tbuckley/cabot-search huggingface dataset:
Impact of Onset-to-Reperfusion Time on Stroke Mortality
Authors: Mikael Mazighi, Saqib A. Chaudhry, Marc Ribo, Pooja Khatri, David Skoloudik, Maxim Mokin, Julien Labreuche, Elena Meseguer, Sharon D. Yeatts, Adnan H. Siddiqui, Joseph Broderick, Carlos A. Molina, Adnan I. Qureshi, Pierre Amarenco
Journal: Circulation (2013)

Background— Onset-to-reperfusion time has been reported to be associated with clinical prognosis. However, its impact on mortality remained to be assessed. Using a collaborative pooled analysis, we examined whether early mortality after successful endovascular treatment is time dependent. Methods and Results— In a collaborative pooled analysis of 7 endovascular databases, we assessed the impact of onset-to-reperfusion time in large-artery occlusion (internal carotid artery or middle cerebral artery) on outcomes. Successful reperfusion was defined as complete or partial restoration of blood flow within 8 hours from symptom onset. Primary outcome was 90-day all-cause mortality. Secondary outcomes included 90-day favorable outcome (modified Rankin Scale score, 0–2), 90-day excellent outcome (modified Rankin Scale score, 0–1), and occurrence of any intracerebral hemorrhage within 24 to 36 hours after treatment. A total of 480 cases with successful reperfusion (median time, 285 minutes) contributed to the present pooled analysis (120 with internal carotid artery occlusion and 360 with isolated middle cerebral artery occlusion). Increasing onset-to-reperfusion time was associated with an increased rate of mortality and intracerebral hemorrhage and with a decreased rate of favorable and excellent outcomes, without heterogeneity across studies. The adjusted odds ratio for each 30-minute time increase was 1.21 (95% confidence interval, 1.09–1.34; P &lt;0.001) for mortality, 0.79 (95% confidence interval, 0.72–0.87) for favorable outcome, 0.78 (95% confidence interval, 0.71–0.86) for excellent outcome, and 1.21 (95% confidence interval, 1.10–1.33) for intracerebral hemorrhage. Conclusion— Onset-to-reperfusion time affects mortality and favorable outcome and should be considered the main goal in acute stroke patient management.
A single base substitution in the coding region for neurophysin II associated with familial central diabetes insipidus.
Authors: M Ito, Y Mori, Y Oiso, H Saito
Journal: Journal of Clinical Investigation (1991)

To elucidate the molecular mechanism of familial central diabetes insipidus (FDI), we sequenced the arginine vasopressin-neurophysin II (AVP-NPII) gene in 2 patients belonging to a pedigree that is consistent with an autosomal dominant mode of inheritance. 10 patients with idiopathic central diabetes insipidus (IDI) and 5 normals were also studied. The AVP-NPII gene, locating on chromosome 20, consists of three exons that encode putative signal peptide, AVP, NPII, and glycoprotein. Using polymerase chain reaction, fragments including the promoter region and all coding regions were amplified from genomic DNA and subjected to direct sequencing. Sequences of 10 patients with IDI were identical with those of normals, while in 2 patients with FDI, a single base substitution was detected in one of two alleles of the AVP-NPII gene, indicating they were heterozygotes for this mutation. It was a G----A transition at nucleotide position 1859 in the second exon, resulting in a substitution of Gly for Ser at amino acid position 57 in the NPII moiety. It was speculated that the mutated AVP-NPII precursor or the mutated NPII molecule, through their conformational changes, might be responsible for AVP deficiency.
Recession could increase alcohol and drug addiction and mental health problems, watchdog warns
Authors: A. O'Dowd
Journal: BMJ (2009)

The economic recession could lead to a rise in the number of people with alcohol or mental health problems and in drug misuse, says a report from one of the United Kingdom’s main watchdog organisations.

The public services watchdog the Audit Commission has warned that the recession will start to have a “second wave” effect on the UK, triggering social problems.

Its new report focuses on local government but gives details on how some health problems will also be exacerbated by the economic downturn.

The report is based on academic research, a survey of chief executives …
Somatic mosaicism: a cause for unexplained cases of FAP?
Authors: T. M Tuohy, R. W Burt
Journal: Gut (2007)

Somatic mosaicism is the increasingly recognised phenomenon where there are two populations of cells that differ genetically in the same individual. When one considers that there are approximately 1014 cells in the adult human body, about 30 000 genes and approximately 10−6–10−7 mutations per gene per cell division, it follows that all of us are mosaic at some level, for some genes. Recently, two reports, by Hes et al 1 in this issue ( see page 71 ) and by Aretz et al ,2 demonstrated that somatic mosaicism can be found in about 20% of sporadic cases of familial adenomatous polyposis coli (FAP) in which mutation of APC can be found. Genetic testing of the affected individuals revealed mutation, but at a level that accounted for less than all copies of the implicated allele, suggesting that some cells and/or tissues had the mutation while others did not.

Mosaicism of NF1 and NF2 has been reported several times.3 Mutations are only found in pathologically affected tissues, and the clinical features and course of disease are often milder than usual.4 5 This is presumably because not all the susceptible tissues have inherited the causative mutation. Mosaicism has also be reported in Marfan syndrome, tuberous sclerosis, achrondroplasia, Duchenne muscular dystrophy and retinoblastoma among many other conditions.6 7

The point in embryological development at which a mutation arises has profound consequences for the individual and the family. If it arises in an essential domain of the APC gene in a single colonic epithelial stem cell, the only consequence will probably be adenomatous polyps in the segment of the colon that eventually becomes populated with the descendants of that single stem cell (eg, as hypothesised in the discussion of patient 7 in the series presented by Hes et al 1 …
Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido
Authors: Vinod P Balachandran, Michael J Cavnar, Shan Zeng, Zubin M Bamboat, Lee M Ocuin, Hebroon Obaid, Eric C Sorenson, Rachel Popow, Charlotte Ariyan, Ferdinand Rossi, Peter Besmer, Tianhua Guo, Cristina R Antonescu, Takahiro Taguchi, Jianda Yuan, Jedd D Wolchok, James P Allison, Ronald P DeMatteo
Journal: Nature Medicine (2011)
Growth hormone secretion during sleep
Authors: Y. Takahashi, D. M. Kipnis, W. H. Daughaday
Journal: Journal of Clinical Investigation (1968)

Plasma growth hormone (GH), insulin, cortisol, and glucose were measured during sleep on 38 nights in eight young adults. Blood was drawn from an indwelling catheter at 30-min intervals; EEG and electrooculogram were recorded throughout the night. In seven subjects, a plasma GH peak (13-72 mmug/ml) lasting 1.5-3.5 hr appeared with the onset of deep sleep. Smaller GH peaks (6-14 mmug/ml) occasionally appeared during subsequent deep sleep phases. Peak GH secretion was delayed if the onset of sleep was delayed. Subjects who were awakened for 2-3 hr and allowed to return to sleep exhibited another peak of GH secretion (14-46 mmug/ml). Peak GH secretion was not correlated with changes in plasma glucose, insulin, and cortisol. The effects of 6-CNS-active drugs on sleep-related GH secretion were investigated. Imipramine (50 mg) completely abolished GH peaks in two of four subjects, whereas chlorpromazine (30 mg), phenobarbital (97 mg), diphenylhydantoin (90 mg), chlordiazepoxide (20 mg), and isocarboxazid (30 mg) did not inhibit GH peaks. Altered hypothalamic activity associated with initiation of sleep results in a major peak of growth hormone secretion unrelated to hypoglycemia or changes in cortisol and insulin secretion.
Apelin-APJ Signaling Is a Critical Regulator of Endothelial MEF2 Activation in Cardiovascular Development
Authors: Yujung Kang, Jongmin Kim, Joshua P. Anderson, Jingxia Wu, Scott R. Gleim, Ramendra K. Kundu, Danielle L. McLean, Jun-dae Kim, Hyekyung Park, Suk-won Jin, John Hwa, Thomas Quertermous, Hyung J. Chun
Journal: Circulation Research (2013)

The peptide ligand apelin and its receptor APJ constitute a signaling pathway with numerous effects on the cardiovascular system, including cardiovascular development in model organisms such as xenopus and zebrafish.This study aimed to characterize the embryonic lethal phenotype of the Apj-/- mice and to define the involved downstream signaling targets.We report the first characterization of the embryonic lethality of the Apj-/- mice. More than half of the expected Apj-/- embryos died in utero because of cardiovascular developmental defects. Those succumbing to early embryonic death had markedly deformed vasculature of the yolk sac and the embryo, as well as poorly looped hearts with aberrantly formed right ventricles and defective atrioventricular cushion formation. Apj-/- embryos surviving to later stages demonstrated incomplete vascular maturation because of a deficiency of vascular smooth muscle cells and impaired myocardial trabeculation and ventricular wall development. The molecular mechanism implicates a novel, noncanonical signaling pathway downstream of apelin-APJ involving Gα13, which induces histone deacetylase (HDAC) 4 and HDAC5 phosphorylation and cytoplasmic translocation, resulting in activation of myocyte enhancer factor 2. Apj-/- mice have greater endocardial Hdac4 and Hdac5 nuclear localization and reduced expression of the myocyte enhancer factor 2 (MEF2) transcriptional target Krüppel-like factor 2. We identify a number of commonly shared transcriptional targets among apelin-APJ, Gα13, and MEF2 in endothelial cells, which are significantly decreased in the Apj-/- embryos and endothelial cells.Our results demonstrate a novel role for apelin-APJ signaling as a potent regulator of endothelial MEF2 function in the developing cardiovascular system.
Impact of abdominal visceral fat, growth hormone, fitness, and insulin on lipids and lipoproteins in older adults
Authors: Arthur Weltman, Jean Pierre Despres, Jody L. Clasey, Judy Y. Weltman, Laurie Wideman, Jill Kanaley, James Patrie, Jean Bergeron, Michael O. Thorner, Claude Bouchard, Mark L. Hartman
Journal: Metabolism (2003)
Angiotensin II type-1 receptor activation in the adult heart causes blood pressure-independent hypertrophy and cardiac dysfunction
Authors: Justin F.X. Ainscough, Mark J. Drinkhill, Alicia Sedo, Neil A. Turner, David A. Brooke, Anthony J. Balmforth, Stephen G. Ball
Journal: Cardiovascular Research (2008)

Sustained hypertension leads to cardiac hypertrophy that can progress, through pathological remodelling, to heart failure. Abnormality of the renin-angiotensin system (RAS) has been strongly implicated in this process. Although hypertrophy in human is an established risk factor independent of blood pressure (BP), separation of remodelling in response to local cues within the differentiated myocardium from that related to pressure overload is unresolved. This study aimed to clarify the role of local RAS activity, specifically in the adult heart, in modulating cardiac hypertrophy and pathological remodelling.Transgenic mice with inducible cardiomyocyte-specific expression of a wild-type or N111G mutant form of the human angiotensin II (Ang II) type-1 receptor (hAT1R) were generated. The wild-type receptor is primarily stimulated by Ang II. In contrast, the N111G receptor can also be fully stimulated by the Ang II derivative, Ang IV, at levels that do not stimulate the wild-type receptor. The unique properties of these models were used to investigate the myocardial growth, remodelling and functional responses to hAT1R stimulation, specifically in adult cardiomyocytes, under normal conditions and following Ang IV infusion. Low-level expression of wild-type or N111G hAT1R at the cardiomyocyte membrane, from the onset of adolescence, induced enhanced myocyte growth and associated cardiac hypertrophy in the adult. This was not associated with change in resting BP or heart rate, measured by longitudinal telemetric analysis, and did not progress to pathological remodelling or heart failure. However, selective activation of cardiomyocyte-specific N111G receptors by Ang IV peptide infusion induced adverse ventricular remodelling within 4 weeks. This was characterized by increased interstitial fibrosis, dilatation of the left ventricle, and impaired cardiac function.Low-level local AT1R activity in differentiated myocardium causes compensated cardiac hypertrophy, that is, increased myocardial mass but with the retention of normal function, whereas short-term increased stimulation induces cardiac dysfunction with dilatation, reduced ejection fraction, and increased fibrosis in the absence of change in systemic BP.
Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation
Authors: Filipa G. Pinho, Adam E. Frampton, Joao Nunes, Jonathan Krell, Heba Alshaker, Jimmy Jacob, Loredana Pellegrino, Laura Roca-Alonso, Alexander de Giorgio, Victoria Harding, Jonathan Waxman, Justin Stebbing, Dmitry Pchejetski, Leandro Castellano
Journal: Cancer Research (2013)

Sphingosine kinase 1 (SK1) plays an important role in estrogen-dependent breast tumorigenesis, but its regulation is poorly understood. A subset of microRNAs (miRNA, miR) is regulated by estrogen and contributes to cellular proliferation and cancer progression. Here, we describe that miR-515-5p is transcriptionally repressed by estrogen receptor α (ERα) and functions as a tumor suppressor in breast cancer. Its downregulation enhances cell proliferation and estrogen-dependent SK1 activity, mediated by a reduction of miR-515-5p posttranscriptional repression. Enforced expression of miR-515-5p in breast cancer cells causes a reduction in SK1 activity, reduced cell proliferation, and the induction of caspase-dependent apoptosis. Conversely, opposing effects occur with miR-515-5p inhibition and by SK1 silencing. Notably, we show that estradiol (E2) treatment downregulates miR-515-5p levels, whereas the antiestrogen tamoxifen causes a decrease in SK1, which is rescued by silencing miR-515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERα within its promoter. RNA-sequencing (RNA-Seq) analysis of breast cancer cells after overexpressing miR-515-5p indicates that it partly modulates cell proliferation by regulating the Wnt pathway. The clinical implications of this novel regulatory system are shown as miR-515-5p is significantly downregulated in ER-positive (n = 146) compared with ER-negative (n = 98) breast cancers. Overall, we identify a new link between ERα, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis.
Phase I Study of Capecitabine With Concomitant Radiotherapy for Patients With Locally Advanced Pancreatic Cancer: Expression Analysis of Genes Related to Outcome
Authors: M. Wasif Saif, Mohammaed A. Eloubeidi, Suzanne Russo, Adam Steg, Jennifer Thornton, John Fiveash, Mark Carpenter, Carmello Blanquicett, Robert B. Diasio, Martin R. Johnson
Journal: Journal of Clinical Oncology (2005)

To establish the feasibility of capecitabine with concurrent radiotherapy (XRT) in patients with locally advanced (LA) pancreatic cancer and evaluate the effect of XRT on thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and tumor necrosis factor-alpha (TNF-alpha).Fifteen patients with LA pancreatic cancer received three-dimensional conformal XRT to a dose of 50.4 Gy with capecitabine at escalating doses from 600 to 1,250 mg/m2 bid (Monday through Friday). Following chemo-XRT, stable and responding patients were treated with capecitabine 2,000 mg/m2 orally bid for 14 days every 21 days. Tumor specimens were procured with endoscopic ultrasound-guided fine-needle aspiration 1 week before and 2 weeks after chemo-XRT to evaluate TP, DPD, and TNF-alpha mRNA levels.Dose-limiting grade 3 diarrhea was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m2 with XRT. Three patients (20%) achieved partial response. Mean percent difference in TP pre- and post-XRT was 119.2% (P = .1934). There was no significant differences in mean TNF-alpha, or DPD levels pre- and post-XRT (P = .1934 and .4922, respectively). TP and TNF-alpha levels were not significantly correlated both at pre- and post-XRT (P = .670 and P < .154, respectively). Median value of TP:DPD ratios at baseline was 2.65 (range, 0.36 to 11.08). No association between TP:DPD ratio and efficacy of capecitabine or severity of toxicities was identified.The recommended dose for phase II evaluation is capecitabine 800 mg/m2 bid (Monday through Friday) with concurrent XRT. This approach offers an easy alternative to intravenous fluorouracil as a radiosensitizer in these patients. Role of TP and TP:DPD ratio warrants further investigation in a larger clinical trial.
Female patients with ankylosing spondylitis: analysis of the impact of gender across treatment studies
Authors: Irene E van der Horst-Bruinsma, Debra Jeske Zack, Annette Szumski, Andrew S Koenig
Journal: Annals of the Rheumatic Diseases (2012)

Objectives To examine the impact (if any) of gender on the clinical, functional and patient-reported outcomes of treatment using data pooled from four controlled clinical trials. Methods Study data were pooled from four clinical control trials in which 1283 adult patients with active ankylosing spondylitis (AS) were treated with etanercept, sulfasalazine or placebo. Patients were stratified by gender and analysed for differences/similarities in baseline demographics, disease characteristics, and efficacy in AS outcome measures and safety and discontinuation rates after 12 weeks of therapy. Results Significant baseline differences were observed between 326 female patients compared with 957 male patients. Female patients had an older mean age of disease onset (35.0 vs 31.2 years; p&lt;0.001), shorter mean time of disease duration (7.4 vs 9.5 years; p&lt;0.001) and lower mean baseline C-reactive protein (13.1 vs 20.9 mg/l; p&lt;0.001); a lower proportion was HLA-B27 positive (76.3% vs 85.2%; p&lt;0.001) compared with male patients. Women had significantly (p&lt;0.001) smaller differences in all week 12 efficacy assessments including AS disease activity score (0.87 vs −1.08), Bath AS disease activity index (−19.22 vs −23.41) and Bath AS functional index (−13.89 vs −16.88) relative to men. A similar relationship was observed between women and men in the adjusted mean difference of nocturnal back pain (4.04, 95% CI 0.77 to 7.32; p&lt;0.05), total back pain (3.80, 95% CI 0.77 to 7.32; p&lt;0.05) and patient global assessment (4.79, 95% CI 1.51 to 8.08; p&lt;0.01). Conclusions Women had a higher burden of disease and less improvement in AS outcome measures compared with men. This was observed despite women having a later disease onset of shorter duration; the mechanism behind this observation is unclear. Additional research is necessary to better understand female patients with AS and the burden of disease in this population.
Thymidine Phosphorylase Expression Is Associated With Response to Capecitabine Plus Irinotecan in Patients With Metastatic Colorectal Cancer
Authors: Neal J. Meropol, Philip J. Gold, Robert B. Diasio, Michael Andria, Mandeep Dhami, Thomas Godfrey, Albert J. Kovatich, Kirk A. Lund, Edith Mitchell, Roland Schwarting
Journal: Journal of Clinical Oncology (2006)

To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.
Whey mineral supplementation and arterial tone in mineralocorticoid-NaCl hypertension
Authors: X WU, H MAKYNEN, R KORPELA, I PORSTI
Journal: Cardiovascular Research (1996)

The aim was to study the effects of supplementation of rat chow diet with whey mineral concentrate (Whey), a diet rich in milk minerals, on arterial responses in vitro in mineralocorticoid-NaCl hypertension. Methods: Forty young Wistar rats were allocated to four groups: Wistar, Whey-Wistar, deoxycorticosterone (DOC), and Whey-DOC. DOC (10 mg kg−1 s.c.) was given twice a week and these rats drank 0.7% NaCl solution, while the others received equal volumes of vehicle (sesame oil) and drank tap water. The supplementation was performed by adding 25% whey mineral concentrate to the chow, which in particular increased the intake of potassium and also that of calcium and magnesium in the rats. Responses of mesenteric arterial rings were examined in standard organ chambers after 10 study weeks. Results: During the 10 week study the DOC-NaCl treatment had a marked hypertensive effect in rats, while the whey mineral supplementation was without significant effect on blood pressure in the Whey-DOC and Whey-Wistar groups. Arterial relaxation induced by nitroprusside was attenuated in the DOC-treated rats, but was significantly shifted towards that of controls in the Whey-DOC group. Interestingly, endothelium-dependent relaxation to acetylcholine (ACh), which was clearly impaired in the DOC group, was comparable in the Whey-DOC and Wistar groups. Moreover, only in the DOC group the relaxation was improved by diclofenac suggesting that ACh was releasing cyclo-oxygenase-derived contractile factors from the endothelium, and the response was completely abolished by NG-nitro-l-arginine methyl ester (l-NAME). In contrast, diclofenac had a negligible effect on the response in the other groups which also showed distinct relaxations to ACh in the presence of l-NAME. This remaining response to ACh in Wistar rats was inhibited by the addition of apamin and glibenclamide, inhibitors of calcium-activated and ATP-sensitive potassium channels, respectively, suggesting that it was mediated by endothelium-dependent hyperpolarization. In the Whey-Wistar group arterial function did not differ from control Wistars. Conclusions: Supplementation with whey mineral concentrate had a protective effect on endothelium-mediated control of arterial tone in experimental DOC-NaCl hypertension.