tbuckley/cabot-search huggingface dataset:
Getting consent for necropsies
Authors: J. L Burton, I. Scheimberg, A. W Bates, A. Lee, M Holbrook, G Morgan
Journal: BMJ (2001)

Editor—Sayers and Mair highlight the reasons for which hospital (consent) necropsies are performed and for which clinicians are now faced with the task of seeking informed consent—to confirm the cause of death, to answer diagnostic queries, and to obtain and retain material for research and teaching.1 Another key use of a necropsy, not mentioned on the consent form, is in undergraduate teaching. Many medical students will encounter the necropsy during their training, either witnessing the whole procedure or as a demonstration of the pathological findings of the procedure in which organs and tissues are displayed (perhaps with the patient's body in the background) before their return to the body.

Should explicit informed consent be obtained to use necropsy in this way? The short report by Westberg et al in the same issue serves to highlight the importance of obtaining consent for students to witness invasive procedures such as a vaginal examination, even though most patients do not object.2 Necropsy is no less invasive. Whether patients and relatives would object to a group of students viewing the body after death is not known. It is established, however, that “an important precondition for good education of medical students is that patients are prepared to participate in training.”3 Failure to obtain consent denies the autonomy of both the patient and the relatives.

Some people argue that, once death has occurred and the decision to allow a necropsy has been taken, the worst is over and therefore the presence of students at the necropsy is of no consequence and does not require consent. This denies relatives the opportunity to be altruistic and know of the benefits that come to students from the procedure. We should be as concerned that consent is adequate as we are with who obtains it.
Interleukin 1 beta, hand and foot bone mineral content and the development of joint erosions in rheumatoid arthritis.
Authors: J North, R D Situnayake, M Tikly, A Cremona, J Nicoll, D S Kumararatne, G Nuki
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVE--To assess the relationship between plasma levels of the cytokine interleukin-1 beta (IL-1 beta) and the progression of rheumatoid arthritis (RA). METHODS--Two subgroups of patients, one with persistently raised ESR (&gt;/= 50 mm/hour, n = 16, group A) and one with persistently low ESR (&lt;/= 28 mm/hour), n = 18, group I) were chosen to represent stable extremes of inflammatory activity from a prospective study of 106 patients with active RA studied over one year in a single centre. The change from baseline in hand, foot and calcaneal bone mineral content measured by single photon absorptiometry and radiographic score of joint damage was measured over 12 months, together with plasma IL-1 beta and erythrocyte sedimentation rate. RESULTS--Significant progression of joint damage occurred in both subgroups over one year (p &lt; 0.0001, paired t test) though progression was significantly less in the subgroup with low ESR (p &lt; 0.05, ANOVA). Hand and foot bone mineral content decreased by almost 10% in the subgroup with raised ESR (p &lt; 0.005, paired t test). Stepwise linear regression analysis revealed significant independent relationships between radiographic progression over one year and plasma IL-1 beta and ESR (multiple R 0.674, F = 11.64, p &lt; 0.0002). No such relationships were observed for changes in bone mineral content parameters. CONCLUSIONS--Plasma IL-1 beta levels correlate weakly with progression of joint damage though not with loss of peripheral bone density in RA. A significant reduction in peripheral bone mineral content occurs over one year in patients with active RA with persistently raised ESR.
Significance of filamin A in mTORC2 function in glioblastoma
Authors: Naphat Chantaravisoot, Piriya Wongkongkathep, Joseph A. Loo, Paul S. Mischel, Fuyuhiko Tamanoi
Journal: Molecular Cancer (2015)

Glioblastoma multiforme (GBM) is one of the most highly metastatic cancers. GBM has been associated with a high level of the mechanistic target of rapamycin complex 2 (mTORC2) activity. We aimed to observe roles of mTORC2 in GBM cells especially on actin cytoskeleton reorganization, cell migration and invasion, and further determine new important players involved in the regulation of these cellular processes. To further investigate the significance of mTORC2 in GBM, we treated GBM cells with PP242, an ATP-competitive inhibitor of mTOR, and used RICTOR siRNA to knock down mTORC2 activity. Effects on actin cytoskeleton, focal adhesion, migration, and invasion of GBM cells were examined. To gain insight into molecular basis of the mTORC2 effects on cellular cytoskeletal arrangement and motility/invasion, we affinity purified mTORC2 from GBM cells and identified proteins of interest by mass spectrometry. Characterization of the protein of interest was performed. In addition to the inhibition of mTORC2 activity, we demonstrated significant alteration of actin distribution as revealed by the use of phalloidin staining. Furthermore, vinculin staining was altered which suggests changes in focal adhesion. Inhibition of cell migration and invasion was observed with PP242. Two major proteins that are associated with this mTORC2 multiprotein complex were found. Mass spectrometry identified one of them as Filamin A (FLNA). Association of FLNA with RICTOR but not mTOR was demonstrated. Moreover, in vitro, purified mTORC2 can phosphorylate FLNA likewise its known substrate, AKT. In GBM cells, colocalization of FLNA with RICTOR was observed, and the overall amounts of FLNA protein as well as phosphorylated FLNA are high. Upon treatments of RICTOR siRNA or PP242, phosphorylated FLNA levels at the regulatory residue (Ser2152) decreased. This treatment also disrupted colocalization of Actin filaments and FLNA. Our results support FLNA as a new downstream effector of mTORC2 controlling GBM cell motility. This new mTORC2-FLNA signaling pathway plays important roles in motility and invasion of glioblastoma cells.
Maternal and paternal contribution to intergenerational recurrence of breech delivery: population based cohort study
Authors: Tone Irene Nordtveit, Kari Klungsoyr Melve, Susanne Albrechtsen, Rolv Skjaerven
Journal: BMJ (2008)

<b>Objective</b> To investigate intergenerational recurrence of breech delivery, with a hypothesis that both women and men delivered in breech presentation contribute to increased risk of breech delivery in their offspring. <b>Design</b> Population based cohort study for two generations. <b>Setting</b> Data from the medical birth registry of Norway, based on all births in Norway 1967-2004 (2.2 million births). <b>Participants</b> Generational data were provided through linkage by national identification numbers, forming 451 393 mother-offspring units and 295 253 father-offspring units. We included units where both parents and offspring were singletons and offspring were first born, forming 232 704 mother-offspring units and 154 851 father-offspring units for our analyses. <b>Main outcome measure</b> Breech delivery in the second generation. <b>Results</b> Men and women who themselves were delivered in breech presentation had more than twice the risk of breech delivery in their own first pregnancies compared with men and women who had been cephalic presentations (odds ratios 2.2, 95% confidence interval 1.8 to 2.7, and 2.2, 1.9 to 2.5, for men and women, respectively). The strongest risks of recurrence were found for vaginally delivered offspring and were equally strong for men and women. Increased risk of recurrence of breech delivery in offspring was present only for parents delivered at term. <b>Conclusion</b> Intergenerational recurrence risk of breech delivery in offspring was equally high when transmitted through fathers and mothers. It seems reasonable to attribute the observed pattern of familial predisposition to term breech delivery to genetic inheritance, predominantly through the fetus.
A Maladaptive Role for EP4 Receptors in Podocytes
Authors: Erin M. Stitt-Cavanagh, Wissam H. Faour, Kaede Takami, Anthony Carter, Barbara Vanderhyden, Youfei Guan, Andre Schneider, Matthew D. Breyer, Christopher R.J. Kennedy
Journal: Journal of the American Society of Nephrology (2010)

Inhibition of p38 mitogen-activated protein kinase and cyclooxygenase-2 reduces albuminuria in models of chronic kidney disease marked by podocyte injury. Previously, we identified a feedback loop in podocytes whereby an in vitro surrogate for glomerular capillary pressure (i.e., mechanical stretch) along with prostaglandin E(2) stimulation of its EP4 receptor induced cyclooxygenase-2 in a p38-dependent manner. Here we asked whether stimulation of EP4 receptors would exacerbate glomerulopathies associated with enhanced glomerular capillary pressure. We generated mice with either podocyte-specific overexpression or depletion of the EP4 receptor (EP4(pod+) and EP4(pod-/-), respectively). Glomerular prostaglandin E(2)-stimulated cAMP levels were eightfold greater for EP4(pod+) mice compared with nontransgenic (non-TG) mice. In contrast, EP4 mRNA levels were >50% lower, and prostaglandin E(2)-induced cAMP synthesis was absent in podocytes isolated from EP4(pod-/-) mice. Non-TG and EP4(pod+) mice underwent 5/6 nephrectomy and exhibited similar increases in systolic BP (+25 mmHg) by 4 weeks compared with sham-operated controls. Two weeks after nephrectomy, the albumin-creatinine ratio of EP4(pod+) mice (3438 μg/mg) was significantly higher than that of non-TG mice (773 μg/mg; P < 0.0001). Consistent with more severe renal injury, the survival rate for nephrectomized EP4(pod+) mice was significantly lower than that for non-TG mice (14 versus 67%). In contrast, 6 weeks after nephrectomy, the albumin-creatinine ratio of EP4(pod-/-) mice (753 μg/mg) was significantly lower than that of non-TG mice (2516 μg/mg; P < 0.05). These findings suggest that prostaglandin E(2), acting via EP4 receptors contributes to podocyte injury and compromises the glomerular filtration barrier.
Radiation synovectomy with yttrium-90 for persisting arthritis has direct harmful effects on human cartilage that cannot be prevented by co-administration of glucocorticoids: an in vitro study
Authors: Z N Jahangier
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> It was recently shown that radiation synovectomy with yttrium-90 (<sup>90</sup>Y) and glucocorticoids is not superior to intra-articular glucocorticoids alone in the treatment of persistent gonarthritis. In that study, it seemed that in patients treated by radiation synovectomy, progression of radiographic joint damage occurred. <b>Objective:</b> To test in vitro the direct effects of radiation synovectomy with <sup>90</sup>Y on human cartilage. <b>Methods:</b> Human cartilage tissue was exposed to <sup>90</sup>Y, glucocorticoids or the combination. 1:2000 to 1:20 dilutions of the clinical dose of 5 mCi/ml <sup>90</sup>Y and 20 mg/ml glucocorticoids were used. After a 4-day exposure and a subsequent 12-day recovery period, proteoglycan synthesis, proteoglycan release and proteoglycan content were measured. In addition, human synovial tissue was cultured for 4 days with <sup>90</sup>Y or glucocorticoids. Culture supernatants were analysed for cartilage-destructive activity. <b>Results:</b><sup>90</sup>Y, glucocorticoids and the combination inhibited proteoglycan synthesis considerably and dose dependently, an effect that sustained for at least 12 days. Proteoglycan release was transiently increased by <sup>90</sup>Y, an effect that was not changed by addition of glucocorticoids, which had no effect on its own. Proteoglycan content was eventually adversely affected by <sup>90</sup>Y, an effect hardly influenced by glucocorticoids. Neither <sup>90</sup>Y nor glucocorticoids changed the cartilage-destructive properties of synovial tissue. <b>Conclusions:</b><sup>90</sup>Y, but not glucocorticoids, has direct harmful effects on cartilage in vitro. Indirect beneficial effects of <sup>90</sup>Y via inhibition of cartilage-destructive properties of synovial tissue could not be shown. These observations may explain the possible radiographic joint damage on radiation synovectomy.
An Address ON ERRORS OF DIAGNOSIS IN MEDICINE: Delivered before the Bradford Medico-Chirurgical Society, November 23rd, 1904
Authors: J. R. Bradford
Journal: BMJ (1905)

GENTLEMEN,-In seeking a subject upon which to address you in response to the kind invitation of yourself and the Council of the Society I thought it desirable to choose one of general interest, and therefore I have selected after consideration the subject of *" Errors of Diagnosis in Medicine."This is a matter of importance to all practitioners, not only from the frequency of our errors dependent largely on the complexity of the subject of medicine, but also,' I think, because every one will admit that we learn more from a consideration of our errors than from the study of cases where the diagnosis is verified.One of the
Immune-mediated inflammation directly impairs pulmonary function, contributing to the pathogenesis of Pneumocystis carinii pneumonia
Authors: Terry W. Wright, Francis Gigliotti, Jacob N. Finkelstein, John T. McBride, Chun Li An, Allen G. Harmsen
Journal: Journal of Clinical Investigation (1999)

The clinical severity of Pneumocystis carinii pneumonia (PCP) correlates closely with the appearance of pulmonary markers of inflammation. Therefore, a model system was developed whereby physiological studies could be performed on live mice to determine the extent to which pulmonary inflammation contributes to respiratory impairment during PCP. P. carinii–infected severe combined immunodeficient mice displayed little evidence of pulmonary inflammation and exhibited normal oxygenation and dynamic lung compliance. When comparably infected littermates were immunologically reconstituted, however, an intense immune-mediated inflammatory response was observed that resulted in significant decreases in both lung compliance and oxygenation. As the pneumonia resolved pulmonary function returned toward normal. To begin to define the cell populations contributing to inflammation-associated respiratory impairment during PCP, similar studies were performed in CD4+ T cell–depleted mice. Mice depleted of both CD4+ and CD8+ cells developed infection, but they demonstrated neither abnormal lung compliance nor increased respiratory rate and displayed no markers of lung injury. In contrast, mice depleted of only CD4+ T cells exhibited severe pulmonary inflammation and injury, decreased oxygenation and lung compliance, and increased respirations. Respiratory compromise was associated with the presence of activated CD8+ cells and neutrophils in broncho-alveolar lavage fluid. These observations provide direct experimental evidence that the host’s response to P. carinii directly impairs pulmonary function and contributes to the pathogenesis of PCP. Furthermore, CD8+ T cells likely contribute to the respiratory compromise observed during PCP.
Betacellulin and Amphiregulin Induce Upregulation of Cyclin D1 and DNA Synthesis Activity Through Differential Signaling Pathways in Vascular Smooth Muscle Cells
Authors: Hyoung Seek Shin, Hyo Jeong Lee, Makoto Nishida, Mi-Sook Lee, Ritsu Tamura, Shizuya Yamashita, Yuji Matsuzawa, In-Kyu Lee, Gou Young Koh
Journal: Circulation Research (2003)

Activation of EGF receptors is closely involved in vascular proliferative diseases. The signaling mechanisms of EGF ligands, including betacellulin (BTC) and amphiregulin (AR), are poorly understood. We examined how BTC and AR induced DNA synthesis activity in primary cultures of human thoracic aortic smooth muscle cells (HTASMCs). BTC induced phosphorylation of all four EGF receptors present on HTASMCs: ErbB1, ErbB2, ErbB3, and ErbB4. BTC rapidly induced the phosphorylation of Akt, GSK3α/β, and two FoxO factors, FKHR and AFX, in a dose- and time-dependent manner. BTC increased nuclear β-catenin accumulation. BTC increased cyclin D1 mRNA, cyclin D1 protein, and DNA synthesis activity. Pretreatment with the phosphatidylinositol 3′-kinase (PI 3′-kinase) inhibitor wortmannin suppressed BTC-induced cyclin D1 mRNA and protein and DNA synthesis activity. In contrast, AR, a specific ErbB1 ligand, induced sustained ERK1/2 and Elk1 phosphorylation, increased cyclin D1 mRNA and protein, and increased DNA synthesis activity. AR did not produce any changes in Akt phosphorylation. Pretreatment with PD98059 suppressed AR-induced cyclin D1 mRNA and protein. Thus, the PI 3′-kinase/Akt/GSK/FoxO/β-catenin pathway could be the major signaling cascade for BTC-induced upregulation of cyclin D1 protein, whereas a sustained ERK/Elk1 activation could be the major signaling cascade for AR-induced upregulation of cyclin D1 protein in HTASMCs. Moreover, immunohistochemical staining revealed that that BTC, ErbB1, and ErbB4 are upregulated in the plaques of human atherosclerotic coronary arteries. Taken together, BTC and AR could be potent growth factors in proliferative vascular diseases.
Dependence of antibody gene diversification on uracil excision
Authors: Javier M. Di Noia, Gareth T. Williams, Denice T.Y. Chan, Jean-Marie Buerstedde, Geoff S. Baldwin, Michael S. Neuberger
Journal: The Journal of Experimental Medicine (2007)

Activation-induced deaminase (AID) catalyses deamination of deoxycytidine to deoxyuridine within immunoglobulin loci, triggering pathways of antibody diversification that are largely dependent on uracil-DNA glycosylase (uracil-N-glycolase [UNG]). Surprisingly efficient class switch recombination is restored to ung−/− B cells through retroviral delivery of active-site mutants of UNG, stimulating discussion about the need for UNG's uracil-excision activity. In this study, however, we find that even with the overexpression achieved through retroviral delivery, switching is only mediated by UNG mutants that retain detectable excision activity, with this switching being especially dependent on MSH2. In contrast to their potentiation of switching, low-activity UNGs are relatively ineffective in restoring transversion mutations at C:G pairs during hypermutation, or in restoring gene conversion in stably transfected DT40 cells. The results indicate that UNG does, indeed, act through uracil excision, but suggest that, in the presence of MSH2, efficient switch recombination requires base excision at only a small proportion of the AID-generated uracils in the S region. Interestingly, enforced expression of thymine-DNA glycosylase (which can excise U from U:G mispairs) does not (unlike enforced UNG or SMUG1 expression) potentiate efficient switching, which is consistent with a need either for specific recruitment of the uracil-excision enzyme or for it to be active on single-stranded DNA.
Protein Haptenation by Amoxicillin: Immunological Detection with Monoclonal Anti-Amoxicillin Antibodies and Identification of Candidate Target Proteins in Human Serum
Authors: Adriana Ariza, Daniel Ruiz-Abánades, Vivian de los Ríos, Miguel Blanca, María José Torres, Dolores Pérez-Sala
Journal: Journal of Allergy and Clinical Immunology (2013)
Effect of YM529 on a Model of Mandibular Invasion by Oral Squamous Cell Carcinoma in Mice
Authors: Nianhui Cui, Takeshi Nomura, Hiroyasu Noma, Keiko Yokoo, Ryo Takagi, Sadamitsu Hashimoto, Masato Okamoto, Mitsunobu Sato, Guangyan Yu, Chuanbin Guo, Takahiko Shibahala
Journal: Clinical Cancer Research (2005)

Abstract Purpose: This study examined the mechanisms of osteoclast-mediated bone invasion in a model of oral squamous cell carcinoma (OSCC). C3H/HeN mice were inoculated with SCC VII cells into the masseter region to establish an animal model of mandibular invasion by OSCC. Experimental Design: The mice were divided into three groups: a control group, given daily s.c. injections of saline; group 1, given 2 μg per mouse per day of the bisphosphonate YM529; and group 2, given 10 μg per mouse per day of YM529. After 3 weeks of treatment, the lesions were studied by micro-computed tomography. After tartrate-resistant acid phosphatase (TRAP) staining, the osteoclasts were easily identified, and the percentages of the area occupied by osteoclasts were calculated by computer for each sample. The tumors were analyzed by RT-PCR to determine the mRNA expression of interleukin-6 (IL-6), parathyroid hormone–related protein (PTHrP), tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin. Results: SCC VII cells rapidly multiplied in the masseter muscle of the mice. Bone invasion was evident only in the control group on micro-computed tomography. On TRAP-stained slices, the percentages of osteoclasts in groups 1 and 2 were significantly lower than that in the control group. The mRNA expressions of IL-6, PTHrP, THF-α, and RANK decreased as the concentration of YM529 increased. Conclusions: We conclude that various cancer-derived cytokines play important roles in the invasion of bone by OSCC. YM529, a third-generation bisphosphonate, can suppress osteoclast-mediated bone invasion by OSCC. The mechanism of this effect might involve inhibition of cytokines such as IL-6, PTHrP, TNF-α, and RANK by YM529.
IgE Reactivity to Paecilomyces variotii Antigens in Fungal Sensitized Patients
Authors: B.J. Green, F.M. Blachere, D.H. Beezhold, D.N. Weissman, M.B. Hogan, N.W. Wilson, D. Schmechel
Journal: Journal of Allergy and Clinical Immunology (2007)
Chk2 Molecular Interaction Map and Rationale for Chk2 Inhibitors
Authors: Yves Pommier, John N. Weinstein, Mirit I. Aladjem, Kurt W. Kohn
Journal: Clinical Cancer Research (2006)

Abstract To organize the rapidly accumulating information on bioregulatory networks related to the histone γ-H2AX-ATM-Chk2-p53-Mdm2 pathways in concise and unambiguous diagrams, we used the molecular interaction map notation (http://discover.nci.nih.gov/min). Molecular interaction maps are particularly useful for networks that include protein-protein binding and posttranslational modifications (e.g., phosphorylation). Both are important for nearly all of the proteins involved in DNA double-strand break signaling. Visualizing the regulatory circuits underlying cellular signaling may help identify key regulatory reactions and defects that can serve as targets for anticancer drugs.