tbuckley/cabot-search huggingface dataset:
Molecular Basis of Celiac Disease
Authors: Ludvig M. Sollid
Journal: Annual Review of Immunology (2000)

Celiac disease (CD) is an intestinal disorder with multifactorial etiology. HLA and non-HLA genes together with gluten and possibly additional environmental factors are involved in disease development. Evidence suggests that CD4 + T cells are central in controlling an immune response to gluten that causes the immunopathology, but the actual mechanisms responsible for the tissue damage are as yet only partly characterized. CD provides a good model for HLA-associated diseases, and insight into the mechanism of this disease may well shed light on oral tolerance in humans. The primary HLA association in the majority of CD patients is with DQ2 and in the minority of patients with DQ8. Gluten-reactive T cells can be isolated from small intestinal biopsies of celiac patients but not of non-celiac controls. DQ2 or DQ8, but not other HLA molecules carried by patients, are the predominant restriction elements for these T cells. Lesion-derived T cells predominantly recognize deamidated gluten peptides. A number of distinct T cell epitopes within gluten exist. DQ2 and DQ8 bind the epitopes so that the glutamic acid residues created by deamidation are accommodated in pockets that have a preference for negatively charged side chains. Evidence indicates that deamidation in vivo is mediated by the enzyme tissue transglutaminase (tTG). Notably, tTG can also cross-link glutamine residues of peptides to lysine residues in other proteins including tTG itself. This may result in the formation of complexes of gluten-tTG. These complexes may permit gluten-reactive T cells to provide help to tTG-specific B cells by a mechanism of intramolecular help, thereby explaining the occurrence of gluten-dependent tTG autoantibodies that is a characteristic feature of active CD.
Effects of Adjuvant Tamoxifen on the Endometrium in Postmenopausal Women With Breast Cancer: A Prospective Long-Term Study Using Transvaginal Ultrasound
Authors: Bernd Gerber, Annette Krause, Heiner Müller, Toralf Reimer, Thomas Külz, Josef Makovitzky, Guenter Kundt, Klaus Friese
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To study the value of transvaginal ultrasound (TVS) in endometrial screening of postmenopausal breast cancer patients treated with tamoxifen. PATIENTS AND METHODS: In 247 tamoxifen-treated (20 to 30 mg/d for ≥ 2 years) women and 98 controls, the endometrium was prospectively followed-up by means of TVS every 6 months for up to 5 years. Patients with homogeneous endometrium of more than 10-mm thickness were then scanned repeatedly every 3 months. RESULTS: The mean endometrial thickness was 3.5 ± 1.1 mm before treatment and increased to a maximum of 9.2 ± 5.1 mm after 3 years of tamoxifen application (P &lt; .0001), which was significantly (P &lt; .0001) thicker compared with controls. Fifty-two asymptomatic patients with thickened or morphologically suspect endometrium underwent hysteroscopy and dilatation and curettage (D&amp;C), resulting in four uterine perforations. Histopathologically, atrophy was found in 38 patients (73.1%), polyps in nine, hyperplasia in four, and endometrial cancer in one case. In 20 screened patients who reported vaginal bleeding, five atrophies (25%), five polyps, four hyperplasias, and two endometrial cancers were found. Before hysteroscopy and D&amp;C were performed, 36 (69.2%) of 52 asymptomatic and four (20%) of 20 symptomatic patients were scanned by repeated TVS over 2 to 30 months. Invasive diagnostic procedures were significantly (P &lt; .05) more frequent in younger and obese patients. In the controls, one asymptomatic polyp and one symptomatic hyperplasia were found. CONCLUSION: In tamoxifen-treated patients, TVS offered a high false-positive rate, even with a cutoff value of 10 mm for endometrial thickness and repeated TVS scans. Increased iatrogenic morbidity and only one asymptomatic endometrial carcinoma do not warrant endometrial screening by TVS in tamoxifen-treated patients.
Cut‐off value of red‐blood‐cell‐bound IgG for the diagnosis of Coombs‐negative autoimmune hemolytic anemia
Authors: Toyomi Kamesaki, Takashi Oyamada, Mitsuhiro Omine, Keiya Ozawa, Eiji Kajii
Journal: American Journal of Hematology (2008)

Direct antiglobulin test (DAT)-negative autoimmune hemolytic anemia (Coombs-negative AIHA) is characterized by laboratory evidence of in vivo hemolysis, together with a negative DAT performed by conventional tube technique (CTT) in clinically suspected AIHA patients. The immunoradiometric assay (IRMA) for red-blood-cell-bound immunoglobulin G (RBC-IgG) can be used to diagnose patients in whom CTT does not detect low levels of red cell autoantibodies. We investigated the diagnostic cutoff value of the IRMA for RBC-IgG in Coombs-negative AIHA and calculated its sensitivity and specificity. Of the 140 patients with negative DAT by CTT referred to our laboratory with undiagnosed hemolytic anemia, AIHA was clinically diagnosed in 64 patients (Coombs-negative AIHA). The numbers of Coombs-negative AIHA and non-AIHA patients changed with age and gender. The cutoff values were determined from receiver operating characteristic (ROC) curve according to age and gender. The IRMA for RBC-IgG proved to be sensitive (71.4%) and specific (87.8%) when using these cutoffs. Using these cutoffs for 41 patients with negative DAT referred to our laboratory in 2006, all the pseudonegative cases were treated with steroids before the test. The 31 untreated cases could be grouped using one cutoff value of 78.5 and showed 100% sensitivity and 94% specificity, independent of gender and age. Results indicate that RBC-IgG could become a standard approach for the diagnosis of Coombs-negative AIHA, when measured before treatment.
Mechanical Signaling and the Cellular Response to Extracellular Matrix in Angiogenesis and Cardiovascular Physiology
Authors: Donald E. Ingber
Journal: Circulation Research (2002)

Great advances have been made in the identification of the soluble angiogenic factors, insoluble extracellular matrix (ECM) molecules, and receptor signaling pathways that mediate control of angiogenesis--the growth of blood capillaries. This review focuses on work that explores how endothelial cells integrate these chemical signals with mechanical cues from their local tissue microenvironment so as to produce functional capillary networks that exhibit specialized form as well as function. These studies have revealed that ECM governs whether an endothelial cell will switch between growth, differentiation, motility, or apoptosis programs in response to a soluble stimulus based on its ability to mechanically resist cell tractional forces and thereby produce cell and cytoskeletal distortion. Transmembrane integrin receptors play a key role in this mechanochemical transduction process because they both organize a cytoskeletal signaling complex within the focal adhesion and preferentially focus mechanical forces on this site. Molecular filaments within the internal cytoskeleton--microfilaments, microtubules, and intermediate filaments--also contribute to the cell's structural and functional response to mechanical stress through their role as discrete support elements within a tensegrity-stabilized cytoskeletal array. Importantly, a similar form of mechanical control also has been shown to be involved in the regulation of contractility in vascular smooth muscle cells and cardiac myocytes. Thus, the mechanism by which cells perform mechanochemical transduction and the implications of these findings for morphogenetic control are discussed in the wider context of vascular development and cardiovascular physiology.
Female drug misuse deaths reach new peak in England and Wales
Authors: Adrian O'Dowd
Journal: BMJ (2005)

The annual number of deaths in England and Wales relating to drug misuse has fallen slightly, but the number of women dying has risen, new data from the Office for National Statistics show.

The office's data show that the number of deaths from drug misuse fell from 1565 in 2002 to 1388 in 2003, the lowest figure since 1997 ( Health Statistics Quarterly 2005;25:52-9). Although women are still very much a minority in terms of number of deaths, the number has risen to its highest ever level, 346 (compared …
The Management of Anterior and Posterior Displacements of the Uterus
Authors: J. H. Croom
Journal: BMJ (1888)

<h3>Abstract</h3> The impact of vaccination on SARS-CoV-2 infectiousness is not well understood. We compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P=0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset. <h3>Significance statement</h3> We present longitudinal data on the magnitude, duration and decay rate of viral RNA and the magnitude and duration of infectious virus in nasal specimens from vaccinated and unvaccinated participants. On average, vaccinated participants (infected with the highly transmissible Delta variant) showed a lower probability of having infectious virus after 5 days of symptoms compared to unvaccinated participants (infected with mostly pre-delta viral lineages), even though both groups had a similar magnitude of infectious virus at or near the peak. These data help improve our understanding of the duration of the infectious period when infection occurs following vaccination and serves as a reference for future studies of shedding dynamics following infections with novel variants of concern.
Clinical and Psychosocial Predictors of Suicide Attempts and Nonsuicidal Self-Injury in the Adolescent Depression Antidepressants and Psychotherapy Trial (ADAPT)
Authors: Paul Wilkinson, Raphael Kelvin, Chris Roberts, Bernadka Dubicka, Ian Goodyer
Journal: American Journal of Psychiatry (2011)

Objective: The authors assessed whether clinical and psychosocial factors in depressed adolescents at baseline predict suicide attempts and nonsuicidal self-injury over 28 weeks of follow-up. Method: Participants were 164 adolescents with major depressive disorder taking part in the Adolescent Depression Antidepressants and Psychotherapy Trial (ADAPT). Clinical symptoms, family function, quality of current personal friendships, and suicidal and nonsuicidal self-harm were assessed at baseline. Suicidal and nonsuicidal self-harm thoughts and behaviors were assessed during 28 weeks of follow-up. Results: High suicidality, nonsuicidal self-injury, and poor family function at entry were significant independent predictors of suicide attempts over the 28 weeks of follow-up. Nonsuicidal self-injury over the follow-up period was independently predicted by nonsuicidal self-injury, hopelessness, anxiety disorder, and being younger and female at entry. Conclusions: Both suicidal and nonsuicidal self-harm persisted in depressed adolescents receiving treatment in the ADAPT study. A history of nonsuicidal self-injury prior to treatment is a clinical marker for subsequent suicide attempts and should be as carefully assessed in depressed youths as current suicidal intent and behavior.
Response to Letter Regarding Article, “Differential Cardiac Remodeling in Preload Versus Afterload”
Authors: Karl Toischer, Adam G. Rokita, Bernhard Unsöld, Samuel Sossalla, Alexander Becker, Tim Seidler, Cornelia Grebe, Lena Preuß, Shamindra N. Gupta, Kathie Schmidt, Stephan E. Lehnart, Katrin Schäfer, Lars S. Maier, Gerd Hasenfuss, Wuqiang Zhu, Sean P. Reuter, Loren J. Field, Georgios Kararigas, Vera Regitz-Zagrosek, Nils Teucher, Martina Krüger, Wolfgang A. Linke, Johannes Backs
Journal: Circulation (2011)
Screening for Prostate Cancer: An Update of the Evidence for the U.S. Preventive Services Task Force
Authors: Russell Harris
Journal: Annals of Internal Medicine (2002)

Background: In U.S. men, prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer death. Screening for prostate cancer is controversial. Purpose: To examine for the U.S. Preventive Services Task Force the evidence of benefits and harms of screening and earlier treatment. Data Sources: MEDLINE and the Cochrane Library, experts, and bibliographies of reviews. Study Selection: Researchers developed eight questions representing a logical chain between screening and reduced mortality, along with eligibility criteria for admissible evidence for each question. Admissible evidence was obtained by searching the data sources. Data Extraction: Two reviewers abstracted relevant information using standardized abstraction forms and graded article quality according to Task Force criteria. Data Synthesis: No conclusive direct evidence shows that screening reduces prostate cancer mortality. Some screening tests can detect prostate cancer at an earlier stage than clinical detection. One study provides good evidence that radical prostatectomy reduces disease-specific mortality for men with localized prostate cancer detected clinically. No study has examined the additional benefit of earlier treatment after detection by screening. Men with a life expectancy of fewer than 10 years are unlikely to benefit from screening even under favorable assumptions. Each treatment is associated with several well-documented potential harms. Conclusions: Although potential harms of screening for prostate cancer can be established, the presence or magnitude of potential benefits cannot. Therefore, the net benefit of screening cannot be determined.
Is Optimal Medical Therapy “Optimal Therapy” for Multivessel Coronary Artery Disease?
Authors: David O. Williams, Samip C. Vasaiwala, William E. Boden
Journal: Circulation (2010)

W hen treating patients with coronary artery disease (CAD), clinicians consider whether management should be medical therapy (MT) alone or in addition to coronary revascularization.When revascularization is recommended, both coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) are potential options.Typically, the treatment recommendation is based on clinical presentation, severity and magnitude of ischemia, extent and distribution of coronary anatomic disease, presence of other noncardiac medical conditions, and evidence of the effectiveness of each strategy.
Frequency of occurrence of idiotypes associated with anti-p-azophenylarsonate antibodies arising in mice immunologically suppressed with respect to a cross-reactive idiotype.
Authors: S Ju, A Gray, A Nisonoff
Journal: The Journal of Experimental Medicine (1977)

Inoculation of rabbit anti-idiotypic (anti-id) antibodies suppresses the subsequent appearance of a cross-reactive idiotype (CRI) associated with the anti-p-azophenylarsonate (anti-Ar) antibodies of A/J mice. Such suppressed mice produce normal concentrations of anti-Ar antibodies which lack the CRI, but against which anti-id antisera can be prepared. The anti-Ar antibodies of an individual, suppressed mouse do not in general share idiotype with anti-Ar antibodies of other A/J mice, either suppressed or nonsuppressed. The present experiments were undertaken to quantitate several "private idiotypes" in a large number of hyperimmunized A/J mice. Anti-Ar antibodies of three mice, suppressed for the CRI, were labeled with 125I and subjected to isoelectric focusing. Four single peaks, that were over 90% reactive with autologous antiid, were randomly selected for use as ligands in a radioimmunoassay, and ascitic fluids containing anti-Ar antibodies from 181 A/J mice were tested as inhibitors. Two of the four idiotypes could not be detected in any mouse other than the donor. The concentration of the idiotype was less than 1 part in 1,250 to less than 1 part in 25,000 of the anti-Ar antibody population; these are minimum values. A third idiotype was detected in 3 of the 181 mice, but at very low concentrations. The fourth idiotype was present in 28% of the mice, again at a low concentration. The data support the existence of a very large repertoire of anti-Ar antibodies in the A/J strain and are consistent with a process of random somatic mutation for generating diversity in hypervariable regions. It is proposed that the cross-reactive idiotype may be controlled by a germ line gene or a gene related to a germ line gene through a small number of somatic mutations; and that the idiotypes that were not detectable in other mice were the products of genes that had undergone extensive mutations, with a low probability of recurrence in other mice.
B Lymphocyte Chemotaxis Regulated in Association with Microanatomic Localization, Differentiation State, and B Cell Receptor Engagement
Authors: Conrad C. Bleul, Joachim L. Schultze, Timothy A. Springer
Journal: The Journal of Experimental Medicine (1998)

Migration of mature B lymphocytes within secondary lymphoid organs and recirculation between these sites are thought to allow B cells to obtain T cell help, to undergo somatic hypermutation, to differentiate into effector cells, and to home to sites of antibody production. The mechanisms that direct migration of B lymphocytes are unknown, but there is evidence that G protein–coupled receptors, and possibly chemokine receptors, may be involved. Stromal cell– derived factor (SDF)-1α is a CXC chemokine previously characterized as an efficacious chemoattractant for T lymphocytes and monocytes in peripheral blood. Here we show with purified tonsillar B cells that SDF-1α also attracts naive and memory, but not germinal center (GC) B lymphocytes. Furthermore, GC B cells could be converted to respond to SDF-1α by in vitro differentiation into memory B lymphocytes. Conversely, the migratory response in naive and memory B cells was significantly reduced after B cell receptor engagement and CD40 signaling. The receptor for SDF-1, CXC chemokine receptor 4 (CXCR4), was found to be expressed on responsive as well as unresponsive B cell subsets, but was more rapidly downregulated on responsive cells by ligand. Finally, messenger RNA for SDF-1 was detected by in situ hybridization in a layer of cells surrounding the GC. These findings show that responsiveness to the chemoattractant SDF-1α is regulated during B lymphocyte activation, and correlates with positioning of B lymphocytes within a secondary lymphoid organ.
Finding NEMO mutations
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

A wide variety of inflammatory stimuli trigger the activation of IκB kinase (IKK), the enzyme complex that activates the NF-κB transcription factors. But all NF-κB–inducing signals are not the same, according to Filipe-Santos and colleagues (page 1745), who identify mutations in the regulatory subunit of IKK that selectively disarm just one of these pathways.






Figure 1

CD40-induced nuclear accumulation of NF-κB (green) is blocked by NEMO mutations.




Most NF-κB–inducing stimuli, including byproducts of microbial infection and inflammatory cytokines, trigger the phosphorylation of the α and β subunits of IKK. Heterodimers of IKKα and β then bind to IKKγ (or NEMO)—the regulatory subunit of the complex. Thus assembled, this protein complex phosphorylates the NF-κB inhibitor proteins (IκBs), tagging it for proteasomal degradation and freeing NF-κB for translocation into the nucleus.

Here, Filipe-Santos et al. identify two point mutations in NEMO in patients with an X-linked susceptibility to mycobacterial infection. These mutations blocked the NF-κB–driven production of interleukin (IL)-12 by monocytes and dendritic cells (DCs). But this block occurred only in response to T cell–based signals, triggered by the interaction between CD40 ligand (on activated T cells) and its partner CD40 (on monocytes and DCs). IL-12 production in response to other IKK-inducing stimuli (including bacterial LPS and live mycobacteria) was unaffected.

It is unclear why these NEMO mutations, both in the protein's leucine zipper (LZ) domain, preferentially affect CD40-induced signals. One possibility is that NEMO interacts with distinct IKK-activating kinases depending on the upstream signal, and the LZ domain is required for NEMO to latch on to a specific CD40-triggered kinase.

From the disease standpoint, it makes sense that IL-12-blocking NEMO mutations predispose people to mycobacterial infection, as IL-12 is known to be essential for defending against mycobacteria. Monocytes infected with mycobacteria themselves produce IL-12, but these data suggest that infection-induced IL-12 is not enough to control the growth of the bug. Perhaps the amount of IL-12 is simply too low unless T cells get in on the act.
Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma
Authors: Yuanyuan Ruan, Linlin Sun, Yuqing Hao, Lijing Wang, Jiejie Xu, Wen Zhang, Jianhui Xie, Liang Guo, Lei Zhou, Xiaojing Yun, Hongguang Zhu, Aiguo Shen, Jianxin Gu
Journal: Journal of Clinical Investigation (2012)

Coordinated translation initiation is coupled with cell cycle progression and cell growth, whereas excessive ribosome biogenesis and translation initiation often lead to tumor transformation and survival. Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. We found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in HCC. Aberrant expression of RACK1 contributed to in vitro chemoresistance as well as in vivo tumor growth of HCC. These effects depended on ribosome localization of RACK1. Ribosomal RACK1 coupled with PKCβII to promote the phosphorylation of eukaryotic initiation factor 4E (eIF4E), which led to preferential translation of the potent factors involved in growth and survival. Inhibition of PKCβII or depletion of eIF4E abolished RACK1-mediated chemotherapy resistance of HCC in vitro. Our results imply that RACK1 may function as an internal factor involved in the growth and survival of HCC and suggest that targeting RACK1 may be an efficacious strategy for HCC treatment.
Counter-regulation of T cell effector function by differentially activated p38
Authors: Muhammad S. Alam, Matthias M. Gaida, Youichi Ogawa, Antonios G.A. Kolios, Felix Lasitschka, Jonathan D. Ashwell
Journal: The Journal of Experimental Medicine (2014)

Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323+ T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.