tbuckley/cabot-search huggingface dataset:
<i>IRF8</i>Mutations and Human Dendritic-Cell Immunodeficiency
Authors: Sophie Hambleton, Sandra Salem, Jacinta Bustamante, Venetia Bigley, Stéphanie Boisson-Dupuis, Joana Azevedo, Anny Fortin, Muzlifah Haniffa, Lourdes Ceron-Gutierrez, Chris M. Bacon, Geetha Menon, Céline Trouillet, David McDonald, Peter Carey, Florent Ginhoux, Laia Alsina, Timothy J. Zumwalt, Xiao-Fei Kong, Dinakantha Kumararatne, Karina Butler, Marjorie Hubeau, Jacqueline Feinberg, Saleh Al-Muhsen, Andrew Cant, Laurent Abel, Damien Chaussabel, Rainer Doffinger, Eduardo Talesnik, Anete Grumach, Alberto Duarte, Katia Abarca, Dewton Moraes-Vasconcelos, David Burk, Albert Berghuis, Frédéric Geissmann, Matthew Collin, Jean-Laurent Casanova, Philippe Gros
Journal: New England Journal of Medicine (2011)

The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained.We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease.We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells.These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).
Tumorigenicity and Antigenicity of Mouse Cells Infected With Simian Virus 40. I. Relationship of Growth In Vitro and In Vivo in Immunosuppressed and Immunocompetent Recipients2
Authors: Peter W. Wright, Helene S. Smith, James McCoy
Journal: JNCI Journal of the National Cancer Institute (1973)

The relationship between tumorigenicity and antigenicity of transformed cells in culture was examined. BALB/3T3 and several different classes of simian virus 40 (SV40) transformants derived from BALB/3T3 were tested for their ability to produce tumors in immunosuppressed recipients and to induce specific transplantation resistance to a transplantable SV40 tumor in immunocompetent recipients. SV40 tumors were defined by expression of the SV40 tumor (T) antigen and the SV40 tumor-specific transplantation (TST) antigen. Only SV40-transformed cell lines expressing the TST antigen caused SV40 tumors. Although the “flat” transformants contained the T antigen in culture, they produced no SV40 tumors. Some cell lines lacking the SV40 TST antigen were tumorigenic, but the tumors were not SV40 derived. The SV40 TST antigen appeared to represent a unique marker for cells with the potential to become SV40 tumors.
Mcl-1 Phosphorylation Defines ABT-737 Resistance That Can Be Overcome by Increased NOXA Expression in Leukemic B cells
Authors: Suparna Mazumder, Gaurav S. Choudhary, Sayer Al-harbi, Alexandru Almasan
Journal: Cancer Research (2012)

ABT-737 is a small molecule Bcl-2 homology (BH)-3 domain mimetic that binds to the Bcl-2 family proteins Bcl-2 and Bcl-xL and is currently under investigation in the clinic. In this study, we investigated potential mechanisms of resistance to ABT-737 in leukemia cell lines. Compared with parental cells, cells that have developed acquired resistance to ABT-737 showed increased expression of Mcl-1 in addition to posttranslational modifications that facilitated both Mcl-1 stabilization and its interaction with the BH3-only protein Bim. To sensitize resistant cells, Mcl-1 was targeted by two pan-Bcl-2 family inhibitors, obatoclax and gossypol. Although gossypol was effective only in resistant cells, obatoclax induced cell death in both parental and ABT-737-resistant cells. NOXA levels were increased substantially by treatment with gossypol and its expression was critical for the gossypol response. Mechanistically, the newly generated NOXA interacted with Mcl-1 and displaced Bim from the Mcl-1/Bim complex, freeing Bim to trigger the mitochondrial apoptotic pathway. Together, our findings indicate that NOXA and Mcl-1 are critical determinants for gossypol-mediated cell death in ABT-737-resistant cells. These data therefore reveal novel insight into mechanisms of acquired resistance to ABT-737.
Effect of ethanol on electrogram changes and regional myocardial blood flow during acute myocardial ischaemia
Authors: R. F GILMOUR, R. RUFFY, D E. LOVELACE, T. M MUELLER, D. P ZIPES
Journal: Cardiovascular Research (1981)

Acute occlusion of the left anterior descending coronary artery in dogs produced delayed conduction and diminished amplitude of bipolar electrograms recorded from ischaemic zones. Intravenous infusion of ethanol (1.2 g·kg−1), before coronary artery occlusion, delayed conduction and reduced the amplitude of electrograms recorded in normal myocardium, but attenuated ischaemia-induced electrogram changes produced by the subsequent occlusion. Ethanol (0.6 g·kg−1 iv) did not significantly alter activation of electrograms recorded from normal myocardium, but reduced ischaemia-induced electrogram changes and decreased the incidence of ventricular fibrillation elicited by rapid ventricular pacing from five of eight to one of eight dogs. Infusion of 10 or 30% (V/V) ethanol directly into a non-occluded coronary artery significantly increased conduction time and reduced electrogram amplitude recorded in the epicardium perfused by that coronary artery. These effects were more pronounced when ethanol was infused into an occluded coronary artery distal to the site of occlusion. Ethanol did not alter regional myocardial blood flow determined by labelled microspheres during ischaemia. Thus, despite a direct depressant effect on extracellular electrical activity recorded from normal and ischaemic myocardium, ethanol reduced the severity of ischaemia-induced electrogram alterations and decreased the incidence of ventricular fibrillation when given intravenously prior to coronary artery occlusion
ULTRASTRUCTURE OF ADULT EPIDERMAL CELLS IN MONOLAYER CULTURE
Authors: HILARY CONSTABLE
Journal: British Journal of Dermatology (1972)

Journal Article ULTRASTRUCTURE OF ADULT EPIDERMAL CELLS IN MONOLAYER CULTURE Get access HILARY CONSTABLE HILARY CONSTABLE MRC Unit on the Experimental Pathology of Skin, The Medical School, The University, Birmingham 15 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 86, Issue 1, 1 January 1972, Pages 27–39, https://doi.org/10.1111/j.1365-2133.1972.tb01888.x Published: 01 January 1972 Article history Accepted: 08 September 1971 Published: 01 January 1972
The Pathophysiology of Schizophrenia Disorders: Perspectives From the Spectrum
Authors: Larry J Siever, Kenneth L Davis
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: This overview focuses on neurobiological abnormalities found in subjects with schizotypal personality disorder, the prototype of the schizophrenia spectrum disorders, and chronic schizophrenia in the context of common vulnerabilities shared by schizotypal personality disorder and schizophrenia, as well as the factors that protect against the severe cognitive/social deficits and frank psychosis of chronic schizophrenia. A pathophysiological model of the relationship between schizotypal personality disorder and schizophrenia was developed based on this data. METHOD: The authors provide a selective review of major findings regarding the pathophysiology of schizotypal personality disorder and integrate these results in conjunction with preclinical studies into a model of the pathophysiology of the spectrum. RESULTS: People with schizotypal personality disorder share phenomenological, genetic, and cognitive abnormalities with people with chronic schizophrenia. While temporal volume reductions appear to be common to both groups, there may be preservation of frontal lobe volume in schizotypal personality disorder compared to schizophrenia. Findings to date regarding striatal volume, metabolic rate, and dopamine release in subjects with schizotypal personality disorder compared to subjects with chronic schizophrenia are consistent with hypotheses of reduced striatal dopaminergic activity in schizotypal personality disorder compared to schizophrenia. CONCLUSIONS: Genetic or environmental factors that promote greater frontal capacity and reduced striatal dopaminergic reactivity might contribute to sparing people with schizotypal personality disorder from the psychosis and severe social and cognitive deterioration of chronic schizophrenia. Further research is required to test these hypotheses more definitively.
Erythromelalgia Treated with Posterior Pituitary Extract: Report of a Case
Authors: M. HILL METZ
Journal: Circulation (1950)

Erythromelalgia is a rare vasomotor neurosis of the extremities, with no accepted form of treatment. Posterior pituitary desiccated powder administered by nasal insufflation has a vasoconstricting action lasting for eight to twelve hours. With the use of this agent, one patient was protected from the incapacitating symptoms of erythromelalgia during the summer months.
The Patient-Centered Medical Home and Nephrology
Authors: Thomas D. DuBose, Mary Tessie Behrens, Arnold Berns, Connie Davis, Stanley Goldfarb, Thomas Hostetter, Paul Klotman, Stuart Linas, Susan Owens, Lynda Szczech, Jonathan Himmelfarb
Journal: Journal of the American Society of Nephrology (2009)

The notion of a patient-centered medical home (PCMH) is rapidly gaining traction as the latest idea to transform health care delivery in the United States. In broad terms, PCMH is “a physician-directed practice that provides care that is accessible, continuous, comprehensive and coordinated and
Association between Polymorphisms in DNA Base Excision Repair Genes<i>XRCC1, APE1</i>, and<i>ADPRT</i>and Differentiated Thyroid Carcinoma
Authors: Feng-Yu Chiang, Che-Wei Wu, Pi-Jung Hsiao, Wen-Rei Kuo, Ka-Wo Lee, Jen-Chih Lin, Yi-Chu Liao, Suh-Hang Hank Juo
Journal: Clinical Cancer Research (2008)

Abstract Purpose: DNA BER pathway is related with carcinogenesis. We hypothesized that functional polymorphisms of three BER genes, XRCC1, apurinic/apyrimidinic endonuclease (APE1), and ADPRT, confer risks for DTC and its progression. Experimental Design: Five common nonsynonymous single nucleotide polymorphisms (Arg194Trp, Arg280His, and Arg399Gln for XRCC1; Asp148Glu for APE1; and Val762Ala for ADPRT) were genotyped in Chinese DTC cases and controls. Results: The XRCC1-194Trp/Trp genotype showed a significantly increased risk for DTC (odds ratio, 1.85; 95% confidence interval, 1.11-3.07; P = 0.018). Subset analysis based on regional LN metastasis showed that the genetic effect came primarily from the subjects with LN metastasis (odds ratio, 4.54; 95% confidence interval, 2.11-9.79; P = 0.0001), but no significant association for subjects without LN metastasis. The other four single nucleotide polymorphisms did not show significant results. Haplotype analysis of XRCC1 polymorphisms yielded a significant result (P = 0.004), especially in the subjects with LN metastasis (P = 0.0002). Moreover, we found that XRCC1-194Trp and ADPRT-762Ala variants collectively contributed to an increased risk of the disease and LN metastasis, with the combined variant homozygotes exhibiting the highest 3.18-fold risk for DTC (P = 0.046) and 9.25-fold risk for DTC with LN metastasis (P = 0.004). Conclusions: The XRCC1 polymorphisms, especially the 194Trp allele, may have an effect on DTC development and progression. This variant can interact with ADPRT-762Ala variant to further substantially increase susceptibility to the disease and regional LN metastasis. Identifying these risk genetic markers could provide more insight into the DTC pathogenesis and may also provide information to develop better prevention and therapeutic strategies.
Occupational Allergy in Nurses to a Bulk Laxative
Authors: Lavinia Machado, Olle Zetterström, Erik Fagerberg
Journal: Allergy (1979)

Finely ground psyllium (Plantago ovata) seeds, so-called ispaghula powder is used in bulk laxatives. During the dispensing of these medicines some dust is generated. Allergic symptoms from exposure to this dust was reported by two nurses, one of whom was wroking in a department where exposure to the powder could be considered high. Nineteen other subjects working in the same department were investigated with regard to allergy to ispaghula powder. An extract from ispaghula powder was made and used in RAST and skin tests. Exposure tests with ispaghula powder mixed with crushed rusks were made in symptomatic subjects. Eight out of the 20 investigated subjects from this department reported symptoms which could possibly have been elicited by ispaghula powder. Evidence of sensitization was found in five of them. The use of less dusty (granulated) forms of ispaghula laxatives might diminish the risk of sensitization.
Lung Dose-Volume Parameters and the Risk of Pneumonitis for Patients Treated With Accelerated Partial-Breast Irradiation Using Three-Dimensional Conformal Radiotherapy
Authors: Abram Recht, Marek Ancukiewicz, Mohamed A. Alm El-Din, Xing-Qi Lu, Chrystalla Martin, Stuart M. Berman, Ariel E. Hirsch, Lisa A. Kachnic, Angela Katz, Shannon MacDonald, Elena A. Nedea, Mary Ann Stevenson, Simon N. Powell, Alphonse G. Taghian
Journal: Journal of Clinical Oncology (2009)

There are no data on how complication rates after accelerated partial-breast irradiation delivered by three-dimensional conformal radiotherapy are affected by treatment technique. We therefore examined the risk of pneumonitis in relation to lung dose-volume parameters.Our prospective dose-escalation trial enrolled 198 treated patients from 2003 to 2007. Patients received 32 or 36 Gy in 4-Gy fractions, given twice daily: 29 (14%) were treated with pure photons; 149 (77%) with mixed photons and electrons; and 20 (10%) with protons.There were four cases of pneumonitis at 4, 4, 7, and 9 months after treatment. All were in the 36-Gy cohort and were treated with pure photons. The risk of pneumonitis for the two cohorts combined was: 17% (four of 24) for an ipsilateral lung volume (ILV) receiving 20 Gy or higher (ILV, 20 Gy) of 3% or higher (P = .0002 for comparison to ILV 20 Gy < 3%, Fisher's exact test); 20% (four of 20) for an ILV 10 Gy of 10% or higher (P = .0001); and 15% (four of 26) for an ILV 5 Gy of 20% or higher (P = .0002).The risk of pneumonitis appeared related to the ILV treated. This volume can be reduced by using mixed photons and electron when possible. We recommend that the ILV 20 Gy should be lower than 3%, the ILV 10 Gy lower than 10%, and the ILV 5 Gy lower than 20% when purely coplanar techniques are used.
Specific drugs for a complex disease: can there be a magic bullet against rheumatoid arthritis?
Authors: H.R Barthel, G.R Burmester
Journal: Annals of the Rheumatic Diseases (1995)

The complexity of RA challenges our search for a better understanding of the interconnected networks. Early treatment will certainly avoid some of the problems presented by the complexity of the disease, and combined treatments seem advantageous for advanced disease. The complexity of overt RA will probably not allow a single agent to exert superior efficacy. Unless a treatable infectious cause is identified, a magic bullet, though theoretically possible, might not exist in reality, in particular if the disease is advanced.
PPM1D: The new marker for intestinal stem cells and its role in tumorigenesis.
Authors: Oleg Demidov, Oleg Timofeev, Lwin Hnin, Calvina Kek, Ettore Appella, Dmitry Bulavin
Journal: Clinical Cancer Research (2007)

C5   Colorectal cancer is one of the major causes of cancer-related deaths. To gain further insights into the mechanisms underlying its development, we investigated the role of Wip1 (PPM1D) oncogene using a genetically defined mouse model of APCMin-driven polyposis. We found that the removal of Wip1 phosphatase increased the life-span of APC(Min) mice through a drastic suppression of polyp formation. This protection was dependent on the p53 tumor suppressor, while WNT-beta-catenin pathway, the major driving force in APC(Min) tumorigenesis, was not affected by Wip1 removal. We observed that Wip1 phosphatase was highly expressed in intestinal stem cells (ISC). The long life and rapid rate of cell division make ISC primary candidates for conversion into cancer stem cells through the accumulation of genetic defects associated with cancer induction In Wip1 deficient, but not wild-type, APC(Min) mice ISC undergo p53-dependent apoptosis that significantly increased when the Wnt pathway was constitutively activated, thus eliminating cells with higher oncogenic potential. We propose that Wip1 modulates APC(Min) -driven polyposis by setting a threshold for p53-dependent apoptosis of stem cells, thus preventing their conversion into cancer stem cells.
Mechanism of renin release during acute ureteral constriction in dogs.
Authors: I Eide, E Loyning, O Langård, F Kiil
Journal: Circulation Research (1977)

The relationship between renal arterial pressure and renin release was examined in anesthetized dogs during complete or partial ureteral constriction. During complete ureteral occlusion ureteral pressure rose to 95+/-4 mm Hg and renin release increased from 1.7+/-0.7 to 22.3+/-3.1 mug/min; renal blood flow (RBF) was not significantly changed. Renin release was not further increased during subsequent renal arterial constriction; RBF fell in proportion to perfusion pressure, indicating maximum autoregulated arteriolar dilation. During partial ureteral constriction to a ureteral pressure of 65+/-6 mm Hg, renin release was moderately raised but release mechanisms became fully stimulated when renal arterial pressure was reduced to 104+/-3 mm Hg. By further constricted of the renal artery, RBF fell in proportion to perfusion pressure and renin release remained high and constant. In control experiments without ureteral constriction, renal arterial pressure had to be reduced to below 65+/-8 mm Hg to fully stimulate renin release (22.0+/-3.8 mug/ml which is not different from 22.3+/-3.1 mug/min during ureteral occlusion). During partial ureteral constriction, saline infusion (0.9% NaCl at 40 ml/min) raised urine flow, sodium excretion, renal pelvic pressure, and renin release. Thus, the stimulatory effect on renin release of a rise in ureteral pressure exceeded the inhibitory effect of increased sodium excretion. This observation, together with maximum renin release coinciding with complete arteriolar dilation during various combinations of renal arterial and ureteral constriction, is compatible with the conclusion that arteriolar dilation is predominating stimulus to renin release during ureteral constriction.
Power Doppler sonography in the assessment of synovial tissue of the knee joint in rheumatoid arthritis: a preliminary experience
Authors: M Carotti
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objective:</b> To investigate the intra-articular vascularisation of the synovial pannus in the knee of patients with rheumatoid arthritis (RA) with power Doppler ultrasonography (PDS) and an echo contrast agent and correlate the area under the time-intensity curves with the clinical findings and laboratory measures of disease activity. <b>Method:</b> Forty two patients with RA (31 women, 11 men) with history and signs of knee arthritis, classified according to a modified index of synovitis activity (active, moderately active, and inactive), were studied. Clinical and functional assessment (number of swollen joints, intensity of pain, general health—visual analogue scale, disability index—Health Assessment Questionnaire, Ritchie articular index) and a laboratory evaluation were made on all patients. Disease activity was evaluated using the disease activity score (DAS) and the chronic arthritis systemic index (CASI) for each patient. All patients were examined with conventional ultrasonography and PDS before injection of intravenous ultrasound contrast agent (Levovist). The quantitative estimation of the vascularisation of the synovial membrane was performed with time-intensity curves and calculation of the area under the curves. <b>Results:</b> The mean (SD) value of the area underlying time-intensity curves was 216.2 (33.4) in patients with active synovitis, 186.8 (25.8) in patients with moderately active synovitis, and 169.6 (20.6) in those with inactive synovitis. The mean value of the areas differed significantly between the patients with active and those with inactive synovitis (p&lt;0.01). The mean value of the area under the curve of the entire group was weakly correlated with the number of swollen joints (p=0.038), but a strong correlation was found with composite indexes of disease activity such as the DAS (p=0.006) and CASI (p=0.01). No correlation was found with age, disease duration, and other laboratory and clinical variables. <b>Conclusion:</b> PDS may be a valuable tool to detect fractional vascular volume and to assist clinicians in distinguishing between inflammatory and non-inflammatory pannus. The transit of microbubbles of ultrasound contrast across a tissue can be used to estimate haemodynamic alterations and may have a role in assessing synovial activity and the therapeutic response to treatment of synovitis of the knee joint.
Colo-Broncho-Cutaneous Fistula Complicating Traumatic Diaphragmatic Rupture
Authors: Miles Irving
Journal: Journal of the Royal Society of Medicine (2001)

Dr Biswas and colleagues (February 2001 JRSM, pp. 88-89) indicate that the main message of their case report is that traumatic diaphragmatic hernia can be associated with serious intrathoracic complications, particularly if the colon is ruptured. However, I venture to suggest that this particular case report has a much more important message relating to the failure to follow cumulated experience on how to manage intestinal fistulation following breakdown of intestinal anastomotic repair. It is noteworthy that the previously fit 45-year-old man had two further colonic resections after his initial resection had broken down and formed a fistula. At his second operation, resection was undertaken after failure of attempts at percutaneous drainage and parenteral nutrition to close the fistula. Anastomosis was carried out, despite the fact that there were abscess cavities in the subphrenic space. To those experienced in fistula surgery it would come as no surprise that this second anastomosis, performed in an adverse environment, also broke down and formed a fistula. Despite this, at the third laparotomy yet another anastomosis was carried out although it was considered prudent to ‘protect’ it by a defunctioning loop ileostomy.