tbuckley/cabot-search huggingface dataset:
Super-resolution fluorescence microscopy of the cardiac connexome reveals plakophilin-2 inside the connexin43 plaque
Authors: Esperanza Agullo-Pascual, Dylan A. Reid, Sarah Keegan, Manavjeet Sidhu, David Fenyö, Eli Rothenberg, Mario Delmar
Journal: Cardiovascular Research (2013)

Cell function requires formation of molecular clusters localized to discrete subdomains. The composition of these interactomes, and their spatial organization, cannot be discerned by conventional microscopy given the resolution constraints imposed by the diffraction limit of light (∼200–300 nm). Our aims were (i) Implement single-molecule imaging and analysis tools to resolve the nano-scale architecture of cardiac myocytes. (ii) Using these tools, to map two molecules classically defined as components 'of the desmosome' and 'of the gap junction', and defined their spatial organization. We built a set-up on a conventional inverted microscope using commercially available optics. Laser illumination, reducing, and oxygen scavenging conditions were used to manipulate the blinking behaviour of individual fluorescent reporters. Movies of blinking fluorophores were reconstructed to generate subdiffraction images at ∼20 nm resolution. With this method, we characterized clusters of connexin43 (Cx43) and of 'the desmosomal protein' plakophilin-2 (PKP2). In about half of Cx43 clusters, we observed overlay of Cx43 and PKP2 at the Cx43 plaque edge. SiRNA-mediated loss of Ankyrin-G expression yielded larger Cx43 clusters, of less regular shape, and larger Cx43-PKP2 subdomains. The Cx43-PKP2 subdomain was validated by a proximity ligation assay (PLA) and by Monte–Carlo simulations indicating an attraction between PKP2 and Cx43. (i) Super-resolution fluorescence microscopy, complemented with Monte–Carlo simulations and PLAs, allows the study of the nanoscale organization of an interactome in cardiomyocytes. (ii) PKP2 and Cx43 share a common hub that permits direct physical interaction. Its relevance to excitability, electrical coupling, and arrhythmogenic right ventricular cardiomyopathy, is discussed.
Oral papillary plasmacytosis cleared by radiotherapy
Authors: MAY-SEN LEE, MAY-LIAN LEE, J. FRYER, A. SAURAJEN, J. le
           GUAY
Journal: British Journal of Dermatology (1996)

We report a case of oral papillary plasmacytosis which initially responded well to etretinate and, subsequently, was successfully treated with radiotherapy, with minimal side-effects.
Malnutrition screening in the elderly population
Authors: D. Harris
Journal: Journal of the Royal Society of Medicine (2005)

Malnutrition is a state in which a deficiency, excess or imbalance of energy, protein and other nutrients causes adverse effects on body form, function and clinical outcome.1 To justify screening for this state in the elderly, four criteria must be satisfied: malnutrition must be a frequent cause of ill-health in this population; it must have a negative effect on outcomes; a simple, reliable, valid and acceptable screening test must be available to detect those who are malnourished or at risk of malnutrition; and there must be benefit from nutritional intervention in those identified by screening. In this review we consider whether these conditions are satisfied by tests of various kinds.
Value-Based Payments Require Valuing What Matters to Patients
Authors: Joanne Lynn, Aaron McKethan, Ashish K. Jha
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
An alternative approach to medical genetics based on modern evolutionary biology. Part 4: HERVs in cancer
Authors: Frank P Ryan
Journal: Journal of the Royal Society of Medicine (2009)

In Part 1 we saw that cancer is a multistep process involving complex genetic abnormalities that deregulate signalling pathways, and it involves the cooperation of multiple deregulating genetic pathways.1 Given the widespread involvement of HERVs and related products in human genetic chemistry it is likely that they will be involved in carcinogenesis. We might anticipate that such viral involvement will arise from the known oncogenic potential of viruses, particularly retroviruses. We also need to consider that HERVs, unlike exogenous retroviruses, have been subject to selection working at holobiontic level within the human genome over long time periods. From this we might anticipate additional potential for carcinogenesis deriving from the cooption, or dysregulation, of established symbiotic roles of whole viruses, viral genes and viral regulatory sequences involved in normal genetic pathways.
Frequencies of the separate human B cell subsets activatable to Ig secretion by Epstein-Barr virus and pokeweed mitogen.
Authors: O Martínez-Maza, S Britton
Journal: The Journal of Experimental Medicine (1983)

We have developed a microculture system suitable for limiting dilution analysis of Epstein-Barr virus (EBV)- and pokeweed mitogen (PWM)-induced activation of immunoglobulin secretion by human B cells. It was found that exogenous filler cells were not required to obtain optimal EBV-induced B cell precursor frequency (PF) estimates, although filler T cells were required for optimal PWM activation. In fact, when autologous T cells were used as filler cells, a marked decrease in the EBV-induced IgM PF was noted. Treatment of the T cells with cyclosporin A partially eliminated, and irradiation of the T cells completely eliminated, this decrease. The calculated PF of B cells activated by EBV was from 1/290 to 1/3,700 for IgM, and from 1/920 to 1/3,250 for IgG secretion. PWM activated from 1/140 to 1/3,200 B cells to IgM secretion. The results of experiments in which EBV and PWM were mixed, indicated that these two polyclonal activators operated on different B cell subpopulations. Therefore, both these agents seem to activate small, discrete subpopulations of human peripheral blood B cells to Ig secretion.
Cellular interactions in immune regulation. Hapten-specific suppression by non-T cells and T cell-mediated reversal of suppression
Authors: RH DeKruyff, BG Simonson, GW Siskind
Journal: The Journal of Experimental Medicine (1981)

The ability of lymphoid cells from immunized animals to regulate the response of naive B ceils to the immunizing hapten was studied. Mice were immunized with trinitrophenylated (TNP) bovine gamma globulin (BGG) in complete Freund's adjuvant, and their spleen cells were examined in vivo and in vitro for the presence of specific inhibitory activity. This activity was found to peak 1 wk after immunization, was active against TNP on both T-dependent (BGG) and T-independent (Ficoll and polyacrylamide beads) carriers, and was demonstrable both by mixed cell transfers and mixed cell culture experiments. In in vitro studies, it was shown that the inhibition of the response to TNP- polyacrylamide beads by immune spleen cells was mediated by a non-T cell, possibly a B cell, because the suppressor activity was enriched in a purified B cell preparation. A role for macrophages was not formally ruled out. A specific suppressor factor was produced in vitro by immune spleen cells cultured in the absence of antigen. The suppressor activity was modulated by T .cells because elimination of T cells from the normal spleen cell population decreased suppression; elimination of T cells from the immune spleen cell population did not effect suppression, but elimination of T cells from both the normal and immune spleen cell populations allowed the expression of marked specific suppression. Thus, T cells present in the normal spleen cell population augment the degree of suppression, whereas T cells present in the immune spleen cell population decrease the degree of suppression; that is, T cells present in the immune spleen cell population had the ability to specifically abrogate suppression ("abrosuppression") in a T-independent immune response. It is proposed that the response to a T- independent antigen is regulated by specific suppressor activity generated by a non-T cell and augmented by the interaction of this cell with a T cell. The suppressor activity can be blocked by a specific abrosuppressor T cell. It is suggested that, because suppressor activity appears dominant in the naive state of the immune system, the induction of specific abrosuppressor activity may be essential if an immune response is to take place.
Around 1000 women with private sector PIP implants seek NHS help
Authors: A. O'Dowd
Journal: BMJ (2012)

Around 1000 women in the United Kingdom who had breast implantation procedures carried out privately using implants made by the discredited French manufacturer Poly Implant Prosthese (PIP) have come to the NHS seeking help.

However, it is still unclear just how much the NHS will be asked to help in the cases of the almost 40 000 women in the UK who have PIP implants, said Bruce Keogh, medical director for the NHS in England, who is heading an ongoing inquiry into the issue.

PIP closed last year after it emerged that it had used non-medical grade silicone in its breast implants. The NHS in England has advised women with the implants not to have them removed automatically but to seek clinical advice. With the approval of their doctor they can have them removed by the NHS but will have new implants inserted only in NHS cases ( BMJ 2012;344:e478, 17 Jan, …
Immunosuppression and the rheumatic diseases.
Authors: A M Denman
Journal: Annals of the Rheumatic Diseases (1982)

Ignorance of the basic nature of rheumatoid arthritis precludes the introduction of rational schemes for using cytotoxic drugs. It is still plausible that the autoimmune and other immunological abnormalities which accompany this disease are the secondary effects of persistent antigen, for example, related to microbial infections. In this event, cytotoxic drugs may diminish the inflammatory response but their effects on immune responses would be irrelevant or even undesirable. Should rheumatoid arthritis prove to be a primary immunoproliferative disorder, cytotoxic drugs may prove to be of value not because of their conventional immunosuppressive effects but because of their selective action on the proliferating cells. Indeed, current evidence suggests that these drugs enhance rather than depress conventional immune responses, at least in the doses given to patients with rheumatic disorders.
Gene Expression Signatures for Predicting Prognosis of Squamous Cell and Adenocarcinomas of the Lung
Authors: Mitch Raponi, Yi Zhang, Jack Yu, Guoan Chen, Grace Lee, Jeremy M.G. Taylor, James MacDonald, Dafydd Thomas, Christopher Moskaluk, Yixin Wang, David G. Beer
Journal: Cancer Research (2006)

Abstract Non–small-cell lung cancers (NSCLC) compose 80% of all lung carcinomas with squamous cell carcinomas (SCC) and adenocarcinoma representing the majority of these tumors. Although patients with early-stage NSCLC typically have a better outcome, 35% to 50% will relapse within 5 years after surgical treatment. We have profiled primary squamous cell lung carcinomas from 129 patients using Affymetrix U133A gene chips. Unsupervised analysis revealed two clusters of SCC that had no correlation with tumor stage but had significantly different overall patient survival (P = 0.036). The high-risk cluster was most significantly associated with down-regulation of epidermal development genes. Cox proportional hazard models identified an optimal set of 50 prognostic mRNA transcripts using a 5-fold cross-validation procedure. Quantitative reverse transcription-PCR and immunohistochemistry using tissue microarrays were used to validate individual gene candidates. This signature was tested in an independent set of 36 SCC samples and achieved 84% specificity and 41% sensitivity with an overall predictive accuracy of 68%. Kaplan-Meier analysis showed clear stratification of high-risk and low-risk patients [log-rank P = 0.04; hazard ratio (HR), 2.66; 95% confidence interval (95% CI), 1.01-7.05]. Finally, we combined the SCC classifier with our previously identified adenocarcinoma prognostic signature and showed that the combined classifier had a predictive accuracy of 71% in 72 NSCLC samples also showing significant differences in overall survival (log-rank P = 0.0002; HR, 3.54; 95% CI, 1.74-7.19). This prognostic signature could be used to identify patients with early-stage high-risk NSCLC who might benefit from adjuvant therapy following surgery. (Cancer Res 2006; 66(15): 7466-72)
Autoantibodies to a 38-kDa Glycosylated Islet Cell Membrane–Associated Antigen in (Pre)type 1 Diabetes
Authors: Frederic Winnock, Michael R. Christie, Manou R. Batstra, Henk-Jan Aanstoot, Ilse Weets, Katelijn Decochez, Philippe Jopart, Dany Nicolaij, Frans K. Gorus
Journal: Diabetes Care (2001)

OBJECTIVE—To study the association of autoantibodies against a 38-kDa glycated islet cell membrane–associated (GLIMA) protein with (pre)type 1 diabetes, patient characteristics, and other immune and genetic markers of the disease and to evaluate the possible added value of GLIMA antibody determinations for disease prediction and classification. RESEARCH DESIGN AND METHODS—Recent-onset type 1 diabetic patients (n = 100), prediabetic siblings (n = 23), and nondiabetic control subjects (n = 100) were consecutively recruited by the Belgian Diabetes Registry. GLIMA antibodies were determined by immunoprecipitation of radiolabeled islet cell proteins; islet cell antibodies (ICAs) were determined by indirect immunofluorescence; and insulin autoantibodies (IAAs), insulinoma-associated protein-2 antibodies (IA-2As), and GAD antibodies (GADAs) were determined by radioligand assays. RESULTS— GLIMA antibodies were detected in 38% of type 1 diabetic patients and 35% of prediabetic siblings (during follow-up) vs. 0% in control subjects (P &amp;lt; 0.001). Their prevalence was lower than that of other antibodies and was significantly associated with high levels of IA-2A and ICA (P &amp;lt; 0.0001). In (pre)diabetes, GLIMA antibodies could only be demonstrated in sera positive for ≥1 other autoantibody. CONCLUSIONS— GLIMA antibodies are strongly associated with type 1 diabetes and antibody markers of rapid progression to clinical onset but have a lower diagnostic sensitivity for the disease than IAA, ICA, IA-2A, or GADA. In its present form, the GLIMA antibody assay does not provide much additional information for prediction or classification of diabetes, compared with that obtained from the measurement of IA-2As alone or in combination with IAAs, ICAs, and GADAs.
FTY720 Stimulates 27-Hydroxycholesterol Production and Confers Atheroprotective Effects in Human Primary Macrophages
Authors: Tomas Blom, Nils Bäck, Aino-Liisa Mutka, Robert Bittman, Zaiguo Li, Angel de Lera, Petri T. Kovanen, Ulf Diczfalusy, Elina Ikonen
Journal: Circulation Research (2010)

The synthetic sphingosine analog FTY720 is undergoing clinical trials as an immunomodulatory compound, acting primarily via sphingosine 1-phosphate receptor activation. Sphingolipid and cholesterol homeostasis are closely connected but whether FTY720 affects atherogenesis in humans is not known.We examined the effects of FTY720 on the processing of scavenged lipoprotein cholesterol in human primary monocyte-derived macrophages.FTY720 did not affect cholesterol uptake but inhibited its delivery to the endoplasmic reticulum, reducing cellular free cholesterol cytotoxicity. This was accompanied by increased levels of Niemann-Pick C1 protein (NPC1) and ATP-binding cassette transporter (ABC)A1 proteins and increased efflux of endosomal cholesterol to apolipoprotein A-I. These effects were not dependent on sphingosine 1-phosphate receptor activation. Instead, FTY720 stimulated the production of 27-hydroxycholesterol, an endogenous ligand of the liver X receptor, leading to liver X receptor-induced upregulation of ABCA1. Fluorescently labeled FTY720 was targeted to late endosomes, and the FTY720-induced upregulation of ABCA1 was NPC1-dependent, but the endosomal exit of FTY720 itself was not.We conclude that FTY720 decreases cholesterol toxicity in primary human macrophages by reducing the delivery of scavenged lipoprotein cholesterol to the endoplasmic reticulum and facilitating its release to physiological extracellular acceptors. Furthermore, FTY720 stimulates 27-hydroxycholesterol production, providing an explanation for the atheroprotective effects and identifying a novel mechanism by which FTY720 modulates signaling.
MicroRNAs: tools for cancer diagnostics
Authors: T Paranjape, F J Slack, J B Weidhaas
Journal: Gut (2009)

Recently, a novel class of global gene regulators called microRNAs (miRNAs), were identified in both plants and animals. MiRNAs can reduce protein levels of their target genes with a minor impact on the target genes' mRNAs. Accumulating evidence demonstrates the importance of miRNAs in cancer. MiRNAs that are overexpressed in cancer may function as oncogenes, and miRNAs with tumour suppressor activity in normal tissue may be downregulated in cancer. Although major advances have been achieved in our understanding of cancer biology, as well as in the development of new targeted therapies, the progress in developing improved early diagnosis and screening tests has been inadequate. This results in most cancers being diagnosed in advanced stages, delaying timely treatment and leading to poor outcomes. There is intense research seeking specific molecular changes that are able to identify patients with early cancer or precursor lesions. MiRNA expression data in various cancers demonstrate that cancer cells have different miRNA profiles compared with normal cells, thus underscoring the tremendous diagnostic and therapeutic potential of miRNAs in cancer. These unique properties of miRNAs make them extremely useful potential agents for clinical diagnostics as well as in personalised care for individual patients in the future.
Severe asthma in the workplace
Authors: S Saeed
Journal: Thorax (2007)

▴ Eisner MD, Yelin EH, Katz PP, et al. Risk factors for work disability in severe adult asthma. Am J Med2006;119:884–91.

[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4]



In this study, a cohort of 465 patients with severe asthma was evaluated for the prevalence of and risk factors for asthma-related work disability. Additionally, the longitudinal impact of workplace disability and exposures on asthma outcome and health service use was observed.

The prevalence of asthma-related complete work disability was 14% (95% CI 11% …

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One size does not fit all - Impact of the one liter tidal volume breathing protocol on indices from nitrogen multiple-breath washout in children
Authors: Sophie Yammine, Florian Singer, Philipp Latzin
Journal: European Respiratory Journal (2012)

Background Nitrogen multiple-breath washout (N2MBW) is a useful tidal breathing lung function test to assess ventilation inhomogeneity (VI), e.g. in Cystic Fibrosis (CF) patients. One liter tidal volume (VT) breathing protocols are regarded to improve comparability of results between subjects breathing at different VT and are widely used in adults. The impact of protocols using fixed VT on results in children is unknown. We assessed whether breathing at fixed VT impacts N2MBW indices in school-aged children.

Methods Ten children with CF and 16 healthy children performed six N2MBW tests using a validated setup (Exhalyzer D, Eco Medics, Switzerland). Children performed three baseline N2MBW at free tidal breathing and three N2MBW at increased VT with a target of one liter using an incentive. Outcomes were size and variability of lung clearance index (LCI), functional residual capacity (FRC), Scond and Sacin.

Results All 26 children achieved six N2MBW. Mean (SD) VT at free tidal breathing was 0.5 (0.1) L, at fixed VT 1.2 (0.2) L. Comparing free tidal breathing with the one liter VT N2MBW, LCI increased on average (95% CI) 2.3 (0.6-3.9) in CF children and 1.4 (0.5-2.3) in healthy children. LCI increased by more than one LCI unit in 9 out of 10 CF children and in 14 out of 16 healthy children. FRC decreased, Scond and Sacin increased significantly. Variability within tests and between subjects increased for all MBW outcomes.

Conclusion Fixed tidal breathing protocols impact N2MBW indices as shown for the one liter VT protocol in school-aged children. Underlying physiological mechanisms and applicability in adult patients require further study.
Prevention and Management of Postprostatectomy Sexual Dysfunctions Part 2: Recovery and Preservation of Erectile Function, Sexual Desire, and Orgasmic Function
Authors: Andrea Salonia, Arthur L. Burnett, Markus Graefen, Kostas Hatzimouratidis, Francesco Montorsi, John P. Mulhall, Christian Stief
Journal: European Urology (2012)