tbuckley/cabot-search huggingface dataset:
Microgravity Reduces Sleep-disordered Breathing in Humans
Authors: ANN. R. ELLIOTT, STEVEN A. SHEA, DERK-JAN DIJK, JAMES K. WYATT, EYMARD RIEL, DAVID F. NERI, CHARLES A. CZEISLER, JOHN B. WEST, G. KIM PRISK
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

To understand the factors that alter sleep quality in space, we studied the effect of spaceflight on sleep-disordered breathing. We analyzed 77 8-h, full polysomnographic recordings (PSGs) from five healthy subjects before spaceflight, on four occasions per subject during either a 16- or 9-d space shuttle mission and shortly after return to earth. Microgravity was associated with a 55% reduction in the apnea–hypopnea index (AHI), which decreased from a preflight value of 8.3 ± 1.6 to 3.4 ± 0.8 events/h inflight. This reduction in AHI was accompanied by a virtual elimination of snoring, which fell from 16.5 ± 3.0% of total sleep time preflight to 0.7 ± 0.5% inflight. Electroencephalogram (EEG) arousals also decreased in microgravity (by 19%), and this decrease was almost entirely a consequence of the reduction in respiratory-related arousals, which fell from 5.5 ± 1.2 arousals/h preflight to 1.8 ± 0.6 inflight. Postflight there was a return to near or slightly above preflight levels in these variables. We conclude that sleep quality during spaceflight is not degraded by sleep-disordered breathing. This is the first direct demonstration that gravity plays a dominant role in the generation of apneas, hypopneas, and snoring in healthy subjects.Keywords: obstructive sleep apnea; airway collapse; arousals; gravitational effect
The Oncoprotein c-Ski Functions as a Direct Antagonist of the Transforming Growth Factor-β Type I Receptor
Authors: Nathalie Ferrand, Azeddine Atfi, Céline Prunier
Journal: Cancer Research (2010)

The oncoprotein c-Ski has been implicated in the negative regulation of transforming growth factor-β (TGF-β) signaling owing to its ability to repress Smad transcriptional activity via recruitment of a transcriptional corepressor complex containing histone deacetylases. However, c-Ski has also been shown to localize to the cytoplasm, raising the interesting possibility that it might disable TGF-β signaling through alternative mechanisms. Here, we provide evidence that c-Ski can restrict TGF-β signaling by interacting directly with the activated TGF-β type I receptor (TβRI). We explored the physiologic relevance of the c-Ski/TβRI interaction and found that it can culminate in a constitutive association of TβRI with a nonfunctional R-Smad/Smad4 complex. Based on these findings, we hypothesize that the interaction between c-Ski and TβRI might interfere with nuclear translocation of the R-Smad/Smad4 complex, thereby attenuating TGF-β signaling. Such a mechanism may play a crucial role in tumor progression, because many tumors that express high levels of c-Ski also display impaired nuclear accumulation of Smads.
Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1
Authors: Judy Tellam, Geoff Connolly, Katherine J. Green, John J. Miles, Denis J. Moss, Scott R. Burrows, Rajiv Khanna
Journal: The Journal of Experimental Medicine (2004)

Epstein-Barr virus (EBV)–encoded nuclear antigen (EBNA)1 is thought to escape cytotoxic T lymphocyte (CTL) recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by the glycine-alanine repeat (GAr) domain. Here we show that EBNA1 has a remarkably varied cell type–dependent stability. However, these different degradation rates do not correspond to the level of major histocompatibility complex class I–restricted presentation of EBNA1 epitopes. In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to CD8+ T cells. Furthermore, we show that EBV-infected B cells can readily activate EBNA1-specific memory T cell responses from healthy virus carriers. Functional assays revealed that processing of these EBNA1 epitopes is proteasome and transporter associated with antigen processing dependent. We also show that the endogenous presentation of these epitopes is dependent on the newly synthesized protein rather than the long-lived stable EBNA1. Based on these observations, we propose that defective ribosomal products, not the full-length antigen, are the primary source of endogenously processed CD8+ T cell epitopes from EBNA1.
THE AUTOINOCULATION TEST IN TUBERCULOSIS
Authors: H. W. Crowe
Journal: BMJ (1912)

TLEr BcTTllTJrs X292iliac fossa and h-as been thouglht to arise from an inflamed* appendix, careful manipulation during the a-ray examina- tions may show that the appendix itself is quite free from tenderness to pressure, while some portion of the terminal coil of the ileum is the seat of the tenderness.The usual
Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion
Authors: Nan Chiang, Karsten Gronert, Clary B. Clish, Jennifer A. O’Brien, Mason W. Freeman, Charles N. Serhan
Journal: Journal of Clinical Investigation (1999)

Polymorphonuclear neutrophil (PMN) activation is pivotal in acute inflammation and injury from reperfusion. To elucidate components controlling PMNs in vivo, we prepared novel transgenic mice with the human leukotriene (LT) B4 receptor (BLTR) for functional characterization. Overexpression of BLTR in leukocytes dramatically increased PMN trafficking to skin microabscesses and lungs after ischemia-reperfusion, whereas mice deficient in 5-lipoxygenase (5-LO) showed diminished PMN accumulation in reperfused lungs. Hence, both BLTR expression and LT biosynthesis are critical for PMN infiltration in reperfusion-initiated second-organ injury. Also, in BLTR transgenic mice, 5-LO expression and product formation were selectively increased in exudates, demonstrating that receptor overexpression amplifies proinflammatory circuits. Endogenous lipoxin (LX) A4 was produced in ischemic lungs and elevated by reperfusion. Because LXA4 and aspirin-triggered 15-epimeric LXA4 (ATL) selectively regulate leukocyte responses, they were tested in BLTR transgenic mice. Despite excessive PMN recruitment in BLTR transgenic mice, intravenous injection of ATL sharply diminished reperfusion-initiated PMN trafficking to remote organs, and topical application of LX was protective in acute dermal inflammation. These results demonstrate a direct role for BLTR with positive feedback, involving BLTR and 5-LO signaling in controlling PMNs. Moreover, LXA4 and ATL counter BLTR-amplified networks, revealing a novel protective role for LX and ATL in stress responses that has applications in perioperative medicine.
Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis
Authors: M G Danieli
Journal: Annals of the Rheumatic Diseases (2002)

To describe the treatment of polymyositis (PM) and dermatomyositis (DM) with prednisone (PRED) and cyclosporin A (CSA) alone or associated with intravenous immunoglobulin (IVIg) and plasmapheresis (PEX).Between 1992 and 1999 CSA and PRED were used to treat 20 patients with idiopathic myositis (12 with DM, eight with PM), diagnosed according to the Bohan and Peter criteria. In patients with refractory or relapsed disease, IVIg was added alone (seven cases) or synchronised with PEX (six cases). A standardised protocol was used to evaluate the patients, and assess disease activity and treatment response.Despite a transient response to PRED and CSA in 16/20 cases, this combination did not induce full remission in 13/20 cases, which led to the IVIg trial with or without PEX. Patients receiving PRED and CSA plus IVIg had a significantly higher probability of maintaining complete remission at the end of the four year follow up period than those treated with PRED and CSA alone (p<0.001). No further benefit was added by the PEX. The presence of arthritis significantly correlated with a poorer response to treatment (p<0.05). Adverse effects were gingival hyperplasia (one patient) and transient renal dysfunction (one).This open study suggests that combined treatment with PRED, CSA, and IVIg is useful in patients with myositis, even those with refractory or relapsed disease; no increase in the number or type of side effects is seen.
Cerebral blood flow (CBF) response to orthostatic stress in patients with obstructive sleep apnea (OSA)
Authors: Gianluca Cotta Ramusino, Ana Fortuna, Igor Blanco, Anna Mola, Peyman Zirak, Turgut Durduran, Mercedes Mayos
Journal: European Respiratory Journal (2014)

Background:  In OSA patients the impairment of cerebrovascular reactivity (CVR) likely contributes to the increased incidence of stroke. The technique  Correlation Spectroscopy (DCS) allows non-invasive, continuous measurements of the microvascular cerebral 1,2,  blood flow to evaluate CVR.  Objective:  The aim of the study was to evaluate the effect of orthostatic stress in relative cerebral blood flow (rCBF) measured by DCS in OSA patients.  Method:  We utilized a modified version of a protocol involving orthostatic stress induced by head-of-bed positioning, used in acute ischemic stroke patients 2  and a cohort of healthy subjects 1  . Cerebral hemodynamics were monitored by DCS for 5 min at the following postures: head-of-bed angle 0o to 30o to 0o to 20o to −8o to 0o.  Results:  57 OSA patients were included: mean age: 55 (10) years; mean body mass index (BMI): 31 (6) kg/m 2 . The mean AHI was 39 (33) and the mean nighttime SpO 2 : 93(2,5) %. At 0o to 30o, mild OSA patients showed a similar rCBF response , -18 (9,5)%, as previous data published in healthy subjects 1  .Severe OSA presented lower but not significant rCBF (%) change, -15(10,8)%. There was a significant correlation between rCBF (%) change at 0o to 30owith mean SpO 2 % (r: 0,29; p=0,03) and with BMI (r:- 0,3; p=0,025).  Conclusions:  These preliminary results suggest an impairment cerebral vascular reactivity in severe OSA patients related with obesity and oxygen saturation. Diffuse optical techniques may allow noninvasive assessment of the involvement of the cerebral microvasculature.  1) B. L. Edlow et al, Physiological Meas 2010.  2) T. Durduran et al, Optics Express 2009.  This work was funded by SOCAP ( 2011) and SEPAR (2012).
Do We Know What Homeostasis Model Assessment Measures?
Authors: Edward J. Boyko, Christine Chen Jensen
Journal: Diabetes Care (2007)

The point-counterpoint articles in the September issue of Diabetes Care (1,2) raise several interesting issues on our understanding of insulin resistance, homeostasis model assessment (HOMA), and the future of measurement shortcuts for insulin resistance and secretion. McAuley et al. (1) provide an overview of methods to assess insulin sensitivity and secretion. The conditional nature of the title of their article implies that there is room for improvement and that something better will come along to assess insulin resistance and secretion with the convenience of HOMA but with better accuracy. For the time being, however, they support its use.

Hockaday et al. (2) bring up many points that undermine confidence in HOMA as a measure of insulin resistance. Input into HOMA consists of fasting insulin and glucose concentration and thus will reflect conditions present in the basal state, with the liver as the main target for insulin action as manifested by the suppression of gluconeogenesis. A shortcoming of HOMA is the lack of complete capture of brain glucose uptake, of which 50% is non–insulin mediated. Although HOMA has been compared against the euglycemic hyperinsulinemic clamp, the current gold standard for assessment of insulin sensitivity, the latter method assesses insulin resistance in the stimulated state, which is a function to a large extent of muscle glucose disposal. Thus, an implicit assumption of HOMA is that steady-state and stimulated insulin resistance are highly correlated. Other concerns include test variability over time and the assumption that insulin resistance, if present, is common to major sites of insulin action (liver, muscle, and adipose tissue).

Similarly, a number of concerns are raised about the use of HOMA to assess insulin secretion. Of particular concern is whether β-cell glycemic sensitivity can be assumed constant. In addition, other factors bear on insulin secretion that are not …
A model of decreased functional alpha-1-proteinase inhibitor. Pulmonary pathology of dogs exposed to chloramine T.
Authors: W R Abrams, A B Cohen, V V Damiano, A Eliraz, P Kimbel, D R Meranze, G Weinbaum
Journal: Journal of Clinical Investigation (1981)

The objective of this study was to develop an animal model representative of chronic human alpha-1-proteinase inhibitor deficiency. Eight dogs were treated with a mild oxidizing agent, chloramine T, with varying regimens for 3--27 wk. The capacity of the serum to inhibit both trypsin and elastase was examined and found to respond differently. Although immunologically determined levels of protease inhibitor did not change, the ability of serum to inhibit elastase in an in vitro assay decreased in direct response to chloramine T treatment. The trypsin inhibitory capacity was less affected. Emphysemalike alterations in lung morphology were observable when histologic sections were evaluated both subjectively and objectively by mean linear intercept measurements. The data suggest that this model parallels the emphysema associated with the genetic alpha-1-proteinase inhibitor deficiency in man.
Quantitative General Theory for Periodic Breathing in Chronic Heart Failure and its Clinical Implications
Authors: Darrel P. Francis, Keith Willson, L. Ceri Davies, Andrew J.S. Coats, Massimo Piepoli
Journal: Circulation (2000)

Background —In patients with chronic heart failure (CHF), periodic breathing (PB) predicts poor prognosis. Clinical studies have identified numerous risk factors for PB (which also includes Cheyne-Stokes respiration). Computer simulations have shown that oscillations can arise from delayed negative feedback. However, no simple general theory quantitatively explains PB and its mechanisms of treatment using widely-understood clinical concepts. Therefore, we introduce a new approach to the quantitative analysis of the dynamic physiology governing cardiorespiratory stability in CHF. Methods and Results —An algebraic formula was derived (presented as a simple 2D plot), enabling prediction from easily acquired clinical data to determine whether respiration will be unstable. Clinical validation was performed in 20 patients with CHF (10 with PB and 10 without) and 10 healthy normal subjects. Measurements, including chemoreflex sensitivity (S) and delay (δ), alveolar volume (V L ), and end-tidal CO 2 fraction (C̄), were applied to the stability formula. The breathing pattern was correctly predicted in 28 of the 30 subjects. The principal combined parameter (C̄S)×(δ/V L ) was higher in patients with PB (14.2±3.0) than in those without PB (3.1±0.5; P =0.0005) or in normal controls (2.4±0.5; P =0.0003). This was because of differences in both chemoreflex sensitivity (1749±235 versus 620±103 and 526±104 L/min per atm CO 2 ; P =0.0001 and P &lt;0.0001, respectively) and chemoreflex delay (0.53±0.06 vs 0.40±0.06 and 0.30±0.04 min; P =NS and P =0.02). Conclusion —This analytical approach identifies the physiological abnormalities that are important in the genesis of PB and explicitly defines the region of predicted instability. The clinical data identify chemoreflex gain and delay time (rather than hyperventilation or hypocapnia) as causes of PB.
Darpp-32 and t-Darpp are differentially expressed in normal and malignant mouse mammary tissue
Authors: Jessica L Christenson, Susan E Kane
Journal: Molecular Cancer (2014)

Darpp-32 and t-Darpp are expressed in several forms of breast cancer. Both are transcribed from the gene PPP1R1B via alternative promoters. In humans, Darpp-32 is expressed in both normal and malignant breast tissue, whereas t-Darpp has only been found in malignant breast tissue. The exact biological functions of these proteins in the breast are not known. Although Darpp-32 is a well known regulator of neurotransmission, its role in other tissues and in cancer is less well understood. t-Darpp is known to increase cellular growth, inhibit apoptosis and contribute to acquired drug resistance. The use of transgenic mouse mammary tumor models to study Darpp-32 and t-Darpp in breast cancer in vivo has been limited by a lack of knowledge regarding t-Darpp expression in mice, in both normal and malignant tissue. We used RT-PCR and Western analysis to investigate Darpp-32 and t-Darpp levels in normal and malignant mouse mammary tissue. To determine if Darpp-32 and t-Darpp play a direct role in mammary tumor development, Ppp1r1b gene knockout mice and wild-type mice were crossed with a mouse mammary tumor model. Tumor growth and metastasis were examined. Differences between groups were determined by the two-tailed Student's t-test. We found that Darpp-32 was expressed in normal mouse mammary tissue and in some breast tumors, whereas t-Darpp was found exclusively in tumors, with t-Darpp usually expressed at equal or higher levels than Darpp-32. Ppp1r1b knockout in MMTV-PyMT transgenic tumor mice resulted in a decrease in tumor growth. The shift in expression from Darpp-32 to t-Darpp during mouse mammary tumorigenesis is reminiscent of the expression patterns observed in humans and is consistent with a role for t-Darpp in promoting cell growth and Darpp-32 in inhibiting cell growth. Decreased tumor growth in Ppp1r1b knockout mice also suggests that t-Darpp plays a direct role, predominant to Darpp-32, in mammary tumor development. These results indicate that transgenic mouse mammary tumor models might be valuable tools for future investigation of Darpp-32 and t-Darpp in breast cancer.
Preventing postoperative thromboembolism.
Authors: R H Fell
Journal: BMJ (1979)

technique; and modem techniques using the gamma-camera, 99mTc-MAA, and oblique views3 would be expected to give greater reproducibility.Surely, given these data, the statement that the lung scans "correlated poorly with the results of pulmonary angiography" should be reversed to say that the interpretation of pulmonary angiograms even by experts was, to say the least, difficult and correlated poorly with the findings of perfusion lung scanning.
Influence of elastic bandage on knee pain, proprioception, and postural sway in subjects with knee osteoarthritis
Authors: B S Hassan, S Mockett, M Doherty
Journal: Annals of the Rheumatic Diseases (2002)

Objectives: To investigate whether a "standard" sized (that is, a size that would be prescribed by a physiotherapist) elastic bandage (S-bandage) around the knee of subjects with knee osteoarthritis (OA) would, in the short term (<i>a</i>) reduce pain, (<i>b</i>) improve knee joint proprioception, and (<i>c</i>) decrease sway in comparison with a looser (L-bandage). Methods: In a cross over, within-subject study, 68 subjects (49 women, 19 men; mean age 67.1, range 36–87) with symptomatic and radiographic knee OA were randomly assigned to either an S-bandage or an L-bandage. Two weeks later they were assigned to the opposite bandage size. Knee pain (10 cm visual analogue scale (VAS)), knee proprioception, and static postural sway were assessed for each bandage two weeks apart. During each visit assessments were performed at baseline, after 20 minutes of bandage application, and immediately after bandage removal. Results: The S-bandage did not have any effect on knee pain, proprioception, or postural sway. The L-bandage reduced knee pain significantly (pre-bandage application: median VAS 4.36, IQR 3.84 –4.90; after 20 minutes of bandage application: median VAS 3.80, IQR 3.3–4.3, p&lt;0.001), improved static postural sway (pre-bandage: median sway 4.50, IQ range 3.5–6.4; bandage applied: median sway 4.45, IQ range 3.4–6.3, p=0.027), but had no significant influence on knee proprioception. Conclusions: In subjects with knee OA application of an elastic bandage around the knee can reduce knee pain and improve static postural sway. This outcome depends on the size of applied bandage.
Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism
Authors: Giancarlo Agnelli, Paolo Prandoni, Cecilia Becattini, Mauro Silingardi, Maria Rita Taliani, Maddalena Miccio, Davide Imberti, Renzo Poggio, Walter Ageno, Enrico Pogliani, Fernando Porro, Pietro Zonzin
Journal: Annals of Internal Medicine (2003)

Background: The optimal duration of oral anticoagulant treatment after a first episode of pulmonary embolism remains uncertain. Objective: To evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months (pulmonary embolism associated with temporary risk factors) or to 1 year (idiopathic pulmonary embolism) in patients with a first episode of pulmonary embolism. Design: Multicenter randomized study with independent, blinded assessment of the outcome events. Setting: 19 Italian hospitals. Patients: 326 patients who had had 3 months of oral anticoagulant therapy without experiencing recurrence or bleeding. Measurements: The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism. Results: Among 165 patients assigned to extended anticoagulant therapy, 15 patients (9.1%) had a recurrence of venous thromboembolism (3.1% per patient-year; average follow-up, 34.9 months), as compared with 18 of 161 patients (11.2%) assigned to discontinue treatment (4.1% per patient-year; average follow-up, 32.7 months); the rate ratio was 0.81 (95% CI, 0.42 to 1.56). All but one of the recurrences occurred after anticoagulant treatment was discontinued. Nineteen recurrences (57.6%) were episodes of pulmonary embolism, two of which were fatal. Three major bleeding episodes were observed during extended anticoagulation (1.8%). Among patients with idiopathic venous thromboembolism, 11 of 90 patients assigned to extended anticoagulation and 11 of 91 patients assigned to discontinue treatment experienced a recurrence (relative risk, 0.99 [CI, 0.45 to 2.16]). Conclusion: Patients with pulmonary embolism have a substantial risk for recurrence after discontinuation of oral anticoagulation, regardless of treatment duration. Physicians should try to identify patients who are at high risk for recurrent venous thromboembolism and are therefore potential candidates for indefinite oral anticoagulant therapy. *For a list of the Warfarin Optimal Duration Italian Trial Investigators, see Appendix.