tbuckley/cabot-search huggingface dataset:
A nomogram for venous shunt (QS/QT) calculation
Authors: S. T. Chiang
Journal: Thorax (1968)

Peripheral CD4+CD8αα+TCRαβ+ intraepithelial lymphocytes (pIELs) are a specialised T cell population that require the presence of intestinal microbes for their development, however the microbes and factors involved are not well characterised. pIELs are closely associated with intestinal epithelial cells (IECs) that line the gastrointestinal tract, but the contribution of IECs in shaping pIEL development is also not well defined. We investigated a number of microbial metabolites for their ability to influence pIEL development, and whether this is mediated by microbe-IEC-pIEL interactions. In this study we utilised flow cytometry to characterise pIEL frequencies in GF mice administered with different microbial metabolites, in SPF mice from different colonies and animal facilities, and in GF mice monocolonised with potential pIEL-inducing commensal species. qPCR of IEC RNA isolated from these mice was performed to identify candidate genes expressed by IECs that may influence pIEL development. We identified a common bacterial metabolite that partially restores pIEL development in GF mice, and a novel pIEL-inducing bacterial species. pIEL frequency of SPF mice varied between different sources, and qPCR identified IECs expressed several T-cell-influencing cytokines that correlated with pIEL frequency <i>in vivo</i>. Our results identify a common microbial metabolite that contributes to pIEL development that may mediate IEC expression of T-cell-influencing cytokines. Our work further elucidates the mechanisms of host tolerance triggered by commensal microbes, which will facilitate the development of better strategies to prevent and treat intestinal infections and inflammatory diseases.
Analyzing the Pivotal Trial That Compared Sunitinib and IFN-α in Renal Cell Carcinoma, Using a Method That Assesses Tumor Regression and Growth
Authors: Wilfred D. Stein, Julia Wilkerson, Sindy T. Kim, Xin Huang, Robert J. Motzer, Antonio Tito Fojo, Susan E. Bates
Journal: Clinical Cancer Research (2012)

Abstract Purpose: We applied a method that analyzes tumor response, quantifying the rates of tumor growth (g) and regression (d), using tumor measurements obtained while patients receive therapy. We used data from the phase III trial comparing sunitinib and IFN-α in metastatic renal cell carcinoma (mRCC) patients. Methods: The analysis used an equation that extracts d and g. Results: For sunitinib, overall survival (OS) was strongly correlated with log g (Rsq = 0.44, P &amp;lt; 0.0001); much less with log d (Rsq = 0.04; P = 0.0002). The median g of tumors in these patients (0.00082 per days; log g = −3.09) was about half that (P &amp;lt; 0.001) of tumors in patients receiving IFN-α (0.0015 per day; log g = −2.81). With IFN-α, the OS/log g correlation (Rsq = 0.14) was weaker. Values of g from measurements obtained by study investigators or central review were highly correlated (Rsq = 0.80). No advantage resulted in including data from central review in regressions. Furthermore, g can be estimated accurately four months before treatment discontinuation. Extrapolating g in a model that incorporates survival generates the hypothesis that g increased after discontinuation of sunitinib but did not accelerate. Conclusions: In patients with mRCC, sunitinib reduced tumor growth rate, g, more than did IFN-α. Correlating g with OS confirms earlier analyses suggesting g may be an important clinical trial endpoint, to be explored prospectively and in individual patients. Clin Cancer Res; 18(8); 2374–81. ©2012 AACR.
Moxalactam, Bleeding, and Renal Insufficiency
Authors: John A. D'Elia
Journal: JAMA (1983)

To the Editor.—  Dr Pakter and co-workers have accurately described the cause of hypoprothrombinemic bleeding after use of moxalactam, an antibiotic similar to third-generation cephalosporins, as the destruction of vitamin K-producing bacteria in the gut (1982;248:1100). The prolonged prothrombin time was normalized and further hemorrhage prevented with vitamin K therapy. In their analysis, however, we believe the authors may have understated the impact of renal insufficiency as the ultimate reason for the life-threatening side effect of moxalactam in their two patients, one of whom was transiently azotemic, while the other had previously undergone nephrectomy. When urinary excretion of cephalosporins is impeded, transit of an increased concentration of antibiotic through the enterohepatic circuit may rapidly sterilize the gut flora responsible for synthesis of vitamin K. We thank the authors for their observations and urge physicians to monitor the prothrombin time when potent broad-spectrum antibiotics are employed in the setting of decreased
A tax on luxury: HTLV-I infection of CD4+CD25+ Tregs
Authors: Robert S. Fujinami
Journal: Journal of Clinical Investigation (2005)

Almost a quarter of a century ago, Oldstone and colleagues proposed that infection of cells by noncytopathic viruses may lead to an alteration of the cells’ ability to produce certain products or perform certain tasks, i.e., inhibition of “luxury function.” In this issue of the JCI, this topic has been revisited by Yamano et al., who demonstrate that human T cell lymphotropic virus type I (HTLV-I) infection of CD4+CD25+ Tregs in patients with HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP) results in a decrease in FOXP3 mRNA and protein expression. This leads to the inability of HTLV-I–infected CD4+CD25+ Tregs to inhibit the proliferation of CD4+CD25− Tregs, due to the effect of the HTLV-I tax gene. Defects in the Treg population could be responsible for the large numbers of virus-specific T cells and occurrence of lymphoproliferation and inflammatory autoimmune disease in HAM/TSP patients.
MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis
Authors: Matthew J. Delano, Philip O. Scumpia, Jason S. Weinstein, Dominique Coco, Srinivas Nagaraj, Kindra M. Kelly-Scumpia, Kerri A. O'Malley, James L. Wynn, Svetlana Antonenko, Samer Z. Al-Quran, Ryan Swan, Chun-Shiang Chung, Mark A. Atkinson, Reuben Ramphal, Dmitry I. Gabrilovich, Wesley H. Reeves, Alfred Ayala, Joseph Phillips, Drake LaFace, Paul G. Heyworth, Michael Clare-Salzler, Lyle L. Moldawer
Journal: The Journal of Experimental Medicine (2007)

Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.
Phase-Change Nanoparticles Using Highly Volatile Perfluorocarbons: Toward a Platform for Extravascular Ultrasound Imaging
Authors: Terry O. Matsunaga, Paul S. Sheeran, Samantha Luois, Jason E. Streeter, Lee B. Mullin, Bhaskar Banerjee, Paul A. Dayton
Journal: Theranostics (2012)

Recent efforts using perfluorocarbon (PFC) nanoparticles in conjunction with acoustic droplet vaporization has introduced the possibility of expanding the diagnostic and therapeutic capability of ultrasound contrast agents to beyond the vascular space.Our laboratories have developed phase-change nanoparticles (PCNs) from the highly volatile PFCs decafluorobutane (DFB, bp =-2 °C) and octafluoropropane (OFP, bp =-37 °C ) for acoustic droplet vaporization.Studies with commonly used clinical ultrasound scanners have demonstrated the ability to vaporize PCN emulsions with frequencies and mechanical indices that may significantly decrease tissue bioeffects.In addition, these contrast agents can be formulated to be stable at physiological temperatures and the perfluorocarbons can be mixed to modulate the balance between sensitivity to ultrasound and general stability.We herein discuss our recent efforts to develop finely-tuned diagnostic/molecular imaging agents for tissue interrogation.We discuss studies currently under investigation as well as potential diagnostic and therapeutic paradigms that may emerge as a result of formulating PCNs with low boiling point PFCs.
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease
Authors: Andrew M. Smith, Farooq Z. Rahman, Bu'Hussain Hayee, Simon J. Graham, Daniel J.B. Marks, Gavin W. Sewell, Christine D. Palmer, Jonathan Wilde, Brian M.J. Foxwell, Israel S. Gloger, Trevor Sweeting, Mark Marsh, Ann P. Walker, Stuart L. Bloom, Anthony W. Segal
Journal: The Journal of Experimental Medicine (2009)

The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.
Medicare Reimbursement Policies and Hemodialysis Vascular Access Outcomes
Authors: Michael Allon, Lesley Dinwiddie, Eduardo Lacson, Derrick L. Latos, Charmaine E. Lok, Theodore Steinman, Daniel E. Weiner
Journal: Journal of the American Society of Nephrology (2011)

In March 2010, the Center for Medicare and Medicaid Services (CMS) convened several clinical technical expert panels (C-TEP) to provide recommendations for improving various aspects of hemodialysis management. One of the C-TEPs was tasked with recommending measures to decrease vascular access-related infections. The members of this C-TEP, who are the authors of this manuscript, concluded unanimously that the single most important measure would be to remove financial and regulatory barriers to timely placement and revision of hemodialysis fistulas and the concurrent avoidance of catheter use. The following position paper outlines the financial barriers to improved vascular access outcomes and our proposals for a future CMS demonstration project.
Development of a decision tree to assess the severity and prognosis of stable COPD
Authors: C. Esteban, I. Arostegui, J. Moraza, M. Aburto, J.M. Quintana, J. Pérez-Izquierdo, S. Aizpiri, A. Capelastegui
Journal: European Respiratory Journal (2011)

The aim of this study was to develop and validate a new method: a classification and regression tree (CART) based on easily accessible measures to predict mortality in patients with stable chronic obstructive pulmonary disease (COPD). This was a prospective study of two independent prospective cohorts: a derivation cohort with 611 recruited patients and a validation cohort with 348 patients, all followed for 5 yrs. CART analysis was used to predict 5-yr mortality risk using the following covariates from the derivation cohort: age, % predicted forced expiratory volume in 1 s (FEV(1)), dyspnoea, physical activity, general health and number of hospital admissions for COPD exacerbations in the previous 2 yrs. Age (≥ 75 or <75 yrs) provided the first branch of the COPD-CART. The highest mortality risk (0.74) was seen in patients >75 yrs of age with higher levels of dyspnoea and FEV(1) <50% pred. Patients with the lowest risk of 5-yr mortality (0.04) were <55 yrs of age with FEV(1) >35% pred and one or no recent hospitalisations for COPD exacerbations. A simple decision tree that uses variables commonly gathered by physicians can provide a quick assessment of the severity of the disease, as measured by the risk of 5-yr mortality.
910 EXPANSION OF HEPATIC MACROPHAGES IN ACETAMINOPHEN-INDUCED ACUTE LIVER FAILURE: WHERE DO THEY COME FROM AND WHAT IS THEIR ROLE?
Authors: C.G. Antoniades, A. Quaglia, R. Mitry, M. Bruce, M. Hussain, M. McPhail, H. Al-Hussaini, W. Bernal, G. Auzinger, L. Taams, N. Heaton, M. Thursz, D. Vergani, J. Wendon
Journal: Journal of Hepatology (2011)
Abstract P100: Role of Neutrophils and Preventive Effect of Dexamethasone on Pulmonary Complications during Hypothermic Therapy for Brain-Injured Patients
Authors: Mayuki Aibiki, Saori Ohtsubo, Kensuke Umakoshi, Satoshi Kikuchi, Hironori Matsumoto, Soichi Maekawa, Takashi Nishiyama
Journal: Circulation (2008)

Objectives: To study differences in the rate of occurrence of pneumonia and the time-course changes in oxygenation in brain-injured patients with or without dexamethasone (D), a neutrophil attenuator, during hypothermic or normothermic therapy. For exploring the mechanism of pulmonary complications during hypothermic therapy, to examine the effect of decreasing the culture temperature as well as steroid application on phagocytic and bactericidal functions in neutrophils harvested from normal volunteers. Design: A retrospective observational study and in vitro human neutrophil studies. Setting: Two university hospitals. Subjects and Methods: Brain-injured patients (GCS<8) treated with hypothermic (N=23, 32–33°C) or normothermic (N=16, 36 –37.5°C) therapy were studied. Hypothermic therapy including the rewarming phase usually lasted for seven days. Normothermic therapy also was done for the same period. Their PaO2/FIO2 (P/F) ratios and C-reactive protein (CRP) levels were reviewed. D at the dose of 0.16 mg/...
Chronic Antidiabetic Sulfonylureas In Vivo: Reversible Effects on Mouse Pancreatic β-Cells
Authors: Maria Sara Remedi, Colin G Nichols
Journal: PLoS Medicine (2008)

Background Pancreatic β-cell ATP-sensitive potassium (KATP) channels are critical links between nutrient metabolism and insulin secretion. In humans, reduced or absent β-cell KATP channel activity resulting from loss-of-function KATP mutations induces insulin hypersecretion. Mice with reduced KATP channel activity also demonstrate hyperinsulinism, but mice with complete loss of KATP channels (KATP knockout mice) show an unexpected insulin undersecretory phenotype. Therefore we have proposed an "inverse U" hypothesis to explain the response to enhanced excitability, in which excessive hyperexcitability drives β-cells to insulin secretory failure without cell death. Many patients with type 2 diabetes treated with antidiabetic sulfonylureas (which inhibit KATP activity and thereby enhance insulin secretion) show long-term insulin secretory failure, which we further suggest might reflect a similar progression. Methods and Findings To test the above hypotheses, and to mechanistically investigate the consequences of prolonged hyperexcitability in vivo, we used a novel approach of implanting mice with slow-release sulfonylurea (glibenclamide) pellets, to chronically inhibit β-cell KATP channels. Glibenclamide-implanted wild-type mice became progressively and consistently diabetic, with significantly (p < 0.05) reduced insulin secretion in response to glucose. After 1 wk of treatment, these mice were as glucose intolerant as adult KATP knockout mice, and reduction of secretory capacity in freshly isolated islets from implanted animals was as significant (p < 0.05) as those from KATP knockout animals. However, secretory capacity was fully restored in islets from sulfonylurea-treated mice within hours of drug washout and in vivo within 1 mo after glibenclamide treatment was terminated. Pancreatic immunostaining showed normal islet size and α-/β-cell distribution within the islet, and TUNEL staining showed no evidence of apoptosis. Conclusions These results demonstrate that chronic glibenclamide treatment in vivo causes loss of insulin secretory capacity due to β-cell hyperexcitability, but also reveal rapid reversibility of this secretory failure, arguing against β-cell apoptosis or other cell death induced by sulfonylureas. These in vivo studies may help to explain why patients with type 2 diabetes can show long-term secondary failure to secrete insulin in response to sulfonylureas, but experience restoration of insulin secretion after a drug resting period, without permanent damage to β-cells. This finding suggests that novel treatment regimens may succeed in prolonging pharmacological therapies in susceptible individuals.
Macrovascular disease and systemic sclerosis
Authors: M. Ho
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To determine if macrovascular disease is more prevalent in systemic sclerosis (SSc) compared with unaffected subjects. <h3>METHODS</h3> 54 patients with SSc (both limited and diffuse disease) and 43 unaffected control subjects of similar age and sex were recruited. All subjects underwent a basic screen for conventional atherosclerotic disease risk factors. All had non-invasive vascular assessments—that is, carotid duplex scanning and measurement of ankle brachial blood pressure index—to identify the presence of asymptomatic peripheral vascular disease. <h3>RESULTS</h3> 33 of 52 (64%) patients had carotid artery disease compared with only 15 of 42 (35%) controls (p=0.007). Eleven (21%) of these patients had moderate disease compared with only two (5%) controls (NS). Nine of 53 (17%) SSc patients had evidence of peripheral arterial disease compared with no controls. This result was also statistically significant (p=0.003). There were no significant differences in the basic risk factor profile, which included cigarette smoking, systolic and diastolic blood pressure, cholesterol, trigyceride and glucose concentrations. <h3>CONCLUSION</h3> Macrovascular disease is more common in SSc. Screening of these patients may allow identification of "at risk" patients at an early stage and allow the study of treatments to attenuate the high rate of cardiovascular mortality in these patients.
Electrical potentials of the sigmoid colon and rectum in irritable bowel syndrome and ulcerative colitis
Authors: C. J. Edmonds
Journal: Gut (1970)

Using a simple and rapid method, electrical potential differences across rectal and colonic mucosa have been measured at routine sigmoidoscopy in patients with irritable bowel syndrome and ulcerative colitis. In patients with irritable bowel syndrome, all of whom had diarrhoea, the mucosa was charged negatively on the luminal side and potential differences were not significantly different from those of normal subjects. In acute exacerbations of ulcerative colitis, the potential difference was reversed, the luminal side being positive. This characteristic change was seen even in mild attacks. The potential difference was usually restored to normal within a few weeks of commencing treatment. In some cases, however, it was persistently abnormal for months and failed to show the normal response to stimulation by the mineralocorticoid, fludrocortisone. The way in which measurements of potential difference can be useful in diagnosis, prognosis, and as a guide to treatment is discussed.
Targeting Albumin Excretion Rate in the Treatment of the Hypertensive Diabetic Patient with Renal Disease
Authors: Michael J. Krimholtz, Janaka Karalliedde, Stephen Thomas, Rudy Bilous, Giancarlo Viberti
Journal: Journal of the American Society of Nephrology (2005)

Combination of an angiotensin-converting enzyme inhibitor (ACEI) with an angiotensin II receptor blocker is advocated as a treatment option in diabetic patients with nephropathy and residual albuminuria while on antihypertensive therapy. Abrogation of albuminuria is a key treatment goal to prevent disease progression. The assumption is that albuminuria reduction is the result of more complete blockade of the renin angiotensin system; thus, the ACEI-angiotensin II receptor blocker combination would have a greater albuminuria-lowering effect than the combination of an ACEI with a calcium channel blocker such as amlodipine, which causes similar reductions in BP but does not affect the renin angiotensin system. Twenty-eight patients who had type 1 diabetes and known diabetic renal disease and had a persistently elevated albumin creatinine ratio (ACR) &gt;10 mg/mmol despite office BP recordings ≤140/80 mmHg on maximal recommended dose of the ACEI lisinopril were studied. Patients were allocated to receive either candesartan (16 mg/d) or amlodipine (10 mg/d) in addition to preexisting ACEI inhibition and followed for 24 wk in a randomized, double-blind, parallel-group trial. By week 24, ACR fell by 56% with candesartan and 54% with amlodipine (<i>P</i> &lt; 0.01 <i>versus</i> baseline for both) with no significant difference between groups. Mean arterial BP fell between 3 and 6 mmHg similarly in both groups. In neither group was a significant correlation found between the change in ACR and the change in BP. Candesartan and amlodipine lowered ACR and BP by a similar degree. The fall in ACR was disproportionate to the fall of systemic BP and independent of it. The mechanism of the reduction in albuminuria seen with these agents in combination with an ACEI remains to be elucidated.
Lack of Interference by the Unnatural Isomer of 5-Formyltetrahydrofolate With the Effects of the Natural Isomer in Leucovorin Preparations
Authors: R. Bertrand, J. Jolivet
Journal: JNCI Journal of the National Cancer Institute (1989)

Leucovorin, a mixture of the natural (6S) and unnatural (6R) diastereomers of 5-formyltetrahydrofolate, is administered clinically to enhance the antitumor activity of 5-fluorouracil. Because the 6R isomer persists at high concentrations in plasma for prolonged periods after iv leucovorin administration (J Clin Oncol 4:685-696, 1986), we have examined it to ascertain whether the 6R isomer could interfere with the cellular effects of the 6S isomer. The 6R compound had a poorer uptake into human CCRF-CEM lymphoblastic cells than the 6S compound, but the 6R compound could competitively inhibit the uptake of the natural isomer as determined in defined buffers. However, the 6R compound failed to interfere with cell growth support and enhancement of 5-fluorouracil cytotoxicity by the 6S isomer in CCRF-CEM cells in tissue culture experiments at concentrations up to 1 mM. Thus, the unnatural isomer of 5-formyltetrahydrofolate present in leucovorin preparations seems unlikely to have clinically relevant consequences.