tbuckley/cabot-search huggingface dataset:
The effect of microgrooved culture substrates on calcium cycling of cardiac myocytes derived from human induced pluripotent stem cells
Authors: Christopher Rao, Themistoklis Prodromakis, Ljudmila Kolker, Umar A.R. Chaudhry, Tatiana Trantidou, Arun Sridhar, Claire Weekes, Patrizia Camelliti, Sian E. Harding, Ara Darzi, Magdi H. Yacoub, Thanos Athanasiou, Cesare M. Terracciano
Journal: Biomaterials (2012)

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) have been widely proposed as in vitro models of myocardial physiology and disease. A significant obstacle, however, is their immature phenotype. We hypothesised that Ca2+ cycling of iPSC-CM is influenced by culture conditions and can be manipulated to obtain a more mature cellular behaviour. To test this hypothesis we seeded iPSC-CM onto fibronectin coated microgrooved polydimethylsiloxane (PDMS) scaffolds fabricated using photolithography, or onto unstructured PDMS membrane. After two weeks in culture, the structure and function of iPSC-CM were studied. PDMS microgrooved culture substrates brought about cellular alignment (p < 0.0001) and more organised sarcomere. The Ca2+ cycling properties of iPSC-CM cultured on these substrates were significantly altered with a shorter time to peak amplitude (p = 0.0002 at 1 Hz), and more organised sarcoplasmic reticulum (SR) Ca2+ release in response to caffeine (p < 0.0001), suggesting improved SR Ca2+ cycling. These changes were not associated with modifications in gene expression. Whilst structured tissue culture may make iPSC-CM more representative of adult myocardium, further construct development and characterisation is required to optimise iPSC-CM as a model of adult myocardium.
Alveolar macrophages in idiopathic pulmonary fibrosis display a more monocyte-like immunophenotype and an increased release of free oxygen radicals
Authors: J Kiemle-Kallee, H Kreipe, HJ Radzun, MR Parwaresch, U Auerswald, H Magnussen, J Barth
Journal: European Respiratory Journal (1991)

Bronchoalveolar lavage (BAL) was performed in 13 patients with idiopathic pulmonary fibrosis (IPF) and in 10 control subjects. Free oxygen radical (FOR) production of alveolar macrophages (AM) and of blood monocytes was measured by luminol-dependent chemiluminescence (LDCL) without and after stimulation with zymosan A. We confirmed earlier studies that alveolar macrophages of IPF patients display a significantly elevated release of FOR under basic and under stimulated conditions. In contrast to alveolar macrophages, blood monocytes did not reveal altered LDCL in IPF. This indicates that the functional properties for augmented FOR release by IPF alveolar macrophages are acquired in the lungs and not in the peripheral circulation. To elucidate the possible mechanisms leading to the augmented LDCL response, immunophenotyping of alveolar macrophages was carried out. A panel of new monoclonal antibodies of the Ki-M-series, discriminating differentiation stages of monocyte/macrophage subpopulations, served for immunocytochemical staining. In IPF patients distribution of Ki-M2, Ki-M3, Ki-M6 and Ki-M8 positive AM demonstrated an increased proportion of alveolar macrophages expressing a more monocyte-like immunophenotype. Normally, monocytes as precursors of AM reveal a markedly stronger LDCL than alveolar macrophages themselves. Therefore, it seems likely that the increased LDCL of alveolar macrophages in IPF is due to the higher proportion of more immature monocyte-like cells in the alveoli of these patients.
Circulating p24 Antigen Levels and Responses to Dideoxycytidine in Human Immunodeficiency Virus (HIV) Infections
Authors: Thomas C. Merigan
Journal: Annals of Internal Medicine (1989)

Study Objective: To determine the safety and efficacy of dideoxycytidine in patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. Design: A partially randomized phase I and II outpatient, dose-ranging study. Setting: Four university medical centers involving government-supported referral AIDS Clinical Trial Units. Patients: Sixty-one patients with AIDS or advanced AIDS-related complex and 100 pg/mL or more serum p24 antigen titers. Interventions: Dideoxycytidine was administered orally at 0. 06, 0.03, 0.01, or 0.005 mg/kg body weight every 4 hours for 3 to 6 months depending on tolerance and benefit. Measurements and Main Results: In patients receiving 0. 06 and 0.03 mg/kg, diffuse erythematous rash, fever, and aphthous stomatitis occurred in the first weeks of therapy, but resolved later. Hematopoietic suppression was rare. Peripheral sensory neuropathy occurred in patients receiving 0.06 mg/kg and 0.03 mg/kg and improved after discontinuation of therapy. Serum p24 antigen fell significantly (P < 0.01) from baseline entry values in most of these patients. The CD4 lymphocytes rose transiently at the 0.03 mg/kg dosage. At the 0.005 mg/kg dosage, skin rash, fever, and aphthous stomatitis were mild or absent. Peripheral neuropathy, which occurred in all patients receiving 0.01 mg/kg was less severe than at higher dosages. At the 0.005 mg/kg dosage, peripheral neuropathy was occasionally seen. Significant suppression of serum p24 antigen was seen in most patients with AIDS-related complex receiving 0.01 mg/kg and less frequently in patients receiving 0.005 mg/kg. Conclusions: Less toxic regimens of dideoxycytidine merit clinical assessment for advanced anti-human immunodeficiency virus-1 (HIV) infection. Several studies alternating dideoxycytidine and zidovudine are in progress.
Multiple myeloma–associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress
Authors: Liang Chu, Mack Y. Su, Leonard B. Maggi, Lan Lu, Chelsea Mullins, Seth Crosby, Gaofeng Huang, Wee Joo Chng, Ravi Vij, Michael H. Tomasson
Journal: Journal of Clinical Investigation (2012)

The histone methyltransferase WHSC1 (also known as MMSET) is overexpressed in multiple myeloma (MM) as a result of the t(4;14) chromosomal translocation and in a broad variety of other cancers by unclear mechanisms. Overexpression of WHSC1 did not transform wild-type or tumor-prone primary hematopoietic cells. We found that ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive MM and other cancers. ACA11 localized to nucleoli and bound what we believe to be a novel small nuclear ribonucleoprotein (snRNP) complex composed of several proteins involved in postsplicing intron complexes. RNA targets of this uncharacterized snRNP included snoRNA intermediates hosted within ribosomal protein (RP) genes, and an RP gene signature was strongly associated with t(4;14) in patients with MM. Expression of ACA11 was sufficient to downregulate RP genes and other snoRNAs implicated in the control of oxidative stress. ACA11 suppressed oxidative stress, afforded resistance to chemotherapy, and increased the proliferation of MM cells, demonstrating that ACA11 is a critical target of the t(4;14) translocation in MM and suggesting an oncogenic role in other cancers as well.
EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia
Authors: B V Balgobind, S Lugthart, I H Hollink, S T J C M Arentsen-Peters, E R van Wering, S S N de Graaf, D Reinhardt, U Creutzig, G J L Kaspers, E S J M de Bont, J Stary, J Trka, M Zimmermann, H B Beverloo, R Pieters, R Delwel, C M Zwaan, M M van den Heuvel-Eibrink
Journal: Leukemia (2010)
The Impact of Family History of Diabetes on Glucose Testing and Counseling Behavior in Primary Care
Authors: Harvey J. Murff, Russell L. Rothman, Daniel W. Byrne, Sapna Syngal
Journal: Diabetes Care (2004)

Epidemiological evidence has revealed increasing prevalence rates of type 2 diabetes (1,2), with an estimated 6.3% of the U.S. adult population having either diagnosed or undiagnosed diabetes (3). Individuals with a family history of diabetes are at increased risk of developing diabetes, and lifestyle modification can help reduce this risk (4–6). Several studies have demonstrated that lifestyle choices, such as regular exercise or healthy dietary choices, are associated with a reduced risk of developing diabetes (7–10). The purpose of this study was to determine whether a family history of diabetes was associated with a provider’s decision to screen for diabetes or with a provider’s counseling about lifestyle modifications.

The study was conducted at two academic primary care clinics in Boston, Massachusetts, that are affiliated with Brigham and Women’s Hospital. A consecutive sample of new patients seen between May 2001 and February 2002 were identified through searching clinic administrative databases. Patient visits associated with either an ICD-9-CM code for a routine medical (V70.0 and V70.9) or gynecologic (V72.3 and V76.2) examination (11) or a CPT (Current Procedural Terminology) code for an annual/preventative visit in an adult (99385, 99386, and 99387) (12) were included within our study sample. We excluded …
ON THE CAUSE OF THE HEART BEAT
Authors: W. T. Porter
Journal: The Journal of Experimental Medicine (1897)

1. The cause of the rhythmic contraction of the ventricle lies within the ventricle itself. 2. The cause of the rhythmic contraction is not a single, localized, co-ordination centre; the co-ordination mechanism, whatever it may be, is present in all parts of the ventricle. 3. The integrity of the whole ventricle is not essential to the coordinated contractions of a part of the ventricle. 4. The apex of the mammalian heart possesses spontaneous, rhythmic contractility. 5. Assuming that the general belief in the absence of nerve cells from the apical part of the ventricle is correct, these experiments demonstrate that nerve cells are not essential to spontaneous, long-continued, co-ordinated contractions of the ventricle.
Physiological Basis of Clinically Used Coronary Hemodynamic Indices
Authors: Jos A.E. Spaan, Jan J. Piek, Julien I.E. Hoffman, Maria Siebes
Journal: Circulation (2006)

In deriving clinically used hemodynamic indices such as fractional flow reserve and coronary flow velocity reserve, simplified models of the coronary circulation are used. In particular, myocardial resistance is assumed to be independent of factors such as heart contraction and driving pressure. These simplifying assumptions are not always justified. In this review we focus on distensibility of resistance vessels, the shape of coronary pressure-flow lines, and the influence of collateral flow on these lines. We show that (1) the coronary system is intrinsically nonlinear because resistance vessels at maximal vasodilation change diameter with pressure and cardiac function; (2) the assumption of collateral flow is not needed to explain the difference between pressure-derived and flow-derived fractional flow reserve; and (3) collateral flow plays a role only at low distal pressures. We conclude that traditional hemodynamic indices are valuable for clinical decision making but that clinical studies of coronary physiology will benefit greatly from combined measurements of coronary flow or velocity and pressure.
Fracture Prediction After Discontinuation of 4 to 5 Years of Alendronate Therapy
Authors: Douglas C. Bauer, Ann Schwartz, Lisa Palermo, Jane Cauley, Marc Hochberg, Art Santora, Steven R. Cummings, Dennis M. Black
Journal: JAMA Internal Medicine (2014)

Discontinuation of bisphosphonate therapy after 3 to 5 years is increasingly considered, but methods to monitor fracture risk after discontinuation have not been established.To test methods of predicting fracture risk among women who have discontinued alendronate therapy after 4 to 5 years.The prospective Fracture Intervention Trial Long-term Extension (FLEX) study randomized postmenopausal women aged 61 to 86 years previously treated with 4 to 5 years of alendronate therapy to 5 more years of alendronate or placebo from 1998 through 2003; the present analysis includes only the placebo group. Hip and spine dual-energy x-ray absorptiometry (DXA) were measured when placebo was begun (FLEX baseline) and after 1 to 3 years of follow-up. Two biochemical markers of bone turnover, urinary type 1 collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP), were measured at FLEX baseline and after 1 and 3 years.Symptomatic spine and nonspine fractures occurring after the follow-up measurement of DXA or bone turnover.During 5 years of placebo, 94 of 437 women (22%) experienced 1 or more symptomatic fractures; 82 had fractures after 1 year. One-year changes in hip DXA, NTX, and BAP were not related to subsequent fracture risk, but older age and lower hip DXA at time of discontinuation were significantly related to increased fracture risk (lowest tertile of baseline femoral neck DXA vs other 2 tertiles relative hazard ratio, 2.17 [95% CI, 1.38-3.41]; total hip DXA relative hazard ratio, 1.87 [95% CI, 1.20-2.92]).Among postmenopausal women who discontinue alendronate therapy after 4 to 5 years, age and hip BMD at discontinuation predict clinical fractures during the subsequent 5 years. Follow-up measurements of DXA 1 year after discontinuation and of BAP or NTX 1 to 2 years after discontinuation are not associated with fracture risk and cannot be recommended.clinicaltrials.gov Identifier: NCT00398931.
Signatures of Natural Selection on Mutations of Residues with Multiple Posttranslational Modifications
Authors: V. E. Gray, L. Liu, R. Nirankari, P. V. Hornbeck, S. Kumar
Journal: Molecular Biology and Evolution (2014)

Posttranslational modifications (PTMs) regulate molecular structures and functions of proteins by covalently binding to amino acids. Hundreds of thousands of PTMs have been reported for the human proteome, with multiple PTMs known to affect tens of thousands of lysine (K) residues. Our molecular evolutionary analyses show that K residues with multiple PTMs exhibit greater conservation than those with a single PTM, but the difference is rather small. In contrast, short-term evolutionary trends revealed in an analysis of human population variation exhibited a much larger difference. Lysine residues with three PTMs show 1.8-fold enrichment of Mendelian disease-associated variants when compared with K residues with two PTMs, with the latter showing 1.7-fold enrichment of these variants when compared with the K residues with one PTM. Rare polymorphisms in humans show a similar trend, which suggests much greater negative selection against mutations of K residues with multiple PTMs within population. Conversely, common polymorphisms are overabundant at unmodified K residues and at K residues with fewer PTMs. The observed difference between inter- and intraspecies patterns of purifying selection on residues with PTMs suggests extensive species-specific drifting of PTM positions. These results suggest that the functionality of a protein is likely conserved, without necessarily conserving the PTM positions over evolutionary time.
Informed Consent: Assessment of Comprehension
Authors: Donna A. Wirshing, William C. Wirshing, Stephen R. Marder, Robert P. Liberman, Jim Mintz
Journal: American Journal of Psychiatry (1998)

The authors designed and evaluated a structured and rigorous informed consent procedure involving subjects with schizophrenia.Informed consent forms were read and explained to 49 schizophrenic patients participating in ongoing clinical treatment research trials. The subjects answered a questionnaire relating to each research protocol. Protocol procedures were reiterated until the patients answered 100% of the questions correctly. Subjects were asked the same questions 7 days later to ascertain how much of the information they had retained.The patients' median score on the first trial of the informed consent questionnaire was 80% correct. To achieve 100% correct responses, 53% of the patients required a second trial of the questionnaire, and 37% of them required three or more trials. Scores improved between the first trial and the trial on day 7. Ninety-six percent of the subjects felt adequately informed, 66% reported participating in the research protocol for personal reasons, and 34% reported participating at the suggestion of others.These findings demonstrate that when adequate informed consent procedures are established, schizophrenic research subjects are able to understand and retain critical components of informed consent information.
Acute Myeloid Leukemia With Biallelic <i>CEBPA</i> Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated With a Favorable Clinical Outcome
Authors: Annika Dufour, Friederike Schneider, Klaus H. Metzeler, Eva Hoster, Stephanie Schneider, Evelyn Zellmeier, Tobias Benthaus, Maria-Cristina Sauerland, Wolfgang E. Berdel, Thomas Büchner, Bernhard Wörmann, Jan Braess, Wolfgang Hiddemann, Stefan K. Bohlander, Karsten Spiekermann
Journal: Journal of Clinical Oncology (2009)

CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML).Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we obtained gene expression profiles using oligonucleotide microarrays.Only patients with biCEBPA had an improved median overall survival when compared with patients with wtCEBPA (not reached v 20.4 months, respectively; P = .018), whereas patients with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P = .506). Multivariable analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognostic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated with mutated NPM1 (0% v 43%, respectively; P < .001) and rarely associated with FLT3 internal tandem duplication (ITD; 5% v 23%, respectively; P = .059), whereas patients with moCEBPA had a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD compared with patients with wtCEBPA (44% v 23%, respectively; P = .037). Furthermore, patients with biCEBPA showed a homogeneous gene expression profile that was characterized by downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in their gene expression profiles.Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a different frequency of associated gene mutations. These findings are of great significance for risk-adapted therapeutic strategies in AML.
Unexpected Dissemination Patterns in Lymphoma Progression Revealed by Serial Imaging within a Murine Lymph Node
Authors: Ken Ito, Bryan Ronain Smith, Natesh Parashurama, Joon-Kee Yoon, Si Yeol Song, Cornelius Miething, Parag Mallick, Scott Lowe, Sanjiv Sam Gambhir
Journal: Cancer Research (2012)

Abstract Non-Hodgkin lymphoma (NHL) is a heterogeneous and highly disseminated disease, but the mechanisms of its growth and dissemination are not well understood. Using a mouse model of this disease, we used multimodal imaging, including intravital microscopy (IVM) combined with bioluminescence, as a powerful tool to better elucidate NHL progression. We injected enhanced green fluorescent protein and luciferase-expressing Eμ-Myc/Arf−/− (Cdkn2a−/−) mouse lymphoma cells (EL-Arf−/−) into C57BL/6NCrl mice intravenously. Long-term observation inside a peripheral lymph node was enabled by a novel lymph node internal window chamber technique that allows chronic, sequential lymph node imaging under in vivo physiologic conditions. Interestingly, during early stages of tumor progression we found that few if any lymphoma cells homed initially to the inguinal lymph node (ILN), despite clear evidence of lymphoma cells in the bone marrow and spleen. Unexpectedly, we detected a reproducible efflux of lymphoma cells from spleen and bone marrow, concomitant with a massive and synchronous influx of lymphoma cells into the ILN, several days after injection. We confirmed a coordinated efflux/influx of tumor cells by injecting EL-Arf−/− lymphoma cells directly into the spleen and observing a burst of lymphoma cells, validating that the burst originated in organs remote from the lymph nodes. Our findings argue that in NHL an efflux of tumor cells from one disease site to another, distant site in which they become established occurs in discrete bursts. Cancer Res; 72(23); 6111–8. ©2012 AACR.
Calcium exchange in rabbit myocardium during and after hypoxia: effect of temperature and substrate
Authors: D. P HARDING, P. A POOLE-WILSON
Journal: Cardiovascular Research (1980)

Calcium influx and efflux were measured during hypoxia and on reoxygenation in the isolated arterially perfused septum of the rabbit heart. The uptake of 47Ca2+ was continuously followed with a NaI crystal and counter. The extracellular space (ECS) was measured in a similar manner with 51Cr-EDTA. Calcium efflux was recorded by collection of effluent drops after labelling with 45Ca2+. Hypoxia caused a rapid decline of developed tension followed by a rise in resting tension. The ECS increased initially but decreased as resting tension rose. 51Cr-EDTA did not have free access to the intracellular fluid. Calcium efflux did not change and calcium influx was either unchanged or reduced. On reoxygenation calcium influx increased immediately but efflux was unaltered and 51Cr-EDTA did not enter the cell. The effects of hypoxia were altered by manipulation of temperature and substrate. The recovery of mechanical function was related to the size of the calcium influx on reoxygenation. The experiments show that a rise of resting tension during hypoxia can occur in the absence of a net gain of calcium, calcium accumulation is closely associated with the extent of tissue damage, and that calcium influx on reoxygenation is probably due to a specific abnormality and not gross disruption of the cell membrane.
Severe Diabetic Ketoacidosis Associated With Acute Myocardial Necrosis
Authors: Martin Tretjak, Franc Verovnik, Bojan Vujkovac, Cirila Slemenik-Pusnik, Marko Noc
Journal: Diabetes Care (2003)

We describe a case of a 28-year-old woman who was admitted to our hospital with severe diabetic ketoacidosis. She was known to have had type 1 diabetes for 10 years. During the previous 2 days, she had gone to a party, drank a considerable amount of alcohol, and did not administer her regular dose of insulin.

On admission, she was semicomatose and tachypnoic, her blood pressure was 90/70 mmHg, and her heart rate 80 bpm. Laboratory tests showed severe metabolic acidosis (pH 6.92, bicarbonate 2.2 mmol/l, pCO2 1.49 kPa), very high blood glucose (75 mmol/l), hyponatremia (104.3 …