tbuckley/cabot-search huggingface dataset:
Assist–Control Mechanical Ventilation Attenuates Ventilator-induced Diaphragmatic Dysfunction
Authors: Catherine S. H. Sassoon, Ercheng Zhu, Vincent J. Caiozzo
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Controlled mechanical ventilation induced a profound diaphragm muscle dysfunction and atrophy. The effects of diaphragmatic contractions with assisted mechanical ventilation on diaphragmatic isometric, isotonic contractile properties, or the expression of muscle atrophy factor-box (MAF-box), the gene responsible for muscle atrophy, are unknown. We hypothesize that assisted mechanical ventilation will preserve diaphragmatic force and prevent overexpression of MAF-box. Studying sedated rabbits randomized equally into control animals, those with 3 days of assisted ventilation, and those with controlled ventilation, we assessed in vitro diaphragmatic isometric and isotonic contractile function. The concentrations of contractile proteins, myosin heavy chain isoform, and MAF-box mRNA were measured. Tetanic force decreased by 14% with assisted ventilation and 48% with controlled ventilation. Maximum shortening velocity tended to increase with controlled compared with assisted ventilation and control. Peak power output decreased 20% with assisted ventilation and 41% with controlled ventilation. Contractile proteins were unchanged with either modes of ventilation; myosin heavy chain 2X mRNA tended to increase and that of 2A to decrease with controlled ventilation. MAF-box gene was overexpressed with controlled ventilation. We conclude that preserving diaphragmatic contractions during mechanical ventilation attenuates the force loss induced by complete inactivity and maintains MAF-box gene expression in control.
Differences in Metabolites in Pain-Processing Brain Regions in Patients With Diabetes and Painful Neuropathy
Authors: Lea Sorensen, Philip J. Siddall, Michael I. Trenell, Dennis K. Yue
Journal: Diabetes Care (2008)

Magnetic resonance spectroscopy (MRS) (specifically, (1)H-MRS) has been used to show changes in the brain following peripheral nerve injury in subjects without diabetes. This study used (1)H-MRS to examine the brain in subjects with or without painful diabetic neuropathy.Twenty-six diabetic subjects (12 with and 14 without chronic neuropathic pain) were compared, with 18 subjects without diabetes and pain. The left thalamus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) were assessed using (1)H-MRS.In the DLPFC, diabetic subjects had a decrease in N-acetyl aspartate (NAA) and creatine relative to the control group. In the thalamus, there was a reduction of NAA in the diabetic group with pain compared with that in patients with diabetes and no pain.Subjects with diabetes have metabolite differences in the brain compared with control subjects. Subjects with painful neuropathy showed reduced NAA in the thalamus, which may explain the genesis of pain in some cases.
Cancer and Inflammation: An Old Intuition with Rapidly Evolving New Concepts
Authors: Giorgio Trinchieri
Journal: Annual Review of Immunology (2012)

Recent scientific advances have contributed much to the dissection of the complex molecular and cellular pathways involved in the connection between cancer and inflammation. The evidence for this connection in humans is based on the association between infection or chronic sterile inflammation and cancer. The decreased incidence of tumors in individuals who have used nonsteroidal anti-inflammatory drugs is supportive of a role for inflammation in cancer susceptibility. The increased incidence of tumors in overweight patients points to a role for adipose tissue inflammation and energy metabolism in cancer. Energy metabolism, obesity, and genetic instability are regulated in part by the relationship of the organism with commensal bacteria that affect inflammation with both local and systemic effects. Different aspects of inflammation appear to regulate all phases of malignant disease, including susceptibility, initiation, progression, dissemination, morbidity, and mortality.
Analysis of genetic and phenotypic heterogeneity in juvenile polyposis
Authors: K Woodford-Richens, S Bevan, M Churchman, B Dowling, Daniel Jones, C G Norbury, S Hodgson, D Desai, K Neale, R K S Phillips, J Young, B Leggett, M Dunlop, P Rozen, C Eng, D Markie, M A Rodriguez-Bigas, E Sheridan, T Iwama, D Eccles, G T Smith, J C Kim, K M Kim, J R Sampson, G Evans, S Tejpar, W F Bodmer, I P M Tomlinson, R S Houlston
Journal: Gut (2000)

<h3>BACKGROUND</h3> Juvenile polyposis syndrome (JPS) is characterised by gastrointestinal (GI) hamartomatous polyposis and an increased risk of GI malignancy. Juvenile polyps also occur in the Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS) and Gorlin (GS) syndromes. Diagnosing JPS can be problematic because it relies on exclusion of CS, BRRS, and GS. Germline mutations in the <i>PTCH</i>, <i>PTEN</i>and <i>DPC4 </i>(<i>SMAD4)</i>genes can cause GS, CS/BRRS, and JPS, respectively. <h3>AIMS</h3> To examine the contribution of mutations in <i>PTCH</i>,<i>PTEN</i>, and <i>DPC4</i>(<i>SMAD4)</i> to JPS. <h3>METHODS</h3> Forty seven individuals from 15 families and nine apparently sporadic cases with JPS were screened for germline mutations in<i>DPC4</i>, <i>PTEN</i>, and<i>PTCH</i>. <h3>RESULTS</h3> No patient had a mutation in <i>PTEN</i> or<i>PTCH</i>. Five different germline mutations were detected in <i>DPC4</i>; three of these were deletions, one a single base substitution creating a stop codon, and one a missense change. None of these patients had distinguishing clinical features. <h3>CONCLUSIONS</h3> Mutations in <i>PTEN</i> and <i>PTCH</i>are unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS. A proportion of JPS patients harbour <i>DPC4 </i>mutations (21% in this study) but there remains uncharacterised genetic heterogeneity in JPS.
P115 Induction Immunosuppression (IS) with Antithymocyte Globulin (ATG) Followed by Mycophenolic Acid (MPA) Significantly Reduces Risk of Acute Cellular Rejection (ACR) But May Increase the Risk of Post-Transplant Lymphoproliferative Disease (PTLD) Post Lung Transplantation (LTx)
Authors: M Al-Aloul, B Al-Skeklley, J Salaie, S Koduri, C Leonard
Journal: Thorax (2012)

<h3>Introduction</h3> The ideal IS post LTx is unknown and the balance between graft protection against alloimmune injury <i>vs</i> the risks of infection and malignancy is a delicate one. Our unit adopted induction immunosuppression with ATG followed by cyclosporin (CyA), MPA and prednisolone maintenance in 2000 with good outcomes. However, a high burden of leucopenia and concern over increasing numbers of PTLD lead to protocol change in August 2010 where <i>de nevo</i> azathioprine (AZA) replaced MPA. We now compare short term outcomes of the two strategies. <h3>Methods</h3> Two cohorts were compared: cohort 1 (January 2000-July 2010) vs cohort 2 (August 2010-July 2012). ATG 2mg/kg was adminstered on 3 consecutive post operative days. CyA dosing was guided by trough (C0) and peak (C2) levels. Patients were established on MPA 2–3mg daily in divided doses in the first year and AZA titrated to a maximum of 2mg/kg daily as tolerated. We documented the incidence of biopsy proven PTLD and ACR grade ≥A2, correcting for confounders. T-tests, Chi squared, multivariate regression and Kaplan Meier statistics were applied. <h3>Results</h3> 181 vs 52 underwent LTx in the 2 study periods. There were no differernces in age (mean 48yrs [11] <i>vs</i> 49 [13]; gender (M:F 110:71 <i>vs</i> 31:21), type of surgery (Double:Single lung 110:71 <i>vs</i> 34:18). Donor age, cause of death and ischaemia time were similar in the 2 cohorts. 169/181 and 3/52 received MPA <i>vs</i> 12/181 and 49/52 had AZA respectively. CyA dosing and serum levels did not differ between the 2 cohorts. 29 (16%) and 18 (34%) experienced ACR respectively (P&lt;0.05). 15 patients in cohort 1 developed PTLD (mean age 54 [range 26–63], mean interval from surgery at diagnosis 286 days [73–790], 11/15 developed PTLD in the first post-op year) vs none in cohort 2. Donor:recipient EBV serostatus was similar in the 2 cohorts. Bacterial and fungal infections were documented in 94 <i>vs</i> 25 and 41 <i>vs</i> 7 respectively. Pseudomonas was isolated from a similar percentage in the 2 groups (59 vs 17). CMV viraemia necessitating pre-emptive therapy with valganciclovir was observed in 56 (32%) vs 10 (19%), P&lt;0.05 despite similar distribution of donor:recipient CMV serostatus. <h3>Conclusion</h3> ATG/MPA combination may better protect lung allografts against acute rejection but at the expense of a higher burden of lymphoma and infection. Valganciclovir enhances MPA bioavailability and the high prevalence of CMV activation after ATG/MPA may be a contibutor to our observations. Longer term data, including other malignancies, would further inform this debate.
Sequential alterations of microrna expression in hepatocellular carcinoma development and venous metastasis
Authors: Chun-Ming Wong, Carmen Chak-Lui Wong, Joyce Man-Fong Lee, Dorothy Ngo-Yin Fan, Sandy Leung-Kuen Au, Irene Oi-Lin Ng
Journal: Hepatology (2011)

Hepatocellular carcinoma (HCC) is a prevalent cancer with an extremely high mortality rate attributed to HCC metastasis, which is the major cause of tumor recurrence and organ failure. Presence of tumor thrombi in the portal veins (venous metastases) is a clinicopathological feature of metastatic HCCs. In this study, we analyzed the microRNA (miRNA) expression profiles of nontumorous livers, primary HCCs, and venous metastases in the same livers from 20 HCC patients by way of TaqMan low-density array (TLDA) and identified the precise alterations of miRNA expression from nontumorous livers to primary HCCs and venous metastases globally. By unsupervised clustering analysis, nontumorous livers were distinctly segregated from primary HCCs and venous metastases, whereas no discernible difference in the expression pattern could be found between primary HCCs and venous metastases. However, a marked global reduction of miRNA expression levels was detected in venous metastases, as compared with primary HCCs. These data suggest that miRNA deregulation is an early event in liver carcinogenesis and the later global miRNA down-regulation aggravates the preexisting miRNA deregulation to further promote HCC metastasis.Our study has enriched the current understanding of the deregulation of miRNAs in HCC progression and highlighted the sequential and distinctive alterations of miRNA expression in primary HCC and venous metastasis formation.
Increasing completion of advance directives
Authors: H. Small
Journal: JAMA (1994)

To the Editor.  —Dr Rubin and colleagues 1 erroneously suggest that a simple intervention might increase the completion of proxy forms.  Rubin et al claim to have increased use of proxy forms from 5.8% to 18.5%. They claim their data—particularly the very low baseline rate of completing proxy forms—are comparable with those of other studies. The studies they cite were conducted before the Cruzan ruling, which dramatically increased the use of proxy forms. For example, it has recently been reported that 19.8% of Massachusetts patients had a living will or proxy form during a period similar to that during which the Rubin study was conducted. 2   Rubin et al fail to cite other studies showing higher rates of completing living wills or proxy forms. One study showed 15% of adults over 65 years old had completed living wills. 3 They also misquote the studies with which they do compare their
Angiostatin Is Directly Cytotoxic to Tumor Cells at Low Extracellular pH: A Mechanism Dependent on Cell Surface–Associated ATP Synthase
Authors: Sulene L. Chi, Salvatore V. Pizzo
Journal: Cancer Research (2006)

Abstract Angiostatin, a proteolytic fragment of plasminogen, is a potent angiogenesis inhibitor able to suppress tumor growth and metastasis through inhibition of endothelial cell proliferation and migration. Previously, we showed that angiostatin binds and inhibits F1Fo ATP synthase on the endothelial cell surface and that anti-ATP synthase antibodies reduce endothelial cell proliferation. ATP synthase also occurs on the extracellular surface of a variety of cancer cells, where its function is as yet unknown. Here, we report that ATP synthase is present and active on the tumor cell surface, and angiostatin, or antibody directed against the catalytic β-subunit of ATP synthase, inhibits the activity of the synthase. We show that tumor cell surface ATP synthase is more active at low extracellular pH (pHe). Low pHe is a unique characteristic of the tumor microenvironment. Although the mechanism of action of angiostatin has not been fully elucidated, angiostatin treatment in combination with acidosis decreases the intracellular pH (pHi) of endothelial cells, leading to cell death. We also find that, at low pHe, angiostatin and anti-β-subunit antibody induce intracellular acidification of A549 cells, as well as a direct cytotoxicity that is absent in tumor cells with low levels of extracellular ATP synthase. These results establish angiostatin as an antitumorigenic and antiangiogenic agent through a mechanism implicating tumor cell surface ATP synthase. Furthermore, these data provide evidence that extracellular ATP synthase plays a role in regulating pHi in cells challenged by acidosis. (Cancer Res 2006; 66(2): 875-82)
A Subpopulation of Smooth Muscle Cells in Injured Rat Arteries Expresses Platelet-Derived Growth Factor–B Chain mRNA
Authors: Volkhard Lindner, Cecilia M. Giachelli, Stephen M. Schwartz, Michael A. Reidy
Journal: Circulation Research (1995)

Abstract Proliferation of smooth muscle cells (SMCs) and formation of a neointima are characteristics of the response of rat carotid arteries to balloon injury. Rat platelet-derived growth factor (PDGF)-B was cloned, thus allowing us to use species-specific probes to carry out in situ hybridization on the surface of injured arteries. A distinct population of luminal SMCs (7% to 10%) in the developing neointima expressed PDGF-B mRNA, but very few luminal SMCs still expressed PDGF-B (0.5%) when the lesion had stopped growing. Primary SMC cultures revealed expression of PDGF-B mRNA in 1.6% of SMCs derived from normal tunica media and in 11% of SMCs derived from the neointima. These data demonstrate that SMCs in the injured vessel wall are heterogeneous with regard to PDGF-B expression and that subculturing of these cells may give rise to cultures that are either positive or negative for PDGF-B expression. Furthermore, with abundant expression of the PDGF receptor β-subunit expressed by intimal SMCs, our findings provide evidence that PDGF-B synthesized by these cells may be involved in intimal lesion formation via a paracrine or autocrine mechanism.
Improved Toxicity Profile Following High-Dose Postprostatectomy Salvage Radiation Therapy With Intensity-Modulated Radiation Therapy
Authors: Anuj Goenka, Juan Martin Magsanoc, Xin Pei, Michael Schechter, Marisa Kollmeier, Brett Cox, Peter T. Scardino, James A. Eastham, Michael J. Zelefsky
Journal: European Urology (2011)
Diabetes, Hypertension, and Outcome Studies: Overview 2010
Authors: Peter M. Nilsson, Jan Cederholm
Journal: Diabetes Care (2011)

The treatment of hypertension in type 2 diabetes is of great importance in avoiding costly complications and human suffering. The evidence base for recommending a treatment target for blood pressure control has expanded as the result of the publication of new studies in 2010, which will be summarized and commented on in this overview.

Hypertension is a leading risk factor for mortality in both developing and developed countries (1) and a well established risk factor for cardiovascular disease (CVD) in patients with diabetes (2). An observational analysis from the UK Prospective Diabetes Study (UKPDS) has demonstrated a linear relationship between mean in-study systolic blood pressure (SBP) and the risk of macro- and microvascular complications (3). Tighter blood pressure control in hypertensive patients with type 2 diabetes by use of several antihypertensive drug classes versus placebo has been reported to reduce the risk of both micro- and macrovascular disease in the UKPDS (4,5) as well as several other intervention studies (6–9). Guidelines have so far advocated a treatment target blood pressure of <130/80 mmHg for patients with type 2 diabetes (10–12).

However, the 2009 European guidelines from the European Society of Hypertension (ESH) recommend that patients with diabetes lower their SBP well below 140 mmHg—without mentioning a specific lowest target (13)—against a background of the lower blood pressure goals (<130/80 mmHg) recommended for patients with diabetes, which have never really been achieved in any single large trial and are even more rarely attained in medical practice. This ESH recommendation was also based on the results in some trials (14,15) and post hoc analyses of high-risk hypertensive patients (16,17), as in the Ramipril Global Endpoint Trial (ONTARGET) post hoc study (18,19) of high-risk patients (49% with a previous coronary …
Serum Adipocyte Fatty Acid–Binding Protein Levels Are Associated With Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Patients
Authors: Jang Hyun Koh, Young Goo Shin, Soo Min Nam, Mi Young Lee, Choon Hee Chung, Jang Yel Shin
Journal: Diabetes Care (2008)

Adipocyte fatty acid-binding protein (A-FABP) is a major cytoplasmic protein in adipocytes and macrophages and is closely associated with metabolic syndrome, type 2 diabetes, and atherosclerosis. Here, we investigated whether A-FABP was associated with nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes.We enrolled 181 type 2 diabetic patients. Clinical and biochemical metabolic parameters were measured. The severity of NAFLD was measured by ultrasound. A-FABP, adiponectin, and retinol-binding protein-4 (RBP-4) were determined by enzyme-linked immunosorbent assay.A-FABP levels, defined as more than a moderate degree of fatty liver compared with men, those without metabolic syndrome, and those without NAFLD, were higher in women, patients with metabolic syndrome, and patients with overt NAFLD, respectively. Adiponectin was decreased according to the severity of NAFLD, but RBP-4 showed no difference. Age- and sex-adjusted A-FABP showed positive correlations with BMI, waist-to-hip ratio, waist circumference, triglycerides, gamma-glutamyltransferase, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), A1C, and C-reactive protein (CRP) but showed negative correlation with HDL cholesterol. The odds ratio (OR) for the risk of overt NAFLD with increasing levels of sex-specific A-FABP was significantly increased (OR 2.90 [95% CI 1.15-7.29] vs. 7.87 [3.20-19.38]). The OR in the highest tertile of A-FABP remained significant after adjustments for BMI, waist circumference, A1C, HDL cholesterol, triglycerides, HOMA-IR, CRP, and hepatic enzymes.Our study demonstrates that serum A-FABP is significantly associated with NAFLD in type 2 diabetes, independent of BMI, waist circumference, HOMA-IR, A1C, triglycerides, HDL cholesterol, and CRP.
Rare Tumors in Children: Progress Through Collaboration
Authors: Alberto S. Pappo, Wayne L. Furman, Kris A. Schultz, Andrea Ferrari, Lee Helman, Mark D. Krailo
Journal: Journal of Clinical Oncology (2015)

Rare pediatric tumors account for approximately 10% of all childhood cancers, which in themselves are a rare entity. The diverse histologies and clinical behaviors of rare pediatric tumors pose challenges to the investigation of their biologic and clinical features. National and international cooperative groups such as the Rare Tumor Committee of the Children's Oncology Group, Rare Tumors in Pediatric Age Project, and European Cooperative Study Group for Pediatric Rare Tumors have developed several initiatives to advance knowledge about rare pediatric cancers. However, these programs have been only partially effective, necessitating the development of alternative mechanisms to study these challenging diseases. In this article, we review the current national and international collaborative strategies to study rare pediatric cancers and alternative methods under exploration to enhance those efforts, such as independent registries and disease-specific, National Cancer Institute-sponsored clinics.
Fever episodes in early life and the development of atopy in children with asthma
Authors: M. Calvani, C. Alessandri, E. Bonci
Journal: European Respiratory Journal (2002)

The hygiene hypothesis proposes that declining exposure to infections may contribute to the allergy and asthma “epidemic”, but studies to identify the infections involved have so far provided conflicting data. An alternative approach could be based on an attempt to identify the mechanisms common to several different infections, which may exert an atopy “protective” effect. One of these mechanisms may be fever, which is frequently associated with infections and may stimulate the synthesis of interferon‐γ. The aim of this study was to test whether the frequency of fever episodes in the first years of life are related to the development of atopy. Asthmatic (cases, n=317) and nonasthmatic children (controls, n=304) attending the outpatients' allergy clinic were enrolled. The number of fever episodes in the first 2 yrs of life was retrospectively assessed by parental report via a questionnaire completed by interview. Atopy was determined by skin-prick tests to 10 prevalent inhalant allergens at the time of examination. Fever episodes in the first or in the second year of life were significantly more frequent among children with asthma. However, this difference was totally accounted for by a subgroup of children who started wheezing in the first 12 months of life. A significant inverse association between fever episodes in the first 12 months of life and atopy was found among cases, but not in controls. The association persisted after adjusting for age, sex, daycare attendance and family history of atopic disease and this was totally accounted for by asthmatic children who started wheezing after the first 12 months of life. No significant association was found between fever episodes in the second year of life and atopy for cases and controls. The data presented here suggests that fever episodes early in life may affect the natural history of asthma by preventing the development of atopy and highlights the need to monitor fever episodes of any kind in longitudinal studies aimed at investigating the hygiene hypothesis prospectively.
STUDIES ON HUMAN ANTIBODIES
Authors: James C. Allen, Henry G. Kunkel, Elvin A. Kabat
Journal: The Journal of Experimental Medicine (1964)

Human antibodies against dextran, teichoic acid, blood group A substance, levan, tetanus toxoid, and nuclei were isolated and analyzed for their content of Gm(a), Gm(b), and Inv(a) gamma-globulin genetic factors. The majority of these antibodies contained all the genetic factors determined in the donor's whole gamma-globulin, but in many antibodies at very different concentrations. In a few instances specific factors could not be detected despite their presence in the individual's whole gamma-globulin. Different antibodies isolated from the serum of the same individual showed different relative concentrations of genetic factors. The distribution of genetic factors seen in certain isolated human antibodies appeared to approach the selective occurrence of these factors in myeloma proteins.