tbuckley/cabot-search huggingface dataset:
Molecular imaging of endothelial progenitor cell engraftment using contrast-enhanced ultrasound and targeted microbubbles
Authors: Michael A. Kuliszewski, Hiroko Fujii, Christine Liao, Alexandra H. Smith, Aris Xie, Jonathan R. Lindner, Howard Leong-Poi
Journal: Cardiovascular Research (2009)

Imaging methods to track the fate of progenitor cells after their delivery would be useful in assessing the efficacy of cell-based therapies. We hypothesized that contrast-enhanced ultrasound (CEU) using microbubbles targeted to a genetically engineered cell-surface marker on endothelial progenitor cells (EPCs) would allow the targeted imaging of vascular engraftment. Rodent bone marrow-derived EPCs were isolated, cultured, and transfected to express the marker protein, H-2Kk, on the cell surface. Non-transfected EPCs and EPCs transfected with either null plasmid or Firefly luciferase served as controls. Control microbubbles (MBC) and microbubbles targeted to H-2Kk expressed on EPCs (MBH-2Kk) were constructed. Binding of targeted microbubbles to EPCs was assessed in vitro using a parallel plate flow chamber system. CEU imaging of EPC-targeted microbubbles was assessed in vivo using subcutaneously implanted EPC-supplemented Matrigel plugs in rats. In flow chamber experiments, there was minimal attachment of microbubbles to plated control EPCs. Although numbers of adhered MBC were also low, there was greater and more diffuse attachment of MBH-2Kk to plated H-2Kk-transfected EPCs. Targeted CEU demonstrated marked contrast enhancement at the periphery of the H-2Kk-transfected EPC-supplemented Matrigel plug for MBH-2Kk, whereas contrast enhancement was low for MBC. Contrast enhancement was also low for both microbubbles within control mock-transfected EPC plugs. The signal intensity within the H-2Kk-transfected EPC plug was significantly greater for MBH-2Kk when compared with MBC. Microbubbles targeted to a genetically engineered cell-surface marker on EPCs exhibit specific binding to EPCs in vitro. These targeted microbubbles bind to engrafted EPCs in vivo within Matrigel plugs and can be detected by their enhancement on CEU imaging.
Effects of a Multifaceted Psychiatric Intervention Targeted for the Complex Medically Ill: A Randomized Controlled Trial
Authors: F. Stiefel, C. Zdrojewski, F. Bel Hadj, D. Boffa, Y. Dorogi, A. So, J. Ruiz, P. de Jonge
Journal: Psychotherapy and Psychosomatics (2008)

&lt;i&gt;Background:&lt;/i&gt; This study evaluated a multifaceted psychiatric intervention targeted at the complex medically ill identified by means of the INTERMED, an instrument to assess case complexity. &lt;i&gt;Methods:&lt;/i&gt; Of 885 rheumatology inpatients and diabetes outpatients who were assessed for eligibility, 247 were identified as complex (INTERMED score &gt;20) and randomized to the intervention (n = 125, 84 rheumatology and 41 diabetes patients) or care as usual (n = 122, 78 rheumatology and 44 diabetes patients). For the majority of the cases the multifaceted intervention consisted of an intervention conducted by a psychiatric liaison nurse and/or of referral to a liaison psychiatrist, followed by advice to the treating physician or organization of a multidisciplinary case conference. Baseline and follow-up at months 3, 6, 9 and 12 measured prevalence of major depression (Mini-International Neuropsychiatric Interview), depressive symptoms (Center for Epidemiological Studies Depression Rating Scale), physical and mental health (SF-36), quality of life (EuroQol), health care utilization and HbA&lt;sub&gt;1c&lt;/sub&gt; levels (diabetic patients). &lt;i&gt;Results:&lt;/i&gt; Prevalence of major depression was reduced from 61% (T0) to 28% (T4) in the intervention group and remained stable in care as usual (57% at T0 to 50% at T4). Compared to care as usual, significant improvement over time was observed in the intervention group with regard to depressive symptoms (F = 11.9; p = 0.001), perception of physical (F = 5.7; p = 0.018) and mental health (F = 3.9; p = 0.047) and quality of life (F = 21.8; p &lt; 0.001). Effects tended to be stronger in diabetes patients, in patients with baseline major depression and in patients with moderate INTERMED scores. Finally, hospital admissions occurred less often in the intervention group, reaching statistical significance for the period between 6 and 9 months of follow-up (p = 0.02). &lt;i&gt;Conclusions:&lt;/i&gt; The results suggest that a psychiatric intervention targeted for complex medical patients can improve health outcomes.
Clinical and Genetic Characterization of Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Provides Novel Insights Into Patterns of Disease Expression
Authors: Srijita Sen-Chowdhry, Petros Syrris, Deirdre Ward, Angeliki Asimaki, Elias Sevdalis, William J. McKenna
Journal: Circulation (2007)

According to clinical-pathological correlation studies, the natural history of arrhythmogenic right ventricular dysplasia/cardiomyopathy is purported to progress from localized to global right ventricular dysfunction, followed by left ventricular (LV) involvement and biventricular pump failure. The inevitable focus on sudden death victims and transplant recipients may, however, have created a skewed perspective of a genetic disease. We hypothesized that unbiased representation of the spectrum of disease expression in arrhythmogenic right ventricular dysplasia/cardiomyopathy would require in vivo assessment of families in a genetically heterogeneous population.A cohort of 200 probands and relatives satisfying task force or modified diagnostic criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy underwent comprehensive clinical evaluation. Desmosomal mutations were identified in 39 individuals from 20 different families. Indices of structural severity correlated with advancing age and were increased in long-term endurance athletes. Fulfillment of modified criteria indicated phenotypically mild disease, whereas asymptomatic status did not. In >80%, ECG, rhythm monitoring, and/or gadolinium-enhanced cardiovascular magnetic resonance were suggestive of LV involvement, the extent of which often was marked among individuals with chain-termination mutations and/or desmoplakin disease. Three patterns of disease expression were identified: (1) classic, with isolated right ventricular disease or LV involvement in association with significant right ventricular impairment; (2) left dominant, with early and prominent LV manifestations and relatively mild right-sided disease; and (3) biventricular, characterized by parallel involvement of both ventricles.LV involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy may precede the onset of significant right ventricular dysfunction. Recognition of disease variants with early and/or predominant LV involvement supports adoption of the broader term arrhythmogenic cardiomyopathy.
Molecular Genetics of Clear-Cell Renal Cell Carcinoma
Authors: James Brugarolas
Journal: Journal of Clinical Oncology (2014)

Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.
The stomach talks with the pituitary
Authors: O LUNDGREN
Journal: Gut (2000)

Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary.They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown.Recent cloning of GHS-R strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growthhormone-releasing hormone (GHRH).We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R.The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated.The acylated peptide specifically releases GH both in vivo and in vitro and O-n-octanoylation at serine 3 is essential for the activity.We designate the GHreleasing peptide 'ghrelin' (ghre is the Proto-Indo-European root of the word 'grow').Human ghrelin is homologous to rat ghrelin apart from two amino acids.The occurrence of ghrelin in both rat and humans indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH but also by ghrelin.
Microsatellites Within Genes: Structure, Function, and Evolution
Authors: Y.-C. Li
Journal: Molecular Biology and Evolution (2004)

Recently, increasingly more microsatellites, or simple sequence repeats (SSRs) have been found and characterized within protein-coding genes and their untranslated regions (UTRs). These data provide useful information to study possible SSR functions. Here, we review SSR distributions within expressed sequence tags (ESTs) and genes including protein-coding, 3′-UTRs and 5′-UTRs, and introns; and discuss the consequences of SSR repeat-number changes in those regions of both prokaryotes and eukaryotes. Strong evidence shows that SSRs are nonrandomly distributed across protein-coding regions, UTRs, and introns. Substantial data indicates that SSR expansions and/or contractions in protein-coding regions can lead to a gain or loss of gene function via frameshift mutation or expanded toxic mRNA. SSR variations in 5′-UTRs could regulate gene expression by affecting transcription and translation. The SSR expansions in the 3′-UTRs cause transcription slippage and produce expanded mRNA, which can be accumulated as nuclear foci, and which can disrupt splicing and, possibly, disrupt other cellular function. Intronic SSRs can affect gene transcription, mRNA splicing, or export to cytoplasm. Triplet SSRs located in the UTRs or intron can also induce heterochromatin-mediated–like gene silencing. All these effects caused by SSR expansions or contractions within genes can eventually lead to phenotypic changes. SSRs within genes evolve through mutational processes similar to those for SSRs located in other genomic regions including replication slippage, point mutation, and recombination. These mutational processes generate DNA changes that should be connected by DNA mismatch repair (MMR) system. Mutation that has escaped from the MMR system correction would become new alleles at the SSR loci, and then regulate and/or change gene products, and eventually lead to phenotype changes. Therefore, SSRs within genes should be subjected to stronger selective pressure than other genomic regions because of their functional importance. These SSRs may provide a molecular basis for fast adaptation to environmental changes in both prokaryotes and eukaryotes.
Effects of the Dipeptidyl Peptidase-IV Inhibitor Vildagliptin on Incretin Hormones, Islet Function, and Postprandial Glycemia in Subjects With Impaired Glucose Tolerance
Authors: Julio Rosenstock, James E. Foley, Marc Rendell, Mona Landin-Olsson, Jens J. Holst, Carolyn F. Deacon, Erika Rochotte, Michelle A. Baron
Journal: Diabetes Care (2007)

OBJECTIVE—This study was conducted to determine the effects of vildagliptin on incretin hormone levels, islet function, and postprandial glucose control in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS—A 12-week, double-blind, randomized, parallel-group study comparing vildagliptin (50 mg q.d.) and placebo was conducted in 179 subjects with IGT (2-h glucose 9.1 mmol/l, A1C 5.9%). Plasma levels of intact glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide, and glucagon were measured during standard meal tests performed at baseline and at week 12. Insulin secretory rate (ISR) was estimated by C-peptide deconvolution. The between-group differences (vildagliptin − placebo) in the adjusted mean changes from baseline to end point in the total and incremental (Δ) area under the curve (AUC)0–2 h for these analytes were assessed by ANCOVA; glucose AUC0–2 h was the primary outcome variable. RESULTS—Relative to placebo, vildagliptin increased GLP-1 (ΔAUC, +6.0 ± 1.2 pmol · l−1 · h−1, P &amp;lt; 0.001) and GIP (ΔAUC, +46.8 ± 5.4 pmol · l−1 · h−1, P &amp;lt; 0.001) and decreased glucagon (ΔAUC, −3.0 ± 1.0 pmol · l−1 · h−1, P = 0.003). Although postprandial insulin levels were unaffected (ΔAUC, +20.8 ± 35.7 pmol · l−1 · h−1, P = 0.561), prandial glucose excursions were reduced (ΔAUC, −1.0 ± 0.3 mmol · l−1 · h−1, P &amp;lt; 0.001), representing an ∼30% decrease relative to placebo. β-Cell function as assessed by the ISR AUC0–2 h/glucose AUC0–2 h was significantly increased (+6.4 ± 2.0 pmol · min−1 · m−2 · mmol · l−1, P = 0.002). Adverse event profiles were similar in the two treatment groups, and no hypoglycemia was reported. CONCLUSIONS—The known effects of vildagliptin on incretin levels and islet function in type 2 diabetes were reproduced in subjects with IGT, with a 32% reduction in postprandial glucose excursions and no evidence of hypoglycemia or weight gain.
Establishment of a protocol to test fatigue of the trunk muscles
Authors: G Corin, P H Strutton, A H McGregor
Journal: British Journal of Sports Medicine (2005)

Muscle fatigue has high relevance in human performance yet little research has evaluated how it should be assessed.To perform a pilot study to identify suitable methods of generating and assessing fatigue of the trunk flexor and extensor muscles.Sixteen university rugby players (mean (SEM) age 21.9 (0.2) years) were recruited and subjected to four protocols (A, B, C, D), separated by a week to allow recovery, with peak torque being recorded during each test: A, isokinetic measurements before and after fatigue, with a 10 repetition isokinetic fatigue period; B, isokinetic measurements before and after fatigue with a 45 second isometric fatigue period; C, isometric measurements before and after fatigue with a 10 repetition isokinetic fatigue period; D, isometric measurements before and after fatigue with a 45 second isometric fatigue period. All were conducted during flexion and extension of the trunk on the Cybex Norm Isokinetic Dynamometer trunk flexion-extension unit.All subjects completed all four protocols. Fatigue induction appeared more effective in flexion than extension. Significant differences in mean peak torque before and after fatigue were seen in protocols A, B, and D in flexion and only in protocol D for extension. In flexion, protocol D produced the greatest fatigue, peak torque being 16.2% less after than before fatigue, suggesting greatest sensitivity.Protocol D, which incorporates isometric testing and fatigue protocols, appears to be able to produce fatigue most effectively, and therefore may provide the most valid assessment of fatigue in the trunk flexor and extensor muscles.
P36 Functional class and gas transfer are useful tools in the assessment of pulmonary hypertension associated with sickle cell disease
Authors: H. Ranu, L. Brown, J. Lee, B. Madden
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> WHO Functional class (FC) is an important tool in the management of patients with pulmonary arterial hypertension. There is an increasing awareness of pulmonary hypertension (PH) as a complication of Sickle cell disease (SCD). We wished to evaluate functional class and gas transfer (diffusion capacity DLCOc, KCOc) in patients with SCD (HbSS) with and without PH based on trans thoracic echocardiogram. <h3>Methods</h3> 32 patients were reviewed and their functional class was determined. Trans thoracic echocardiograms were reviewed in these patients for evidence of PH (defined as a tricuspid regurgitation jet velocity TRV ≥ 2. 5 m/s). Haematological and lung function data were also reviewed. Only patients in steady state and without a crisis in the preceding 2 weeks were included. <h3>Results</h3> Of patients with PH 36% (5/14) were FC ≥3 compared to 6% (1/18) without PH. There was a significant difference in functional class in patients with and without PH on echocardiogram (p&lt;0.05). There was a significant correlation between TRV and WHO functional class (p=0.002, r= 0.54). The correlation between TRV and functional class remained significant after correction for haemoglobin. Mean haemoglobin was 8.3±1.3 g/dl in those with PH and 10.1±1.4 g/dl in those without PH (p=0.001). Neither PH nor FC was associated with parenchymal abnormalities visible on CT and/or chest radiograph. PH was also associated with a lower diffusion capacity (DLCOc mmol/min/kPa: 3.60±0.79 vs 7.60±2.66, p=0.034) and a lower diffusion capacity corrected for alveolar volume (KCOc mmol/min/kPa/l: 1.04±0.31 vs 1.96±0.3, p=0.034). TRV was significantly correlated with DLCOc only (p=0.036 r= −0.79). <h3>Conclusion</h3> Although patients with Sickle cell disease may have a number of reasons to account for their breathlessness, functional class and measurements of gas transfer may be useful markers in screening patients for pulmonary hypertension regardless of low steady state anaemia.
A Phase II Trial of Pemetrexed in Advanced Breast Cancer: Clinical Response and Association with Molecular Target Expression
Authors: Henry L. Gomez, Sergio L. Santillana, Carlos S. Vallejos, Raul Velarde, Juvenal Sanchez, Xinpeng Wang, Nancy L. Bauer, Richard D. Hockett, Victor J. Chen, Clet Niyikiza, Axel R. Hanauske
Journal: Clinical Cancer Research (2006)

This phase II trial of pemetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression.Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m2 (10-minute i.v. infusion) on day 1 of a 21-day cycle, with folic acid and vitamin B12 supplementation. Tumors were surgically removed after the last cycle of pemetrexed as clinically indicated. Biopsies were taken at baseline, 24 hours after infusion in cycle 1, and after cycle 3.Sixty-one women (median age, 46 years; range, 32-72 years) were treated and were evaluable for response. Objective response rate was 31%. Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase (TS) and pemetrexed response (P = 0.103). Based on threshold analysis, patients with "low" baseline TS (< or = 71) were more likely to respond to pemetrexed than patients with "high" baseline TS (>71). Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant (P > 0.311). TS expression increased significantly between baseline and biopsy 2 (P = 0.004) and dropped to near baseline levels at biopsy 3. Conversely, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pemetrexed chemotherapy.Our results suggest a potential association between "low" pretreatment TS expression levels and response to pemetrexed chemotherapy. Future trials examining expression levels of other genes important to the folate pathway and/or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate.
Significance of Circulating Troponins in Heart Failure
Authors: Thomas J. Wang
Journal: Circulation (2007)

B iomarkers serve 2 potential roles: They provide insight into the pathophysiology of disease, and they aid clinical decision making by clarifying diagnosis, prognosis, or response to therapy.Fulfillment of one role does not ensure fulfillment of the other.For instance, some biomarkers associated with disease progression turn out to provide little incremental clinical value.Thus, studies like the one by Latini and colleagues 1 in this issue of Circulation are valuable because they couple investigation of a biologically interesting association, in this case the link between circulating troponins and heart failure (HF), with a rigorous assessment of clinical utility.The following commentary focuses on 2 questions raised by the study by Latini et al.First, what is the pathophysiological significance of circulating troponins in HF? Second, should we be measuring cardiac troponins in chronic HF patients? Article p 1242 The Significance of Cardiac Troponins in HFThe troponins comprise 3 proteins (troponin T, I, and C) that regulate actin and myosin interactions during muscle contraction.Troponins T and I have distinct isoforms that exist in skeletal and cardiac muscle; newer-generation assays permit the detection of the isoforms unique to cardiac tissue.The release of these proteins into the bloodstream from cardiomyocyte necrosis accounts for their utility as biomarkers of acute coronary syndromes.In the past decade, it has been recognized that elevated concentrations of cardiac troponins also are detectable in patients with HF in the absence of unstable coronary syndromes.In 1997, Missov and colleagues 2 used a highly sensitive research assay to demonstrate elevated concentrations of troponin I in 35 patients with advanced HF. Subsequent reports extended these observations to troponin T. [3][4][5] For instance, in a Japanese study, troponin T was detectable by a second-generation assay (detection limit, 0.02 ng/mL) in
The Value of Coronary Bypass Surgery Compared With Medical Therapy
Authors: J. Willis Hurst
Journal: JAMA (1989)

I have followed the work of the clinical investigators at Duke University<sup>1</sup>for the last 15 years as they carefully observed and treated patients with atherosclerotic coronary heart disease. Whereas many experts demand randomized trials to determine the value of a specific form of treatment, our Duke friends have emphasized that observational studies are also useful in arriving at a conclusion regarding the value of a specific type of treatment. Accordingly, they studied and followed up 5809 patients who either had coronary bypass surgery or were treated medically. I, too, believe that excellent observational studies by superb clinical investigators can teach us all a great deal. So, I wish to compliment the large number of investigators who assisted in the study that is reported in this issue of<i>JAMA</i>.<sup>1</sup> During the early 1970s, bypass surgery was restricted to patients who were disabled from angina pectoris despite intensive medical
Tension pneumothorax case report is misleading
Authors: Graham Simpson
Journal: Thorax (2011)

The problem with the recent case report ‘Tension pneumothorax mimicking giant emphysematous bullae’1 is that the patient clearly did not have a tension pneumothorax. He was not particularly unwell and had only a minimal mediastinal shift. A much greater mediastinal shift can be seen in non-tension pneumothorax.2 The actual definition of tension pneumothorax is not generally agreed. The 2003 British Thoracic Society guidelines3 refer to tension pneumothorax …