tbuckley/cabot-search huggingface dataset:
An Immune Evasion Mechanism for Spirochetal Persistence in Lyme Borreliosis
Authors: Fang Ting Liang, Mary B. Jacobs, Lisa C. Bowers, Mario T. Philipp
Journal: The Journal of Experimental Medicine (2002)

Borrelia burgdorferi, the Lyme disease spirochete, persistently infects mammalian hosts despite the development of strong humoral responses directed against the pathogen. Here we describe a novel mechanism of immune evasion by B. burgdorferi. In immunocompetent mice, spirochetes that did not express ospC (the outer-surface protein C gene) were selected within 17 d after inoculation, concomitantly with the emergence of anti-OspC antibody. Spirochetes with no detectable OspC transcript that were isolated from immunocompetent mice reexpressed ospC after they were either cultured in vitro or transplanted to naive immunocompetent mice, but not in OspC-immunized mice. B. burgdorferi persistently expressed ospC in severe combined immune-deficient (SCID) mice. Passive immunization of B. burgdorferi–infected SCID mice with an anti-OspC monoclonal antibody selectively eliminated ospC-expressing spirochetes but did not clear the infection. OspC-expressing spirochetes reappeared in SCID mice after the anti-OspC antibody was eliminated. We submit that selection of surface-antigen nonexpressers is an immune evasion mechanism that contributes to spirochetal persistence.
Acute effect of erdosteine on preventing recurrence of exacerbation in COPD patients after hospital discharge
Authors: Maurizio Moretti, Maria Ballabio
Journal: European Respiratory Journal (2012)

Introduction  Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are frequent cause of hospital admission and associated to high risk of recurrence. Preventing exacerbations is a key treatment goal.   Objectives  To evaluate the effect of erdosteine, an anti-oxidant mucolytic agent, given on acute setting during hospitalization for severe AECOPD to prevent subsequent recurrence of exacerbations.   Methods  15 COPD patients hospitalized for severe AECOPD randomly received erdosteine 900mg daily or placebo for 10 days in combination with standard treatment. Recurrence of exacerbations after hospital discharge was assessed at 30 and 60 days. Data were correlated to pulmonary function indices and serum C-reactive protein (CRP) measured at 10 and 30 days after hospitalization.   Results  Table 1. The mean exacerbation recurrence was significantly higher (p   Conclusions  Treatment with erdosteine plus standard therapy in severe AECOPD reduced their early recurrence after hospital discharge. These results were related to improvement in small airway obstruction and decrease of serum CRP at recovery from AECOPD. Mucolytic agents with relevant antioxidant activity may improve clinical outcome after AECOPD by reducing the burst of airway inflammation.
Comparison of sulphur dioxide and metabisulphite airway reactivity in subjects with asthma.
Authors: P I Field, M McClean, R Simmul, N Berend
Journal: Thorax (1994)

In asthmatic subjects bronchoconstriction is induced by inhalation of the common food preservatives sulphur dioxide (SO2) and metabisulphite (MBS). SO2 and MBS challenges share many similarities, but it is not known whether they are equivalent. In this study of subjects with mild clinical asthma equivalence was assessed by comparing SO2 and MBS reactivity by estimating the total dose of SO2 inhaled during SO2 and MBS challenges, and by calculating SO2 uptake during both challenges. In addition, as the MBS solutions inhaled were acidic and hyperosmolar, the effect of these factors on MBS responsiveness was investigated.Fifteen subjects were challenged on separate days with doubling (0.5 to 8.0 ppm) concentrations of SO2 gas inhaled during three minute periods of isocapnic hyperventilation and MBS administered in doses ranging from 0.1 to 12.8 mumol using the Wright protocol. On two other days SO2 and MBS challenges were preceded by a challenge with phosphate buffered saline (PBS) solutions of pH and osmolarity similar to MBS solutions. Response was measured as the dose or concentration causing a 20% fall in FEV1 (PD20 or PC20).All subjects reacted to MBS and 14 responded to SO2. Geometric mean histamine PD20 was 1.61 mumol (95% confidence interval 0.72 to 3.60). MBS and SO2 airway responsiveness were not significantly related. Estimates of the mean concentration of SO2 inhaled during SO2 and MBS challenges differed, as did estimates of the mean SO2 uptake during both challenges. MBS and SO2 reactivity were not affected by prior challenge with PBS solutions.SO2 and MBS challenges are not comparable. MBS reactivity was not affected by the hyperosmolar, acidic nature of its solutions.
Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention
Authors: M. Konigshoff, R. Dumitrascu, S. Udalov, O. V. Amarie, R. Reiter, F. Grimminger, W. Seeger, R. T. Schermuly, O. Eickelberg
Journal: Thorax (2010)

<h3>Background</h3> Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR<sub>2A</sub> and 5-HTR<sub>2B</sub> receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR<sub>2A/B</sub> signalling on lung fibrosis in vivo and in vitro. <h3>Methods and results</h3> Quantitative RT-PCR showed that the expression of 5-HTR<sub>1A/B</sub> and 5-HTR<sub>2B</sub> was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR<sub>2A</sub> was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR<sub>2A</sub> protein largely localised to fibroblasts, 5-HTR<sub>2B</sub> localised to the epithelium. To assess the effects of 5HTR<sub>2A/B</sub> inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR<sub>2A/B</sub> antagonist terguride (or vehicle) in a therapeutic approach (days 14–28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor β<sub>1</sub>- or WNT3a-induced collagen production. <h3>Conclusion</h3> The studies revealed an increased expression of 5-HTR<sub>2A</sub> specifically in IPF. Blockade of 5-HTR<sub>2A/B</sub> signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.
Exercise Can Prevent and Reverse the Severity of Hypertrophic Cardiomyopathy
Authors: John P. Konhilas, Peter A. Watson, Alexander Maass, Dana M. Boucek, Todd Horn, Brian L. Stauffer, Stephen W. Luckey, Paul Rosenberg, Leslie A. Leinwand
Journal: Circulation Research (2006)

Hypertrophic cardiomyopathy (HCM) is the most common form of sudden death in young competitive athletes. However, exercise has also been shown to be beneficial in the setting of other cardiac diseases. We examined the ability of voluntary exercise to prevent or reverse the phenotypes of a murine model of HCM harboring a mutant myosin heavy chain (MyHC). No differences in voluntary cage wheel performance between nontransgenic (NTG) and HCM male mice were seen. Exercise prevented fibrosis, myocyte disarray, and induction of “hypertrophic” markers including NFAT activity when initiated before established HCM pathology. If initiated in older HCM animals with documented disease, exercise reversed myocyte disarray (but not fibrosis) and “hypertrophic” marker induction. In addition, exercise returned the increased levels of phosphorylated GSK-3β to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels. Exercise in HCM mice also favorably impacted components of the apoptotic signaling pathway, including Bcl-2 (an inhibitor of apoptosis) and procaspase-9 (an effector of apoptosis) expression, and caspase-3 activity. Remarkably, there were no differences in mortality between exercised NTG and HCM mice. Thus, not only was exercise not harmful but also it was able to prevent and even reverse established cardiac disease phenotypes in this HCM model.
Repairing the Bond in Important Relationships: A Dynamic for Personality Maturation
Authors: Jerry M. Lewis
Journal: American Journal of Psychiatry (2000)

The author sought to establish a common set of interactional dynamics involved in growth-facilitating interpersonal relationships.Empirical studies of the three most common dyadic relationships associated with personality growth were reviewed: infant-mother attachment behaviors, the psychotherapeutic alliance, and the marital relationship.Empirical and clinical studies support the conclusion that growth is facilitated when a strong affective bond is established with an important other and the inevitable disruptions of this bond are repaired.Personality maturation across the lifespan has been attributed to the internalization of admirable qualities of important others. The data surveyed suggest that the interactional dynamics associated with internalization involve establishing a strong affective bond with an important other and repairing this bond's inevitable ruptures. It is both the rupture and the repair that are crucial.
Introduction of a Glycosylation Site into a Secreted Protein Provides Evidence for an Alternative Antigen Processing Pathway: Transport of Precursors of Major Histocompatability Complex Class I–Restricted Peptides from the Endoplasmic Reticulum to the Cytosol
Authors: Igor Bačík, Heidi Link Snyder, Luis C. Antón, Gustav Russ, Weisan Chen, Jack R. Bennink, Laszlo Urge, Laszlo Otvos, Boguslawa Dudkowska, Laurence Eisenlohr, Jonathan W. Yewdell
Journal: The Journal of Experimental Medicine (1997)

We found that the presentation of a H-2Kd-restricted determinant from influenza virus nucleoprotein (NP) to T cells is strictly dependent on expression of the transporter associated with antigen presentation (TAP), regardless of whether NP is expressed as a cytosolic or secreted NP (SNP). Introducing an N-linked glycosylation site into the determinant selectively reduced presentation of SNP. This indicates that glycosylation does not interfere with TAP-transported peptides, and therefore that cytosolic peptides derived from SNP must have been exposed to the glycosylation machinery of the endoplasmic reticulum (ER) before their existence in the cytosol. Based on these findings, we propose that TAP-dependent processing of at least some ER-targeted proteins entails the reimportation of protein from the secretory pathway to the cytosol, where the protein is processed via the classical pathway.
Phenobarbital induction of α1-acid glycoprotein in primary rat hepatocyte cultures
Authors: Thierry Fournier, Najet Mejdoubi, Dagui Monnet, Geneviève Durand, Dominique Porquet
Journal: Hepatology (1994)

The serum level of rat α 1 -acid glycoprotein is significantly increased by treatment with phenobarbital, and in vivo studies have shown that phenobarbital seems to act mainly at the transcriptional level. To show the direct mediating effect of phenobarbital on α 1 -acid glycoprotein gene expression, we investigated the ability of primary cultured rat hepatocytes to respond to in vitro phenobarbital administration. Phenobarbital increased both α 1 -acid glycoprotein secretion and corresponding mRNA levels in primary rat hepatocytes cultured on matrigel. Used in combination with interleukin-1, interleukin-6 and dexamethasone, phenobarbital had an additive or synergistic effect on α 1 -acid glycoprotein synthesis. These results show that (a) phenobarbital acts directly on hepatocytes by in creasing α 1 -acid glycoprotein gene expression and (b) this effect is mediated by a specific mechanism independent of pathways involved in α 1 -acid glycoprotein induction by interleukin-1, interleukin-6 and glucocorticoids. (Hepatology 1994;20:1584-1588).
CONDITIONS DETERMINING THE TRANSPLANTABILITY OF TISSUES IN THE BRAIN
Authors: James B. Murphy, Ernest Sturm
Journal: The Journal of Experimental Medicine (1923)

In confirmation of Shirai's observation, we find that transplantable mouse tumors grow actively when inoculated into the brains of rats, guinea pigs, and pigeons, whereas subcutaneous or intramuscular grafts in the same animals fail. This growth of foreign tissue in the brain, however, takes place only when the grafted material lies entirely in the brain tissue; if it comes in contact with the ventricle a cellular reaction takes place with resultant destruction of the graft. The growth of foreign tissue in the brain may be completely inhibited by simultaneous inoculations of a small bit of autologous but not by a bit of homologous spleen tissue. Mice highly immune to subcutaneous transplants of mouse cancer show no resistance to such tumors when the inoculation is made into the brain. Although the brain is without obvious power of resistance to implants of transplantable heteroplastic mouse tumors, yet grafts of spontaneous tumors fail to grow there even, as a rule, when tumor implanted and animal host are of the same species.
Monitoring postcolonoscopy colorectal cancers: dangerous crossroads?
Authors: Silvia Sanduleanu, Catherine Dubé
Journal: Gut (2014)

Quality indicators for colonoscopy should be designed to render the outcomes of healthcare services measurable and transparent for both patients and physicians. For example, as the goal of colonoscopy is to prevent and detect colorectal cancer (CRC), improved quality should minimise the postcolonoscopy colorectal cancer (PCCRC) rate. In fact, most other indicators of procedural quality, such as adenoma detection rate and caecal intubation rate, owe their validation to a correlation with PCCRC rate. In an ideal world, rigorous monitoring of PCCRC rates can be used for benchmarking at multiple levels (regional, national, international) and would be a key driver of colonoscopy quality improvement within and outside screening programmes. It is therefore crucial to use a common language and common methodology when measuring, monitoring and reporting PCCRC.

The process of benchmarking is neither quick nor simple. It starts with the implementation of a uniform terminology for a PCCRC. The term ‘PCCRC’ refers to colonoscopy in general, performed for screening, surveillance or symptoms, whereas the term ‘interval CRC’ refers to screening and colonoscopy surveillance, when a follow-up time interval is specified (intention-to-screen).1 The next key issue is what and how to monitor for calculating PCCRC rates. Several caveats should be recalled, foremost of which are the lack of complete clinical information, hurdles in crosslinking a cancer registry to colonoscopy databases and ambiguity on how to calculate rates. Such factors hinder meaningful interpretation of PCCRC rates and defining of quality standards, as shown by Morris et …
FATE OF 395 MILD NEUROPSYCHIATRIC CASES SALVAGED FROM TRAINING PERIOD AND TAKEN INTO COMBAT
Authors: WILLIAM L. SHARP
Journal: American Journal of Psychiatry (1950)

1. Mild psychoneurotics (if they are dispersed among stable personalities) and mild psychopathic personalities (if they can direct their aggression mostly toward the enemy instead of toward their comrades), can be utilized with combat troops. 2. Only 9 cases of an original group of 395 mild neuropsychiatric problems, taken overseas and into combat by the 99th Infantry Division, had to be evacuated subsequently as NP casualties during the first 50 days of combat. The latter 15 days of this combat period included such stress as the Battle of the Ardennes (Battle of the Bulge). 3. A total of 35 former NP problems salvaged from the precombat training period appeared on the A&D (Admission & Disposition) sheet for December 1944, as requiring evacuation for conditions other than neuropsychiatric. 4. Hence, the group of 395 potential NP casualties did very well in the first 50 days of combat, losing only 9 due to the same NP condition as diagnosed in precombat training and only 35 for conditions other than neuropsychiatric (battle wounds 14; trenchfoot 10, etc.). Therefore a total of 44 of these men were lost by evacuation from the original 395. 5. Thus, 351 mild psychoneurotic and psychopaths (who had been considered potential NP combat casualties) remained on duty for the first 50 days of combat as effectives.
Cantuzumab Mertansine, a Maytansinoid Immunoconjugate Directed to the CanAg Antigen: A Phase I, Pharmacokinetic, and Biologic Correlative Study
Authors: Anthony W. Tolcher, Leonel Ochoa, Lisa A. Hammond, Amita Patnaik, Tam Edwards, Chris Takimoto, Lon Smith, Johann de Bono, Garry Schwartz, Theresa Mays, Zdenka L. Jonak, Randall Johnson, Mark DeWitte, Helen Martino, Charlene Audette, Kate Maes, Ravi V.J. Chari, John M. Lambert, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (2003)

To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity.Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized.Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses.The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.
Cortisol Secretion in Patients With Type 2 Diabetes
Authors: Iacopo Chiodini, Guido Adda, Alfredo Scillitani, Francesca Coletti, Valentina Morelli, Sergio Di Lembo, Paolo Epaminonda, Benedetta Masserini, Paolo Beck-Peccoz, Emanuela Orsi, Bruno Ambrosi, Maura Arosio
Journal: Diabetes Care (2006)

The presence of an enhanced cortisol secretion in patients with type 2 diabetes is debated. In type 2 diabetic subjects, cortisol secretion was found to be associated with the complications and metabolic control of diabetes. We evaluated cortisol secretion in 170 type 2 diabetic subjects and in 71 sex-, age-, and BMI-matched nondiabetic subjects.In all subjects, we evaluated ACTH at 8:00 a.m. in basal conditions and serum cortisol levels at 12:00 p.m. (F24) and at 9:00 a.m. after a 1-mg overnight dexamethasone suppression test and 24-h urinary free cortisol (UFC). In diabetic patients, we evaluated the presence of chronic complications (incipient nephropathy, asymptomatic neuropathy, background retinopathy, and silent macroangiopathy). Patients were subdivided according to the absence (group 1, n = 53) or presence (group 2, n = 117) of diabetes complications.In group 2, UFC (125.2 +/- 4.6 nmol/24 h) and F24 (120.6 +/- 4.1 nmol/l) were higher than in group 1 (109.2 +/- 6.8 nmol/24 h, P = 0.057, and 99.7 +/- 6.1 nmol/l, P = 0.005, respectively) and in nondiabetic patients (101.7 +/- 5.9 nmol/24 h, P = 0.002, and 100.3 +/- 5.3 nmol/l, P = 0.003, respectively). In diabetic patients, the number of complications was associated with F24 (R = 0.345; P < 0.0001) and diabetes duration (R = 0.39; P < 0.0001). Logistic regression analysis showed that the presence of diabetes complications was significantly associated with F24, sex, duration of diabetes, and glycated hemoglobin.In type 2 diabetic subjects, hypothalamic-pituitary-adrenal activity is enhanced in patients with diabetes complications and the degree of cortisol secretion is related to the presence and number of diabetes complications.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma
Authors: Tyler R. Simpson, Fubin Li, Welby Montalvo-Ortiz, Manuel A. Sepulveda, Katharina Bergerhoff, Frederick Arce, Claire Roddie, Jake Y. Henry, Hideo Yagita, Jedd D. Wolchok, Karl S. Peggs, Jeffrey V. Ravetch, James P. Allison, Sergio A. Quezada
Journal: The Journal of Experimental Medicine (2013)

Treatment with monoclonal antibody specific for cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti–CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fcγ receptor–expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context-dependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4–based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies.
IAA/GAD-Positive Offspring of Diabetic Parents Have a Different Seasonality in Month of Birth Than Antibody-Negative Offspring
Authors: Michael Hummel, Annete G. Ziegler, Hadas Lewy, Israel Ashkenazi, Zvi Laron
Journal: Diabetes Care (2001)

Nowadays, it is agreed that childhood type 1 diabetes is a progressively developing disease in which the clinical unmasking is usually triggered by an infectious (viral) disease, oftentimes during the yearly viral epidemic in autumn and winter (1). The timing of the onset of the autoimmune process and its initiating factor(s) are uncertain and controversial. One of the proposed mechanisms is that viruses damage the pancreatic β-cells and trigger the autoimmune process (2), which, by subsequent destruction at a loss of 70–80% of β-cells, causes the clinical disease.

Epidemiological studies performed by Z.L. and I.A. in recent years in Israel (3 …