 lysine 16 acetylation (H4K16Ac) to H4 lysine 20 trimethylation (H4K20me3). H4K16Ac and H4K20me3 were found to play antagonistic roles in the regulation of RNA polymerase II promoter-proximal pausing, a critical post-initiation regulatory step that controls the rate of release of initiated Pol II into productive elongation and ultimately transcriptional output. We found that H4K16Ac, mediated by the histone acetyltransferase hMOF and acting in the MSL complex, facilitates the release of paused Pol II by promoting the recruitment of the BRD4/pTEFb complex whereas the local deposition of H4K20me3, mediated by the histone methyltransferase SUV420H2, enforces the pause and promotes gene repression by inhibiting the recruitment of MSL and subsequent H4K16Ac. However, how the local balance between hMOF-mediated H4K16Ac and SUV420H2-mediated H4K20me3 is achieved and converge to regulate Pol II pausing remains unclear. Here, we demonstrate that the histone methyltransferase PR-SET7/SETD8, which monomethylates histone H4 lysine 20 (H4K20me1), controls both H4K16Ac and H4K20me3, and as a result, regulates Pol II pausing and release. Specifically, we show that PR-SET7 and/or H4K20me1 is necessary for the local recruitment of the MSL complex, subsequent H4K16Ac and release from pausing. Although dispensable for SUV420H2 recruitment, PR-SET7 is required for SUV420H2-mediated H4K20me3, playing a role in enforcing Pol II pausing and subsequent epigenetic gene silencing. Whereas depletion of SUV420H2 is sufficient to deplete H4K20me3 and relieve H4K20me3-mediated Pol II pausing, pausing is maintained in the absence of PR-SET7 and local H4K20me1 due to a failure to recruit the MSL complex. These findings highlight the requirement for PR-SET7 and H4K20me1 in establishing both the H4K16Ac and H4K20me3 marks and points to its dual role in the regulation of Pol II pausing dynamics. Furthermore, our data suggests that the reversible repression imposed by the local conversion of H4K20me1 to H4K20me3 is a critical intermediate step in the epigenetic silencing of tumor suppressor genes in cancers. Citation Format: Priya Kapoor, Paula M. Vertino. Dual role of the histone methyltransferase PR-SET7/SETD8 in the local regulation of Pol II promoter-proximal pausing. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A57.
Breath isoprene during acute respiratory exacerbation in cystic fibrosis
Authors: L.T. McGrath, R. Patrick, P. Mallon, L. Dowey, B. Silke, W Norwood, S Elborn
Journal: European Respiratory Journal (2000)

Patients with cystic fibrosis (CF) experience a combination of chronic systemic oxidative stress, generation of free radicals in the lungs due to a hyperimmune response and a diminished ability to scavenge free radicals secondary to malabsorption and increased consumption. The authors asked the question, "Does breath isoprene content reflect systemic oxidative stress?" The study involved 12 CF patients and 12 matched healthy controls. The patients were sampled during acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume (FEV1) of &gt;10%, and a decision to treat with intravenous antibiotics) and after two weeks of antibiotic treatment. Blood samples were examined for markers of oxidative stress. Breath samples were analysed for isoprene content. Malondialdehyde (MDA), erythrocyte membrane polyunsaturated fatty acids, protein sulphydryls and protein carbonyls all showed evidence of increased oxidative stress which was moderated by antibiotic treatment. Breath isoprene production rate was significantly lower in patients during exacerbation than in controls with a mean difference of-39 (95% confidence interval (CI) -11-57) pmol.min.kg(-1) and increased to normal values following treatment (mean change 63 (95% CI 42-84) pmol.min.kg(-1)). In conclusion, breath isoprene cannot be considered a reliable marker of oxidative stress.
Limitations of rapid HIV-1 tests during screening for trials in Uganda: diagnostic test accuracy study
Authors: Ronald H Gray, Fredrick Makumbi, David Serwadda, Tom Lutalo, Fred Nalugoda, Pius Opendi, Godfrey Kigozi, Steven J Reynolds, Nelson K Sewankambo, Maria J Wawer
Journal: BMJ (2007)

To evaluate the limitations of rapid tests for HIV-1.Diagnostic test accuracy study.Rural Rakai, Uganda.1517 males aged 15-49 screened for trials of circumcision for HIV prevention.Sensitivity, specificity, negative predictive values, and positive predictive values of an algorithm using three rapid tests for HIV, compared with the results of enzyme immunoassay and western blotting as the optimal methods.Rapid test results were evaluated by enzyme immunoassay and western blotting. Sensitivity was 97.7%. Among 639 samples where the strength of positive bands was coded if the sample showed positivity for HIV, the algorithm had low specificity (94.1%) and a low positive predictive value (74.0%). Exclusion of 37 samples (5.8%) with a weak positive band improved the specificity (99.6%) and positive predictive value (97.7%).Weak positive bands on rapid tests for HIV should be confirmed by enzyme immunoassay and western blotting before disclosing the diagnosis. Programmes using rapid tests routinely should use standard serological assays for quality control. Trial registration Clinical Trials NCT00425984.
MAURICE C. PINCOFFS, M.D., M.A.C.P.
Authors: GEORGE M. PIERSOL
Journal: Annals of Internal Medicine (1960)

Article1 October 1960MAURICE C. PINCOFFS, M.D., M.A.C.P.A TributeGEORGE M. PIERSOL, M.D.GEORGE M. PIERSOL, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-53-4-633 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptOctober of this year marks the retirement of a man who has become a legend in the history of The American College of Physicians. After 27 years of dedicated service as Editor of the ANNALS OF INTERNAL MEDICINE, Dr. Maurice C. Pincoffs, distinguished and revered Master of the College, has indicated his desire to be relieved of the arduous responsibilities that have proved him to be a brilliant physician, a scholarly gentleman, and a truly remarkable man.Maurice Pincoffs was elected Editor of the ANNALS OFINTERNALMEDICINEat the Annual Session in San Francisco, on April 4, 1932. The... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: GEORGE M. PIERSOL, M.D. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1960Volume 53, Issue 4Page: 633-635 ePublished: 1 December 2008 Issue Published: 1 October 1960 PDF downloadLoading ...
Influenza A Infection Should Not Simulate Pulmonary Embolism
Authors: Philip Matin
Journal: JAMA (1978)

<h3>To the Editor.—</h3> The article by Lynn et al (238:1166, 1977), entitled "Influenza A Infection Simulating Pulmonary Embolism" is misleading. The article states, "Pulmonary perfusion scans may demonstrate segmental, subsegmental, or nonspecific defects that represent relative reduction of regional pulmonary blood flow. These defects could be secondary to obstructive airway disease, pneumonia, atelectasis, effusion, and other acute or chronic pulmonary disease processes.<i>In the absence of these concurrent abnormalities, the diagnosis of PE [pulmonary embolism] is established by perfusion defects demonstrated by pulmonary perfusion scan with the radioisotope-labeled particles</i>[italics added]. The first two sentences are entirely correct. However, the third sentence is incorrect. Since the advent of the ventilation scan in the late 1960s, the diagnosis of pulmonary embolism is established by perfusion defects demonstrated by a pulmonary perfusion scan only when the concurrently performed ventilation scan does not show the same defects. Although the clinical absence of obstructive
Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma
Authors: Masanori Aikawa, Seigo Sugiyama, Christopher C. Hill, Sami J. Voglic, Elena Rabkin, Yoshihiro Fukumoto, Frederick J. Schoen, Joseph L. Witztum, Peter Libby
Journal: Circulation (2002)

Background— Lipid lowering may reduce acute coronary events in patients in part by reducing vascular inflammation. Oxidative stress induces endothelial cell (EC) expression of vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemoattractant protein 1 (MCP-1) and reduces levels of atheroprotective NO, leading to monocyte recruitment and macrophage accumulation. This study tested the hypothesis that lipid lowering decreases oxidative stress and improves EC functions related to inflammatory cell accumulation. Methods and Results— Rabbits consumed an atherogenic diet for 4 months to produce atheroma, followed by a purified chow diet for 16 months. Atherosclerotic aortas from hypercholesterolemic rabbits produced high levels of reactive oxygen species. Oxidized LDL (oxLDL) accumulated in atheroma underlying ECs that overexpress VCAM-1. In contrast, few if any ECs in atheroma stained for endothelial NO synthase (eNOS). Lipid lowering reduced reactive oxygen species production, oxLDL accumulation, and plasma levels of anti-oxLDL IgG. After lipid lowering, VCAM-1 and MCP-1 expression decreased, eNOS expression increased, and ECs exhibited a more normal ultrastructure. Conclusions— These results establish that lipid lowering can reduce oxidative stress and EC activation in vivo. These mechanisms may contribute to improvement in endothelial function and plaque stabilization observed clinically.
INFLUENCE OF EXPERIMENTAL KIDNEY DAMAGE ON HISTOCHEMICALLY DEMONSTRABLE LIPASE ACTIVITY IN THE RAT. COMPARISON WITH ALKALINE PHOSPHATASE ACTIVITY
Authors: M. Wachstein
Journal: The Journal of Experimental Medicine (1946)

Lipase activity was found in the cytoplasm of the proximal convoluted tubules in tissue sections of rat, rabbit, dog, mouse, hamster, and guinea pig, stained according to Gomori's method. Uranium and mercury poisoning do not inactivate the enzyme in necrotic cells of the proximal convoluted tubules. Its activity diminished in the atrophic and regenerating cells of the kidneys of rats, surviving the acute phase of the intoxication. In the acute stage of choline deficiency marked reduction in enzymatic activity was seen in the necrotic tubules, and in the atrophied and regenerating tubules in the subacute stage. Lipase activity was markedly diminished in hydronephrotic kidneys 10 to 12 days after ligation of the ureter. In sections stained for alkaline phosphatase activity nearly identical alterations were found. Experimental damage influences both histochemically demonstrable enzymes in a similar manner.