tbuckley/cabot-search huggingface dataset:
Suppression of matrix metalloproteinase production from nasal fibroblasts by macrolide antibiotics<i>in vitro</i>
Authors: K. Kanai, K. Asano, T. Hisamitsu, H. Suzaki
Journal: European Respiratory Journal (2004)

It is well known that low-dose and long-term administration of macrolide antibiotics favourably modify the clinical status of chronic airway inflammatory diseases. However, the therapeutic mode of action of macrolide antibiotics is not well understood. The present study aimed to examine the influence of macrolide antibiotics, roxithromycin (RXM) and josamycin (JM) on matrix metalloproteinase (MMP) production from nasal polyp fibroblasts (NPF) in vitro . NPF, at a concentration of 2.5×10 5 cells·mL −1 , were stimulated with tumour necrosis factor (TNF)-α in the presence of various concentrations of RXM or JM for 24 h. MMP‐2 and ‐9 levels in culture supernatants were analysed by ELISA, and MMP mRNA expression was examined by RT-PCR. The influence of RXM on nuclear factor (NF)-κB and activator protein (AP)‐1 activation was also examined. Addition of RXM (but not JM) at 5.0 and 7.5 µg·mL −1 significantly suppressed the production of MMP‐2 and ‐9 from NPF induced by TNF-α stimulation. RXM also suppressed MMP mRNA expression through the inhibition of NF-κB and AP-1 activation. The present results suggest that the suppressive activity of roxithromycin on MMP‐2 and ‐9 production is, in part, responsible for the therapeutic action of macrolides on chronic airway inflammatory diseases.
Multiplicity of data in trial reports and the reliability of meta-analyses: empirical study
Authors: B. Tendal, E. Nuesch, J. P. T. Higgins, P. Juni, P. C. Gotzsche
Journal: BMJ (2011)

<b>Objectives</b> To examine the extent of multiplicity of data in trial reports and to assess the impact of multiplicity on meta-analysis results. <b>Design</b> Empirical study on a cohort of Cochrane systematic reviews. <b>Data sources</b> All Cochrane systematic reviews published from issue 3 in 2006 to issue 2 in 2007 that presented a result as a standardised mean difference (SMD). We retrieved trial reports contributing to the first SMD result in each review, and downloaded review protocols. We used these SMDs to identify a specific outcome for each meta-analysis from its protocol. <b>Review methods</b> Reviews were eligible if SMD results were based on two to ten randomised trials and if protocols described the outcome. We excluded reviews if they only presented results of subgroup analyses. Based on review protocols and index outcomes, two observers independently extracted the data necessary to calculate SMDs from the original trial reports for any intervention group, time point, or outcome measure compatible with the protocol. From the extracted data, we used Monte Carlo simulations to calculate all possible SMDs for every meta-analysis. <b>Results</b> We identified 19 eligible meta-analyses (including 83 trials). Published review protocols often lacked information about which data to choose. Twenty-four (29%) trials reported data for multiple intervention groups, 30 (36%) reported data for multiple time points, and 29 (35%) reported the index outcome measured on multiple scales. In 18 meta-analyses, we found multiplicity of data in at least one trial report; the median difference between the smallest and largest SMD results within a meta-analysis was 0.40 standard deviation units (range 0.04 to 0.91). <b>Conclusions</b> Multiplicity of data can affect the findings of systematic reviews and meta-analyses. To reduce the risk of bias, reviews and meta-analyses should comply with prespecified protocols that clearly identify time points, intervention groups, and scales of interest.
The specificity of cellular immune responses in guinea pigs. I. T cells specific for 2,4-dinitrophenyl-o-tyrosyl residues.
Authors: C A Janeway, B E Cohen, S Z Ben-Sasson, W E Paul
Journal: The Journal of Experimental Medicine (1975)

Guinea pigs immunized with the hapten 2,4-dinitrophenyl (DNP) coupled directly to Mycobacterium tuberculosis of strain H37Ra (DNP-H37) show a variety of cell-mediated immune responses to DNP coupled to protein carriers. The cells responsible for this specific response are thought to be T lymphocytes for the following reasons: Guinea pigs immunized with DNP-H37 displayed delayed hypersensitivity reactions to several DNP-proteins and contact sensitivity to dinitrofluorobenzene. Peritoneal exudate lymphocytes (PELs) obtained from DNP-H37 immune animals respond to DNP-proteins with DNA systhesis and cause inhibition of macrophage migration. PELs are highly enriched in T lymphocytes and contain few immunoglobulin-bearing cells. Further depletion of immunoglobulin-bearing cells from this population does not diminish the in vitro proliferative response to antigen. Nitrophenyl conjugates of proteins lacking a paranitro group stimulated DNA synthesis poorly or not at all, indicating the importance of the paranitro group of DNP in antigen recognition by T cells in this system. In this respect, the specificity of T cells resembles that of DNP-specific antibody from the same animals. On the other hand, DNP conjugates of copolymers of glutamic acid and lysine and DNP conjugated to proteins via an interposed beta-alanyl-glycyl-glycyl spacer failed to stimulate DNA synthesis, although such compounds bind very efficiently to anti-DNP antibody. By contrast, DNP conjugates of synthetic polypeptide carriers containing as little as 7% tyrosine strongly stimulated DNA synthesis in DNP-H37 immune PELs. That the determinant responsible for this stimulation was DNP coupled to the hydroxyl group of tyrosine was shown by selective removal of DNP from tyrosine by thiolysis with 2-mercaptoethanol, which abolished their ability to stimulate T cells.
Role of CCR5 in IFN- -induced and cigarette smoke-induced emphysema
Authors: B. Ma
Journal: Journal of Clinical Investigation (2005)

Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-γ–induced inflammation and remodeling in a murine emphysema model. IFN-γ was a potent stimulator of the CCR5 ligands macrophage inflammatory protein–1α/CCL-3 (MIP-1α/CCL-3), MIP-1β/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-γ–induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-γ–dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-γ is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-γ–induced and cigarette smoke–induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-γ stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.
An Integrative Theory of Prefrontal Cortex Function
Authors: Earl K. Miller, Jonathan D. Cohen
Journal: Annual Review of Neuroscience (2001)

▪ Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them. They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. We review neurophysiological, neurobiological, neuroimaging, and computational studies that support this theory and discuss its implications as well as further issues to be addressed
Chance or necessity? Insertional Mutagenesis in Gene Therapy and Its Consequences
Authors: Christopher Baum, Christof von Kalle, Frank J.T Staal, Zhixiong Li, Boris Fehse, Manfred Schmidt, Floor Weerkamp, Stefan Karlsson, Gerard Wagemaker, David A Williams
Journal: Molecular Therapy (2004)

Recently, unusual forms of leukemias have developed as complications following retroviral transfer of potentially therapeutic genes into hematopoietic cells. A crucial component in the pathogenesis of these complications was the upregulation of a cellular proto-oncogene by random insertion of the retroviral gene transfer vector. These findings have great implications for the genetic manipulation of somatic stem cells in medicine. This review discusses the extent to which the random oncogene activation may have required disease-specific stimuli of the transgene and the hematopoietic milieu to become leukemogenic. Based on these considerations, we propose approaches to risk prediction and prevention.
Left Ventricular Systolic and Diastolic Function in Normotensive Type 1 Diabetic Patients With or Without Autonomic Neuropathy
Authors: Triantaffilos P. Didangelos, Georgios A. Arsos, Dimitrios T. Karamitsos, Vasilios G. Athyros, Nikolaos D. Karatzas
Journal: Diabetes Care (2003)

To investigate the relation between diabetic autonomic neuropathy (DAN) and left ventricular (LV) function in type 1 diabetic patients.A total of 57 type 1 diabetic patients free of coronary artery disease and arterial hypertension were studied. Diagnosis of DAN was established by autonomic nervous function (ANF) tests, and LV systolic and diastolic functions were assessed by radionuclide ventriculography at rest.There were 24 patients who had definite DAN, established by the presence of two or more abnormal ANF tests, and 33 subjects were without DAN. DAN patients had impaired LV filling pattern, obvious by a reduced peak filling rate (3.1 +/- 1.1 vs. 3.7 +/- 0.7 end-diastolic volume [EDV]/s, P = 0.011) and first third filling fraction (35.3 +/- 19.5 vs. 50.8 +/- 16%, P = 0.002) as well as an increased time to peak filling (159.4 +/- 45.1 vs. 134.2 +/- 33.4 ms, P = 0.02) after correction for age and heart rate. There were no differences between the two groups with regard to ejection fraction, cardiac output, and cardiac index, whereas the peak emptying rate was greater in DAN patients (4.1 +/- 0.8 vs. 3.6 +/- 0.8 EDV/s, P = 0.019), suggesting LV hypercontractility. DAN patients had an increased heart rate (83.4 +/- 11.9 vs. 72.7 +/- 9.3 bpm, P = 0.001) and slightly higher systolic blood pressure. As a result, LV working load at rest was higher in DAN patients (11,109 vs. 9,096 bpm x mmHg, P < 0.001). Moreover, a correlation was found between abnormal LV systolic and diastolic indexes and the number of abnormal ANF tests.At rest, DAN patients have impaired LV filling pattern, slightly increased LV systolic function, and a higher LV working load, in comparison to non-DAN type 1 diabetic patients.
A 20% dose reduction of the original CISCA/VB regimen allows better tolerance and similar survival rate in disseminated testicular non-seminomatous germ-cell tumors: final resultsof a phase III randomized trial
Authors: K. Fizazi, K.-A. Do, X. Wang, L. Finn, C.J. Logothetis, R.J. Amato
Journal: Annals of Oncology (2002)
The Future of Research in Myasthenia
Authors: David P. Richman
Journal: JAMA Neurology (2015)

Myasthenia results from dysfunction of the neuromuscular synapse (ie, the neuromuscular junction [NMJ]), causing clinical “fatigue,” which is defined as muscle weakness that worsens with muscle use and improves with rest. Electrodiagnostic testing demonstrates either decremental compound muscle action potentials in response to repetitive nerve stimulation at slow rates, generally 2 to 3 Hz, or increased synaptic jitter measured by single fiber electromyography. The majority of the myasthenic disorders result from dysfunction of the postsynaptic component of the NMJ, although involvement of either the synaptic cleft or the presynaptic motor nerve terminal can occasionally produce myasthenia.
Nutritional Aspects of Inflammatory Bowel Disease
Authors: I H Rosenberg, J M Bengoa, M D Sitrin
Journal: Annual Review of Nutrition (1985)

INTRODUCTION  463 MECHANISMS OF NUTRITIONAL DEFICIENCY . . . . . . . . . . .. . .. . . . . . . . . . . ... . . . . . . . .. . . . . . 465 D imin ished Food Intake .........   .   .   ........ ...... 465 M alabsorption . . . . . . . . . . .. . . . . . . . . . . . . . .. . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . .. 466 In cre ased Se cretion and Nutrient Loss.. . . . . . . . .. . . . . . . . . . .. .. . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . 466 Drug -Nutrient E ffe cts . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . .. .. . . . . . . . . 467 Energy and Protein Utilization . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . ... . . . . .. . . . . . .. . . . . . . . . . . . . 467 PREY ALENCE OF NUTRITIONAL DEFICIENCIES  468 Energy-Prote in De f ici ts . . . . . . . . . . . . . . . . . . ..... .. . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 469 Electrolyte and M ineral De f ic ien cies . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 469 Fat -Solu ble Vitamin De fic ien cies . . . . . . . . . . . . .. . . .. .. . . . . . . . . . . . . .. .. .. . . . . . . . . . . . . . . . . . . .. . . . . 470 Water-Solu ble Vitamin Defi c iencies . . . . . . . . . .. . . .. . . ..   471 Trace Element Deficiencies . . . . . . . . . .. .. .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .... . . . . . . . . ... . . . . . .. . 472 NUTRITIONAL ASSESSMENT OF A SERIES OF PATIENTS   473 PRINCIPLES OF NUTRITIONAL THERAPy  474 D iet Modific ations . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . 475 Intens ive Nutrition Supp ort.. . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 477 Tot al P arente ral Nutrition . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .. ... . . . . . . .. . . . . . . 478
Severe Hypoglycemia Identifies Vulnerable Patients With Type 2 Diabetes at Risk for Premature Death and All-Site Cancer: The Hong Kong Diabetes Registry
Authors: Alice P.S. Kong, Xilin Yang, Andrea Luk, Ronald C.W. Ma, Wing Yee So, Risa Ozaki, Rose Ting, Kitty Cheung, Chung Shun Ho, Michael H.M. Chan, Chun Chung Chow, Juliana C.N. Chan
Journal: Diabetes Care (2014)

OBJECTIVE We examined the associations of clinical profiles in type 2 diabetic patients who developed severe hypoglycemia and their clinical outcomes, including death and all-site cancer. RESEARCH DESIGN AND METHODS A consecutive cohort of 8,767 type 2 diabetic patients with and without severe hypoglycemia in the 12 months before enrollment were recruited between 1995 and 2007, with follow-up until 2009. Severe hypoglycemia was defined by ICD-9 codes as hospitalizations resulting from hypoglycemia. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% CIs of clinical factors collected at enrollment for severe hypoglycemia. RESULTS In this cohort, mean age was 57.4 (SD 13.2) years and median disease duration of diabetes was 5 (interquartile range [IQR] 1-11) years. During a median follow-up of 6.71 (IQR 3.47-10.38) years, 235 patients had severe hypoglycemia (incidence 3.96 [95% CI 3.45-4.46] per 1,000 patient-years). At enrollment, patients with and without severe hypoglycemia had similar cancer rates. During follow-up, patients with severe hypoglycemia had a higher incidence of all-site cancer (13.4 vs. 6.4%, P < 0.0001) and mortality (32.8 vs. 11.2%, P < 0.0001) than those without severe hypoglycemia. After adjusting for confounders, old age, low BMI, high glycated hemoglobin, low triglyceride (TG), low LDL cholesterol (LDL-C), albuminuria, and chronic kidney disease were independent predictors for severe hypoglycemia. CONCLUSIONS In type 2 diabetes, severe hypoglycemia is associated with advanced age, renal dysfunction, poor glycemic control, and cancer subphenotypes (low BMI, low LDL-C, and low TG).
Native and reconstituted HDL activate Stat3 in ventricular cardiomyocytes via ERK1/2: Role of sphingosine-1-phosphate
Authors: Miguel A. Frias, Richard W. James, Christine Gerber-Wicht, Ursula Lang
Journal: Cardiovascular Research (2009)

AimsHigh-density lipoprotein (HDL) has been reported to have cardioprotective properties independent from its cholesterol transport activity. The influence of native HDL and reconstituted HDL (rHDL) on Stat3, the transcription factor playing an important role in myocardium adaptation to stress, was analysed in neonatal rat ventricular cardiomyocytes. We have investigated modulating the composition of rHDL as a means of expanding its function and potential cardioprotective effects.
Giving carditis back to the heart
Authors: R M GENTA
Journal: Gut (1999)

In the search for a globally binding ethical minimal consensus in dealing with research on human beings the awareness of the cultural specificity of such questions will be of central importance. France provides a good example of such cultural specificities. Three basic structures of French discussion on research ethics can be enumerated: first the particular weight placed on therapeutic benefit, second a particular accentuation on freedom and voluntarism, and third its lesser attention to the aspect of ability to give consent. The weak emphasis on the ability to give consent is rooted as much in the traditionally paternalistically imbued physician-patient relationship as in the French legal system, in which the doctrine of consent is not given the fundamental position of importance found in the Anglo-Saxon countries. As an important Roman country, a different accentuation in the ethical discussion on research on humans can be recognised, a discussion in which for a long time the right of self determination was less of a criterion for decision than the teleology of medical action. It is precisely this aspect of latent cultural influence in ethical convictions which is of decisive importance for future discussion on research on humans.
The Origins, Evolution, and Functional Potential of Alternative Splicing in Vertebrates
Authors: J. M. Mudge, A. Frankish, J. Fernandez-Banet, T. Alioto, T. Derrien, C. Howald, A. Reymond, R. Guigo, T. Hubbard, J. Harrow
Journal: Molecular Biology and Evolution (2011)

Alternative splicing (AS) has the potential to greatly expand the functional repertoire of mammalian transcriptomes. However, few variant transcripts have been characterized functionally, making it difficult to assess the contribution of AS to the generation of phenotypic complexity and to study the evolution of splicing patterns. We have compared the AS of 309 protein-coding genes in the human ENCODE pilot regions against their mouse orthologs in unprecedented detail, utilizing traditional transcriptomic and RNAseq data. The conservation status of every transcript has been investigated, and each functionally categorized as coding (separated into coding sequence [CDS] or nonsense-mediated decay [NMD] linked) or noncoding. In total, 36.7% of human and 19.3% of mouse coding transcripts are species specific, and we observe a 3.6 times excess of human NMD transcripts compared with mouse; in contrast to previous studies, the majority of species-specific AS is unlinked to transposable elements. We observe one conserved CDS variant and one conserved NMD variant per 2.3 and 11.4 genes, respectively. Subsequently, we identify and characterize equivalent AS patterns for 22.9% of these CDS or NMD-linked events in nonmammalian vertebrate genomes, and our data indicate that functional NMD-linked AS is more widespread and ancient than previously thought. Furthermore, although we observe an association between conserved AS and elevated sequence conservation, as previously reported, we emphasize that 30% of conserved AS exons display sequence conservation below the average score for constitutive exons. In conclusion, we demonstrate the value of detailed comparative annotation in generating a comprehensive set of AS transcripts, increasing our understanding of AS evolution in vertebrates. Our data supports a model whereby the acquisition of functional AS has occurred throughout vertebrate evolution and is considered alongside amino acid change as a key mechanism in gene evolution.
Functional Inactivation of CXC Chemokine Receptor 4–mediated Responses through SOCS3 Up-regulation
Authors: Silvia F. Soriano, Patricia Hernanz-Falcón, José Miguel Rodríguez-Frade, Ana Martín de Ana, Ruth Garzón, Carla Carvalho-Pinto, Antonio J. Vila-Coro, Angel Zaballos, Dimitrios Balomenos, Carlos Martínez-A., Mario Mellado
Journal: The Journal of Experimental Medicine (2002)

Hematopoietic cell growth, differentiation, and chemotactic responses require coordinated action between cytokines and chemokines. Cytokines promote receptor oligomerization, followed by Janus kinase (JAK) kinase activation, signal transducers and transactivators of transcription (STAT) nuclear translocation, and transcription of cytokine-responsive genes. These include genes that encode a family of negative regulators of cytokine signaling, the suppressors of cytokine signaling (SOCS) proteins. After binding their specific receptors, chemokines trigger receptor dimerization and activate the JAK/STAT pathway. We show that SOCS3 overexpression or up-regulation, stimulated by a cytokine such as growth hormone, impairs the response to CXCL12, measured by Ca2+ flux and chemotaxis in vitro and in vivo. This effect is mediated by SOCS3 binding to the CXC chemokine receptor 4 receptor, blocking JAK/STAT and Gαi pathways, without interfering with cell surface chemokine receptor expression. The data provide clear evidence for signaling cross-talk between cytokine and chemokine responses in building a functional immune system.