tbuckley/cabot-search huggingface dataset:
Patients with Mutations in NPHS2 (Podocin) Do Not Respond to Standard Steroid Treatment of Nephrotic Syndrome
Authors: Rainer G. Ruf, Anne Lichtenberger, Stephanie M. Karle, Johannes P. Haas, Franzisco E. Anacleto, Michael Schultheiss, Isabella Zalewski, Anita Imm, Eva-Maria Ruf, Bettina Mucha, Arvind Bagga, Thomas Neuhaus, Arno Fuchshuber, Aysin Bakkaloglu, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2004)

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.
Autoantibodies to type II collagen: occurrence in rheumatoid arthritis, other arthritides, autoimmune connective tissue diseases, and chronic inflammatory syndromes.
Authors: E K Choi, P A Gatenby, N W McGill, J F Bateman, W G Cole, J R York
Journal: Annals of the Rheumatic Diseases (1988)

Serum IgG antibodies to native and denatured human type II collagen (Col II) were measured using an enzyme linked immunosorbent assay (ELISA). One hundred and thirty one patients with various forms of arthritis such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PSA). Reiter9s Syndrome (RS), osteoarthritis (OA), and gout, 60 with autoimmune connective tissue disease, and 37 with the chronic inflammatory conditions--graft versus host disease and leprosy--were studied. With the exception of RS, PSA, OA, and gout, significant levels of Col II antibodies were detected in each disease group. Blocking studies with types I and II collagen on selected serum samples confirmed the specificity to native Col II, though some cross reactivity was apparent with denatured collagen. The patients with RA who were Col II antibody positive tended to fall into stage III of disease progression. There was, however, no correlation with rheumatoid factor, erythrocyte sedimentation rate, or disease duration and this, together with the finding that Col II antibodies are present in a wide array of diseases, makes their role in the pathogenesis of RA questionable. They may arise as a secondary disease perpetuating mechanism in some patients, or in turn may be an epiphenomenon secondary to generalised disturbed immunoregulation or B cell hyperreactivity, or both, that characterises these clinical conditions.
Forward genetic analysis of Toll-like receptor responses in wild-derived mice reveals a novel antiinflammatory role for IRAK1BP1
Authors: James R. Conner, Irina I. Smirnova, Alexander Poltorak
Journal: The Journal of Experimental Medicine (2008)

Although inflammatory cytokines produced by activation of Toll-like receptors (TLRs) are essential for early host defense against infection, they also mediate a vast array of pathologies, including autoimmune disease, hypersensitivity reactions, and sepsis. Thus, numerous regulatory mechanisms exist in parallel with proinflammatory pathways to prevent excessive release of these potent effector molecules. We report elucidation of a novel regulatory function for interleukin receptor–associated kinase (IRAK)-1 binding protein 1 (IRAK1BP1, also known as SIMPL) through quantitative trait locus mapping of the TLR response in wild-derived mouse strains. This gene emerged as a negative regulator of TLR2-mediated interleukin (IL)-6 production in MOLF/Ei mice, which expressed IRAK1BP1 mRNA in an allele-specific manner when crossed with the C57BL/6J strain. Human peripheral blood mononuclear cells and primary macrophages from two other wild-derived mouse strains also induced IRAK1BP1 mRNA by 4 hours after stimulation with agonists of various TLRs. Examination of its effects on IL-6 and other cytokines demonstrated that IRAK1BP1 regulates transcription of a specific subset of TLR-responsive genes, producing an overall antiinflammatory profile. Our results reveal that IRAK1BP1 is a critical factor in preventing dangerous overproduction of proinflammatory cytokines by the innate immune system and in influencing the specificity of TLR responses. Furthermore, these results show that the genetic diversity of wild-derived mouse strains makes them a valuable model of important human gene functions that have been lost in some laboratory-inbred strains.
Mitral Annular Dilatation and Papillary Muscle Dislocation Without Mitral Regurgitation in Sheep
Authors: G. R. Green, P. Dagum, J. R. Glasson, G. T. Daughters, A. F. Bolger, L. E. Foppiano, G. J. Berry, N. B. Ingels, D. C. Miller
Journal: Circulation (1999)

Asymmetrical mitral annular (MA) dilatation and papillary muscle dislocation are implicated in the pathogenesis of functional mitral regurgitation (MR).To determine the mechanism by which annular and papillary muscle geometric alterations result in MR, we implanted radiopaque markers in the left ventricle, mitral annulus, anterior and posterior mitral leaflets, and papillary muscle tips and bases in 2 groups of sheep. One group served as controls (CTL, n=7); an experimental group (EXP, n=9) underwent topical phenol application to obliterate anterior annular and leaflet muscle (confirmed histologically ex vivo). After 1 week of recovery, markers were imaged with biplane videofluoroscopy, and hemodynamic data were recorded. MA area (computed from 3-dimensional marker coordinates) was 11% to 13% larger in the EXP group than in the CTL group (P<0.05 by ANOVA). This area increase resulted exclusively from intercommissural axis increase except in 1 heart with large (>1 cm) increases in both the intercommissural and septolateral annular axes. The anterior papillary muscle tip in EXP was displaced from CTL by 2.9+/-0.23 mm toward the anterolateral left ventricle and 2.5+/-0.12 mm toward the mitral annulus at end systole; the posterior papillary muscle geometry was unchanged. Transthoracic echocardiography revealed MR only in the heart exhibiting biaxial annular enlargement.MA dilatation in the intercommissural dimension with anterior papillary muscle tip displacement toward the annulus is insufficient to produce MR in sheep. Functional MR may require MA dilatation in the septolateral axis, as observed with proximal circumflex coronary occlusion.
Impact of Randomized Trial Results on Acute Lung Injury Ventilator Therapy in Teaching Hospitals
Authors: Craig R. Weinert, Cynthia R. Gross, William A. Marinelli
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Reducing tidal volumes administered to patients with acute lung injury is the only intervention reported to decrease mortality resulting from this life-threatening condition. Whereas many medical advances are slowly brought into practice, clinicians in teaching hospitals are often assumed to be early adopters of new medical advances. Our objective was to examine trends in the ventilatory prescription for 398 patients with acute lung injury treated in three teaching hospitals from 1994 to 2001. There was no change in tidal volumes until mid to late 1998, when volumes started to slowly decline at the rate of 48.0 (95% confidence interval, 21.0 to 74.4) ml/year. In the 2 years after the results were released from a large trial that demonstrated the superiority of 6 ml/kg tidal volume therapy over 12 ml/kg, clinicians prescribed tidal volumes of 651 ± 128 ml or 10.1 ± 1.9 ml/kg. Tidal volumes after intubation were minimally reduced over the subsequent 2 days of mechanical ventilation (mean reduction, 33 ml). Hospital category, male sex, and disease onset before May 1999 were associated with higher volumes whereas lung injury severity was inversely associated. We conclude that clinicians practicing at these teaching hospitals have not rapidly adopted low tidal volume ventilation that may reduce mortality.
The Prospects of HPV Vaccination in Cervical Cancer Prevention: Results of a New Independent Trial
Authors: F. Xavier Bosch, Silvia de Sanjose, Xavier Castellsague
Journal: Cancer Discovery (2011)

Abstract Herrero and colleagues show that in a phase III randomized trial in Guanacaste, Costa Rica, the use of a human papillomavirus type 16 (HPV16) and HPV18 ASO4-adjuvanted vaccine (Cervarix) resulted in complete efficacy against 12-month persistent HPV16 and HPV18 infections and partial protection against HPV31, 33, and 45 in HPV-naïve young women ages 18 to 25. Cancer Discovery; 1(5): 377–80. ©2011 AACR. Commentary on Herrero et al., p. 408.
Dominant Myelopoietic Effector Functions Mediated by Chemokine Receptor CCR1
Authors: Hal E. Broxmeyer, Scott Cooper, Giao Hangoc, Ji-Liang Gao, Philip M. Murphy
Journal: The Journal of Experimental Medicine (1999)

Macrophage inflammatory protein (MIP)-1α, a CC chemokine, enhances proliferation of mature subsets of myeloid progenitor cells (MPCs), suppresses proliferation of immature MPCs, and mobilizes mature and immature MPCs to the blood. MIP-1α binds at least three chemokine receptors. To determine if CCR1 was dominantly mediating the above activities of MIP-1α, CCR1-deficient (−/−) mice, produced by targeted gene disruption, were used. MIP-1α enhanced colony formation of marrow granulocyte/macrophage colony-forming units (CFU-GM), responsive to stimulation by granulocyte/macrophage colony-stimulating factor (GM-CSF), and CFU-M, responsive to stimulation by M-CSF, from littermate control CCR1+/+ but not CCR1−/− mice. Moreover, MIP-1α did not mobilize MPCs to the blood or synergize with G-CSF in this effect in CCR1−/− mice. However, CCR1−/− mice were increased in sensitivity to MPC mobilizing effects of G-CSF. Multi-growth factor–stimulated MPCs in CCR1−/− and CCR1+/+ marrow were equally sensitive to inhibition by MIP-1α. These results implicate CCR1 as a dominant receptor for MIP-1α enhancement of proliferation of lineage-committed MPCs and for mobilization of MPCs to the blood. CCR1 is not a dominant receptor for MIP-1α suppression of MPC proliferation, but it does negatively impact G-CSF–induced MPC mobilization.
Engagement of S1P1-degradative mechanisms leads to vascular leak in mice
Authors: Myat Lin Oo, Sung-Hee Chang, Shobha Thangada, Ming-Tao Wu, Karim Rezaul, Victoria Blaho, Sun-Il Hwang, David K. Han, Timothy Hla
Journal: Journal of Clinical Investigation (2011)

GPCR inhibitors are highly prevalent in modern therapeutics. However, interference with complex GPCR regulatory mechanisms leads to both therapeutic efficacy and adverse effects. Recently, the sphingosine-1-phosphate (S1P) receptor inhibitor FTY720 (also known as Fingolimod), which induces lymphopenia and prevents neuroinflammation, was adopted as a disease-modifying therapeutic in multiple sclerosis. Although highly efficacious, dose-dependent increases in adverse events have tempered its utility. We show here that FTY720P induces phosphorylation of the C-terminal domain of S1P receptor 1 (S1P₁) at multiple sites, resulting in GPCR internalization, polyubiquitinylation, and degradation. We also identified the ubiquitin E3 ligase WWP2 in the GPCR complex and demonstrated its requirement in FTY720-induced receptor degradation. GPCR degradation was not essential for the induction of lymphopenia, but was critical for pulmonary vascular leak in vivo. Prevention of receptor phosphorylation, internalization, and degradation inhibited vascular leak, which suggests that discrete mechanisms of S1P receptor regulation are responsible for the efficacy and adverse events associated with this class of therapeutics.
Effect of Minimally Invasive Surgery on the Risk for Surgical Site Infections
Authors: Giorgio Gandaglia, Khurshid R. Ghani, Akshay Sood, Jessica R. Meyers, Jesse D. Sammon, Marianne Schmid, Briony Varda, Alberto Briganti, Francesco Montorsi, Maxine Sun, Mani Menon, Adam S. Kibel, Quoc-Dien Trinh
Journal: JAMA Surgery (2014)

Surgical site infection (SSI) represents the second most common cause of hospital-acquired infection and the most common type of infection in patients undergoing surgery. However, evidence is scarce regarding the effect of the surgical approach (open surgery vs minimally invasive surgery [MIS]) on the risk for SSIs.To evaluate the role of the surgical approach on the risk for SSIs in a large contemporary cohort of patients undergoing surgery across different specialties.The American College of Surgeons National Surgical Quality Improvement Program database is a national, prospective perioperative database specifically developed to assess quality of surgical care. We queried the database from January 1, 2005, through December 31, 2011, for patients undergoing appendectomy (n = 97,780), colectomy (n = 118,407), hysterectomy (n = 26,639), or radical prostatectomy (n = 11,183).Thirty-day SSIs.We abstracted the data on 30-day SSIs and compared patients undergoing open procedures and MIS using propensity score matching. Logistic regression analyses of the matched cohorts tested the association between the surgical approach and risk for SSIs.The overall 30-day rates of SSIs were 5.4% for appendectomy, 12.1% for colectomy, 2.8% for hysterectomy, and 1.7% for prostatectomy. After propensity score matching, MIS was associated with lower rates of postoperative SSIs in patients undergoing MIS vs open procedures for appendectomy (3.8% vs 7.0%; P < .001), colectomy (9.3% vs 15.0%; P < .001), hysterectomy (1.8% vs 3.9%; P < .001), and radical prostatectomy (1.0% vs 2.4%; P < .001). In logistic regression analyses, MIS was associated with lower odds of SSIs in patients treated with appendectomy (odds ratio [OR], 0.52 [95% CI, 0.48-0.58]; P < .001), colectomy (OR, 0.58 [95% CI, 0.55-0.61]; P < .001), hysterectomy (OR, 0.44 [95% CI, 0.37-0.53]; P < .001), and radical prostatectomy (OR, 0.39 [95% CI, 0.25-0.61]; P < .001).The proportion of patients developing SSIs within 30 days after surgery can be substantial and depends on the type of surgery. Minimally invasive surgery is significantly associated with reduced odds of SSIs. This advantage should be considered when assessing the overall benefits of minimally invasive techniques.
I-E+ nonobese diabetic mice develop insulitis and diabetes.
Authors: P L Podolin, A Pressey, N H DeLarato, P A Fischer, L B Peterson, L S Wicker
Journal: The Journal of Experimental Medicine (1993)

The development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E+ or I-E- non-NOD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congenic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E+ NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E- F1 strains were no more protected from diabetes than I-E+ F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived cells, is not sufficient to provide protection from diabetes.
Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy
Authors: Wyndham H. Wilson, Michael L. Grossbard, Stefania Pittaluga, Diane Cole, Deborah Pearson, Nicole Drbohlav, Seth M. Steinberg, Richard F. Little, John Janik, Martin Gutierrez, Mark Raffeld, Louis Staudt, Bruce D. Cheson, Dan L. Longo, Nancy Harris, Elaine S. Jaffe, Bruce A. Chabner, Robert Wittes, Frank Balis
Journal: Blood (2002)
EAR COMPLICATIONS OF INFLUENZA
Authors: J. F. O'Malley
Journal: BMJ (1932)

BRITISHand W. W., who is a moderate drinker and weighs 10 st., both produce urine with, throughout the experiment, a lower concentration of alcohol than that of C2, who is not in the habit of taking alcohol regularly, and who weighs 12 st.In these cases, however, as in all others we ~~~~~~~~~~~------ JAN.16, 1932] EAR COMPLICATIONS OF INFLUENZA~~~~~~~~~~~~~~~~~~~~~~~~~~g iddiness had gone, mastoid was opened, and pus found in antrum only; there was none in cells of mastoid.The pro- jecting granulating nipple was picked up by forceps, and the malleus came away.It had necrosed at malleo-incudal joint.Aural discharge ceased with first dressing.Three wN-eeks later mastoid and middle ear dry.Whisper easily heard at 15 feet.CASE VI Woman, aged 25, with middle-ear suppuration, external ear inflammation, furunculosis, perichondritis, cellulitis, and mastoiditis.March 18th, 1931.--Attendingout-patient department.Seen for pain and discharge in left ear one week, following influenza a few days earlier.Membrana tympani swollen, malleus ill defined.Treated with glycerin acid carbolic drops, etc. March 25th-.Discharge still present, meatus swollen, drum invisible, oedema behind pinna, no pyrexia.March 31st.-Muchbetter.Ruptured furuncle visible in meatus.Slightly tender over mastoid tip
Impacting Quality of Life for Patients With Advanced Cancer With a Structured Multidisciplinary Intervention: A Randomized Controlled Trial
Authors: Teresa A. Rummans, Matthew M. Clark, Jeff A. Sloan, Marlene H. Frost, John Michael Bostwick, Pamela J. Atherton, Mary E. Johnson, Gail Gamble, Jarrett Richardson, Paul Brown, James Martensen, Janis Miller, Katherine Piderman, Mashele Huschka, Jean Girardi, Jean Hanson
Journal: Journal of Clinical Oncology (2006)

The primary goal of this study was to evaluate the feasibility and effectiveness of a structured, multidisciplinary intervention targeted to maintain the overall quality of life (QOL), which is more comprehensive than psychosocial distress, of patients undergoing radiation therapy for advanced-stage cancer.Radiation therapy patients with advanced cancer and an estimated 5-year survival rate of 0% to 50% were randomly assigned to either an eight-session structured multidisciplinary intervention arm or a standard care arm. The eight 90-minute sessions addressed the five domains of QOL including cognitive, physical, emotional, spiritual, and social functioning. The primary end point of maintaining overall QOL was assessed by a single-item linear analog scale (Linear Analog Scale of Assessment or modified Spitzer Uniscale). QOL was assessed at baseline, week 4 (end of multidisciplinary intervention), week 8, and week 27.Of the 103 participants, overall QOL at week 4 was maintained by the patients in the intervention (n = 49), whereas QOL at week 4 significantly decreased for patients in the control group (n = 54). This change reflected a 3-point increase from baseline in the intervention group and a 9-point decrease from baseline in the control group (P = .009). Intervention participants maintained their QOL, and controls gradually returned to baseline by the end of the 6-month follow-up period.Although intervention participants maintained and actually improved their QOL during radiation therapy, control participants experienced a significant decrease in their QOL. Thus, a structured multidisciplinary intervention can help maintain or even improve QOL in patients with advanced cancer who are undergoing cancer treatment.
Studies on the mechanism of phagocytosis. I. Requirements for circumferential attachment of particle-bound ligands to specific receptors on the macrophage plasma membrane.
Authors: F M Griffin, J A Griffin, J E Leider, S C Silverstein
Journal: The Journal of Experimental Medicine (1975)

These experiments were designed to evaluate the role of macrophage plasma membrane receptors for the third component of complement (C) and for the Fc portion of IgG in the ingestion phase of phagocytosis. Sheep erythrocyte (E) were coated with anti-E IgG [E(IgG)]; these E(IgG) were then attached to cultivated monolayers of mouse peritoneal macrophages under conditions which reversibly inhibit ingestion of E(IgG). The E(IgG)-macrophage complexes were further incubated under similar conditions with an antimacrophage IgG fraction which blocks Fc receptor-mediated ingestion but has no effect upon ingestion mediated by other phagocytic receptors. When these cultures were subsequently incubated under conditions optimal for particle ingestion, phagocytosis of the IgG-coated erythrocytes did not occur; the erythrocytes remained bound to the Fc receptors of the macrophage plasma membrane. To determine whether ligands must cover the entire surface of an attached particle to permit ingestion of that particle, C-coated E [E(IgM)C] were bound to the C receptors of thioglycollate-induced (activated) macrophages at 4 degrees C. E(IgM)C-macrophage complexes were then trypsinized at 4 degrees C, a procedure which resulted in cleavage of erythrocyte-bound C3b molecules to a form of C3 not recognized by the macrophage receptors for C3b. Under the conditions used, trypsin did not affect the attachment of E(IgM)C to the macrophage surface or the macrophage receptors for C3b. When these trypsin treated E(IgM)C-macrophage complexes were incubated at 37 degrees C, the bound E(IgM)C were not ingested; the erythrocytes remained attached to the macrophage plasma membrane via the macrophage's C receptors. These results indicate that attachment of a particle to specific receptors on the macrophage plasma membrane is not sufficient to trigger ingestion of that particle. Rather, ingestion requires the sequential, circumferential interaction of particle-bound ligands with specific plasma membrane receptors not involved in the initial attachment process.