tbuckley/cabot-search huggingface dataset:
New insights into the roles of microRNAs in drug addiction and neuroplasticity
Authors: Jean-Luc Dreyer
Journal: Genome Medicine (2010)

Drug addiction is a major public health issue. It is typically a multigenetic brain disorder, implying combined changes of expression of several hundred genes. Psychostimulants (such as cocaine, heroin and amphetamines) induce strong and persistent neuroadaptive changes through a surfeit of gene regulatory mechanisms leading to addiction. Activity-dependent synaptic plasticity of the mesolimbic dopaminergic system, known as the 'reward pathway', plays a crucial role in the development of drug dependence. miRNAs are small non-coding RNAs, particularly abundant in the nervous system, that play key roles as regulatory molecules in processes such as neurogenesis, synapse development and plasticity in the brain. They also act as key spatiotemporal regulators during dendritic morphogenesis, controlling the expression of hundreds of genes involved in neuroplasticity and in the function of synapses. Recent studies have identified changes of several specific miRNA expression profiles and polymorphisms affecting the interactions between miRNAs and their targets in various brain disorders, including addiction: miR-16 causes adaptive changes in production of the serotonin transporter; miR-133b is specifically expressed in midbrain dopaminergic neurons, and regulates the production of tyrosine hydroxylase and the dopamine transporter; miR-212 affects production of striatal brain-derived neurotrophic factor and synaptic plasticity upon cocaine. Clearly, specific miRNAs have emerged as key regulators leading to addiction, and could serve as valuable targets for more efficient therapies. In this review, the aim is to provide an overview of the emerging role of miRNAs in addiction.
Laparoscopic Spleen-Preserving Distal Pancreatectomy
Authors: Jean-Philippe Adam, Alexandre Jacquin, Christophe Laurent, Denis Collet, Bernard Masson, Laureano Fernández-Cruz, Antonio Sa-Cunha
Journal: JAMA Surgery (2012)

To compare preservation with the division of the splenic vessels in the surgical management of laparoscopic spleen-preserving distal pancreatectomy.Bicentric retrospective study.Prospectively maintained databases.Between January 1997 and January 2011, 140 patients who underwent laparoscopic spleen-preserving distal pancreatectomy for benign or lowgrade malignant tumors in the body/tail of the pancreas were included. Patients treated with the attempted splenic vessel preservation were compared with patients treated with the attempted division of the splenic vessels (Warshaw technique).Operative outcomes and postoperative morbidity were evaluated.The outcomes of 55 patients in the splenic vessel preservation group were compared with those of 85 patients in the Warshaw technique group. The clinical characteristics were similar in both groups, except for tumor size, which was significantly greater in the Warshaw technique group (33.6 vs. 42.5 mm; P=.001). The mean operative time, mean blood loss, and rate of conversion to the open procedure did not differ between the 2 groups. The rate of successful spleen preservation was significantly improved following the splenic vessel preservation technique (96.4% vs. 84.7%; P=.03). Complications related to the spleen only occurred in the Warshaw technique group (0% vs. 10.5%; P=.03), requiring a splenectomy in 4 patients (4.7%). The mean length of stay was shorter in the splenic vessel preservation group (8.2 vs. 10.5 days; P=.01).The short-term benefits associated with the preservation of the splenic vessels should lead to an increased preference for this technique in selected patients undergoing laparoscopic spleen-preserving distal pancreatectomy for benign or low-grade malignant tumors in the body/tail of the pancreas.
Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes
Authors: Francesca Porcellati, Paolo Rossetti, Natalia Ricci Busciantella, Stefania Marzotti, Paola Lucidi, Steven Luzio, David R. Owens, Geremia B. Bolli, Carmine G. Fanelli
Journal: Diabetes Care (2007)

OBJECTIVE—To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 ± 10 years, BMI 22.4 ± 1.6 kg/m2, and A1C 7.2 ± 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study). RESEARCH DESIGN AND METHODS—Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was &amp;gt;150 mg/dl). RESULTS—With glargine, plasma glucose remained at 103 ± 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose &amp;lt;180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P &amp;lt; 0.001). Estimated total insulin activity (GIR area under the curve [AUC]0–end of GIR) was 1,412 ± 662 and 915 ± 225 mg/kg (glargine vs. detemir, P &amp;lt; 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P &amp;lt; 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids0–24 h 11 ± 1.7 vs. 8 ± 2.8 mmol/l, respectively, P &amp;lt; 0.001). CONCLUSIONS—Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12–24 h.
Is vesicular exocytosis and membrane recycling a mechanism for secretin-induced choleresis in bile duct epithelium?
Authors: Jorge J. Gumucio, Won Kyoo Cho, James L. Broder
Journal: Hepatology (1993)

Intrahepatic bile duct epithelial cells, or cholangiocytes, contribute to bile secretion in response to hormones, including secretin. However, the mechanism by which secretin stimulates ductular bile flow is unknown. Since recent data in nonhepatic epithelia have suggested a role for exocytosis in fluid secretion, we tested the hypothesis that secretin stimulates exocytosis by isolated cholangiocytes. Cholangiocytes were isolated, from normal rat liver by a newly described method employing enzymatic digestion and mechanical disruption followed by immunomagnetic separation using specific monoclonal antibodies, and exocytosis was measured using a fluorescence unquenching assay employing acridine orange. Secretin caused a dose-dependent (10 −12 - 10 −7 M) increase in acridine orange fluorescence by acridine orangeloaded cholangiocytes with a peak response at 10 min; the half-maximal concentration of secretin was 7 × 10 −9 M. The secretin effect was inhibited by preincubation of cholangiocytes with colchicine (30% inhibition, p &lt;0.05) or trypsin (90% inhibition, p &lt;0.001); no inhibition was seen with lumicolchicine and heatinactivated trypsin. Cholecystokinin, insulin, and somatostatin had no effect on fluorescence of acridine orange-loaded cholangiocytes; secretin had no effect on fluorescence of acridine orange-loaded hepatocytes or hepatic endothelial cells. Exposure of isolated cholangiocytes to secretin at doses that stimulated exocytosis caused a dose-dependent increase in cyclic AMP levels (218% maximal increase, p &lt;0.05); moreover, an analogue of cyclic AMP stimulated exocytosis by cholangiocytes. Secretin had no effect on intracellular calcium concentration using Fura-2-loaded cholangiocytes assessed by digitized video microscopy. Our results demonstrate, for the first time, that secretin stimulates exocytosis by rat cholangiocytes. The effect is cell- and hormone-specific, dependent on intact microtubules, on a protein(s) on the external surface of cholangiocytes, and on changes in cellular levels of cyclic AMP. The results are consistent with the hypothesis that secretin-induced changes in bile flow may involve an exocytic process.
Chronic Kidney Disease and Mortality Risk
Authors: Marcello Tonelli, Natasha Wiebe, Bruce Culleton, Andrew House, Chris Rabbat, Mei Fok, Finlay McAlister, Amit X. Garg
Journal: Journal of the American Society of Nephrology (2006)

Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non-dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for < 1 yr or had ESRD. Two reviewers independently extracted data on study setting, quality, participant and renal function characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazards were consistently lower than unadjusted relative risks (median reduction 17%), they remained significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority.
Disease characterization using LQTS-specific induced pluripotent stem cells
Authors: Toru Egashira, Shinsuke Yuasa, Tomoyuki Suzuki, Yoshiyasu Aizawa, Hiroyuki Yamakawa, Tomohiro Matsuhashi, Yohei Ohno, Shugo Tohyama, Shinichiro Okata, Tomohisa Seki, Yusuke Kuroda, Kojiro Yae, Hisayuki Hashimoto, Tomofumi Tanaka, Fumiyuki Hattori, Toshiaki Sato, Shunichiro Miyoshi, Seiji Takatsuki, Mitsushige Murata, Junko Kurokawa, Tetsushi Furukawa, Naomasa Makita, Takeshi Aiba, Wataru Shimizu, Minoru Horie, Kaichiro Kamiya, Itsuo Kodama, Satoshi Ogawa, Keiichi Fukuda
Journal: Cardiovascular Research (2012)

Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). We reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.
Acute effects of hypoxaemia, hyperoxaemia and hypercapnia on renal blood flow in normal and renal transplant subjects
Authors: RA Sharkey, EM Mulloy, SJ O'Neill
Journal: European Respiratory Journal (1998)

The aim of this investigation was to study noninvasively the effects of hypoxaemia, hyperoxaemia and hypercapnia on renal blood flow in normal subjects and renal allograft recipients, i.e. with denervated kidneys. By comparing these two groups, the influence of renal innervation on any resulting changes in renal blood flow could be ascertained. Nine normal and eight renal allograft recipients were studied. Each subject inhaled the following gas mixtures in order: room air, 10% O2 (hypoxaemia), 10% O2 + baseline CO2 (isocapnic hypoxaemia), 10% O2 + high CO2 (hypercapnic hypoxaemia), 100% O2 (hyperoxaemia), 100% O2 + baseline CO2 (isocapnic hyperoxaemia) and 100% O2 + high CO2 (hypercapnia hyperoxaemia). Using Doppler ultrasonography, the pulsatility index (PI), an index of renovascular resistance, was measured at the various gas inhalation levels. In normal subjects, the renovascular resistance increased in response to hypoxaemia, with a greater increase in response to hypercapnic hypoxaemia. Hyperoxaemia caused a decrease in renovascular resistance but this was abolished with the addition of CO2. There was a similar pattern in the PI response to the different gas inhalations in the renal transplant subjects, but these responses were attenuated in comparison with those of the normals. In conclusion, renal denervation does not completely abolish the renovascular responses to inhaled oxygen and carbon dioxide.
Qualitative research in health care: Using qualitative methods in health related action research
Authors: J. Meyer
Journal: BMJ (2000)

This is the last in a series of three articles 

Series editors: Catherine Pope and Nicholas Mays

The barriers to the uptake of the findings of traditional quantitative biomedical research in clinical practice are increasingly being recognised. 1 2 Action research is particularly suited to identifying problems in clinical practice and helping develop potential solutions in order to improve practice.3 For this reason, action research is increasingly being used in health related settings. Although not synonymous with qualitative research, action research typically draws on qualitative methods such as interviews and observation.

#### Summary points

Action research is increasingly being used in healthcare settings

It is a style of research rather than a specific method

Three elements are important: the participatory character of action research; its democratic impulse; and its simultaneous contribution to social science and social change

   ![][1] 

(Credit: LIANE PAYNE)

Action research is not easily defined. It is a style of research rather than a specific method. First used in 1946 by Kurt Lewin, a social scientist concerned with intergroup relations and minority problems in the United States, the term is now identified with research in which the researchers work explicitly with and for people rather than undertake research on them.4 Its strength lies in its focus on generating solutions to practical problems and its ability to empower practitioners—getting them to engage with research and subsequent “development” or implementation activities. Practitioners can choose to research their own practice, or an outside researcher can be engaged to help them identify problems, seek and implement practical solutions, and systematically monitor and reflect on the process and outcomes of change.

Most definitions of action research incorporate three important elements: its participatory character; its democratic impulse; and its simultaneous contribution to social science and social change.5

Participation is fundamental to action research: it is …

 [1]: pending:yes
Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses
Authors: Nicolas Fasnacht, Hsin-Ying Huang, Ute Koch, Stéphanie Favre, Floriane Auderset, Qian Chai, Lucas Onder, Sandra Kallert, Daniel D. Pinschewer, H. Robson MacDonald, Fabienne Tacchini-Cottier, Burkhard Ludewig, Sanjiv A. Luther, Freddy Radtke
Journal: The Journal of Experimental Medicine (2014)

Fibroblast-like cells of secondary lymphoid organs (SLO) are important for tissue architecture. In addition, they regulate lymphocyte compartmentalization through the secretion of chemokines, and participate in the orchestration of appropriate cell–cell interactions required for adaptive immunity. Here, we provide data demonstrating the functional importance of SLO fibroblasts during Notch-mediated lineage specification and immune response. Genetic ablation of the Notch ligand Delta-like (DL)1 identified splenic fibroblasts rather than hematopoietic or endothelial cells as niche cells, allowing Notch 2–driven differentiation of marginal zone B cells and of Esam+ dendritic cells. Moreover, conditional inactivation of DL4 in lymph node fibroblasts resulted in impaired follicular helper T cell differentiation and, consequently, in reduced numbers of germinal center B cells and absence of high-affinity antibodies. Our data demonstrate previously unknown roles for DL ligand-expressing fibroblasts in SLO niches as drivers of multiple Notch-mediated immune differentiation processes.
An integrated approach to characterize genetic interaction networks in yeast metabolism
Authors: Balázs Szappanos, Károly Kovács, Béla Szamecz, Frantisek Honti, Michael T Costanzo, Anastasia Baryshnikova, Gabriel Gelius-Dietrich, Martin J Lercher, Márk Jelasity, Chad L Myers, Brenda J. Andrews, Charles Boone, Stephen G. Oliver, Csaba Pál, Balázs Papp
Journal: Nature Genetics (2011)
Response to Comment. Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?
Authors: Stanley Schwartz, Ralph A. DeFronzo
Journal: Diabetes Care (2014)

We thank Drs. Deane and Horowitz (1) for bringing this work to our attention. Their results provide further support for our contention that glucagon-like peptide 1 (GLP-1) therapy represents a safe and effective intervention to improve glycemic control in critically ill, hospitalized patients both with and without preexisting type 2 diabetes. In agreement with us (2), they recognize that “insulin has substantial limitations, particularly as excess dosing precipitates hypoglycemia” (1), and a number of recent trials have failed to demonstrate any benefit in morbidity or mortality in critically ill hospitalized patients who receive intensive insulin therapy (3 …
The exon junction complex component Magoh controls brain size by regulating neural stem cell division
Authors: Debra L Silver, Dawn E Watkins-Chow, Karisa C Schreck, Tarran J Pierfelice, Denise M Larson, Anthony J Burnetti, Hung-Jiun Liaw, Kyungjae Myung, Christopher A Walsh, Nicholas Gaiano, William J Pavan
Journal: Nature Neuroscience (2010)
Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity
Authors: Douglas Osei-Hyiaman, Michael DePetrillo, Pál Pacher, Jie Liu, Svetlana Radaeva, Sándor Bátkai, Judith Harvey-White, Ken Mackie, László Offertáler, Lei Wang, George Kunos
Journal: Journal of Clinical Investigation (2005)

Endogenous cannabinoids acting at CB(1) receptors stimulate appetite, and CB(1) antagonists show promise in the treatment of obesity. CB(1) (-/-) mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB(1) in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB(1) agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB(1). High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB(1) density, and basal rates of fatty acid synthesis, and the latter is reduced by CB(1) blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB(1) ligands. We conclude that anandamide acting at hepatic CB(1) contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.
Information: In the stimulus or in the context?
Authors: Giulio Tononi, Gerald M. Edelman
Journal: Behavioral and Brain Sciences (1997)

The distinction between receptive field and conceptual field is appealing and heuristically useful. Conceptually, it is more satisfactory to distinguish between information from the environment and from the brain. We emphasize here a selectionist view that considers information transmission within the brain as modulated by a stimulus, rather than information transmission from a stimulus as modulated by the context.
DLG5 variants do not influence susceptibility to inflammatory bowel disease in the Scottish population
Authors: C L Noble
Journal: Gut (2005)

Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G-->A substitution at nucleotide 113, was associated with susceptibility to Crohn's disease (CD) whereas an extended haplotype A conferred protection.Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD15 was investigated in the Scottish population.A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system.On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier frequency (p = 0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p = 0.029 and p = 0.033, respectively). No associations between DLG5 and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15.The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions.
The IL-2 Receptor Complex: Its Structure, Function, and Target Genes
Authors: Y Minami, T Kono, T Miyazaki, T Taniguchi
Journal: Annual Review of Immunology (1993)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More