tbuckley/cabot-search huggingface dataset:
Structural and Functional Evidence for Discrete Exit Pathways That Connect the Canine Sinoatrial Node and Atria
Authors: Vadim V. Fedorov, Richard B. Schuessler, Matthew Hemphill, Christina M. Ambrosi, Roger Chang, Alexandra S. Voloshina, Kathy Brown, William J. Hucker, Igor R. Efimov
Journal: Circulation Research (2009)

Surface electrode recordings cannot delineate the activation within the human or canine sinoatrial node (SAN) because they are intramural structures. Thus, the site of origin of excitation and conduction pathway(s) within the SAN of these mammals remains unknown. Canine right atrial preparations (n=7) were optically mapped. The SAN 3D structure and protein expression were mapped using immunohistochemistry. SAN optical action potentials had diastolic depolarization and multiple upstroke components that corresponded to the separate excitations of the node and surface atrial layers. Pacing-induced SAN exit block eliminated atrial optical action potential components but retained SAN optical action potential components. Excitation originated in the SAN (cycle length, 557±72 ms) and slowly spread (1.2 to 14 cm/sec) within the SAN, failing to directly excite the crista terminalis and intraatrial septum. After a 49±22 ms conduction delay within the SAN, excitation reached the atrial myocardium via superior and/or inferior sinoatrial exit pathways 8.8±3.2 mm from the leading pacemaker site. The ellipsoidal 13.7±2.8/4.9±0.6 mm SAN structure was functionally insulated from the atrium. This insulation coincided with connexin43-negative regions at the borders of the node, connective tissue, and coronary arteries. During normal sinus rhythm, the canine SAN is functionally insulated from the surrounding atrial myocardium except for 2 (or more) narrow superior and inferior sinoatrial exit pathways separated by 12.8±4.1 mm. Conduction failure in these sinoatrial exit pathways leads to SAN exit block and is a modulator of heart rate.
Targeting the Epidermal Growth Factor Receptor: An Important Incremental Step in the Battle Against Colorectal Cancer
Authors: Lee M. Ellis, Paulo M. Hoff
Journal: Journal of Clinical Oncology (2004)

Although colorectal cancer continues to be a majorcause of cancer death worldwide, considerable improve-menthasbeenachievedinthelastdecadewiththeadventofnewer chemotherapy agents such as irinotecan and oxali-platin. This advance is most obvious in the treatment ofpatients with metastatic disease, in whom the median sur-vival now exceeds 20 months.
Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study
Authors: Bharti Mackness, Paul Durrington, Patrick McElduff, John Yarnell, Naheed Azam, Michael Watt, Michael Mackness
Journal: Circulation (2003)

Background— The hypothesis that paraoxonase (PON1) has a role in preventing atherosclerosis is based on experimental, transgenic, and case-control studies but has not previously been tested prospectively. Methods and Results— The Caerphilly Prospective Study is a cohort study of men aged 49 to 65 years observed for coronary heart disease (CHD) events (fatal and nonfatal myocardial infarction) over a mean period of 15 years. Serum PON1 activity toward paraoxon was measured in 1353 participants. PON1 activity was 20% lower in the 163 men who had a coronary event ( P =0.039). Men in the highest quintile of PON1 activity had a decreased risk compared with those in the lowest quintile (OR 0.57 [95% CI, 0.33 to 0.96]). The inverse relationship between quintiles of serum PON1 activity and CHD risk was graded, the median change in OR across each quintile being 0.87 (0.77 to 0.98). After adjustment for all other CHD risk factors, including HDL cholesterol, this median value became 0.90 (0.78 to 1.02). PON1 was most predictive of a new CHD event in patients at highest risk by virtue of preexisting CHD (adjusted median OR for each quintile, 0.74 [0.59 to 0.93]; n=313) or the presence of other risk factors. For the highest tertile of CHD risk (n=390) calculated by the Framingham equation, adjusted median OR for each quintile was 0.84 (0.66 to 1.05); n=390. Conclusions— Low serum PON1 activity toward paraoxon is an independent risk factor for coronary events in men at high risk because of preexisting disease or other CHD risk factors.
The Interstate Compact on Mental Health
Authors: WILFRED BLOOMBERG, MYRON JOHN ROCKMORE
Journal: American Journal of Psychiatry (1967)

The Interstate Compact on Mental Health, formed in 1955, now has 35 states as members. It has been instrumental in facilitating the transfer of patients between mental facilities in different states without the administrative entanglements that formerly accompanied such transfers. The primary consideration of the Compact is the well-being of the patient.
A Preliminary Report on Oocyte Donation Extending Reproductive Potential to Women over 40
Authors: Mark V. Sauer, Richard J. Paulson, Rogerio A. Lobo
Journal: New England Journal of Medicine (1990)

Fertility in women 40 years of age or older is decreased, and in those with ovarian failure it is thought to be irrevocably lost. The donation of oocytes to young (<35 years old) women with ovarian failure has allowed many considered infertile a chance to become pregnant. In these women gonadal hormone replacement results in an endometrium receptive to implantation. It is not known whether the endometrial response to such replacement is decreased in women over the age of 40.
Prognostic Significance of Chromosome Aberrations in High-Grade Soft Tissue Sarcomas
Authors: Fredrik Mertens, Ulf Strömberg, Anders Rydholm, Pelle Gustafson, Henrik C.F. Bauer, Otte Brosjö, Nils Mandahl
Journal: Journal of Clinical Oncology (2005)

Purpose To investigate whether previously observed correlations between tumor karyotype and risk of metastases could be reproduced in an independent set of high-grade soft tissue sarcomas (STSs). Patients and Methods In a previous study on high-grade STSs with clonal chromosome aberrations, we identified a number of cytogenetic variables, besides tumor grade and size, that were associated with significantly increased risk of metastases. In the present study, we have tested the predictive value of these cytogenetic variables in a new set of 156 high-grade STSs, all located in the extremities or trunk wall. Results Of the 10 cytogenetic variables that turned out to provide prognostic information in the previous series, encompassing 122 trunk wall or extremity STSs, three were significantly associated with metastases also in the new series. In a final Cox regression analysis including these three cytogenetic variables, as well as tumor grade and size, on the combined series of 278 high-grade STSs, four parameters were found to be significantly associated with metastasis risk: tumor grade 3, tumor size ≥ 5 cm, breakpoint in region 1p1, and gain of region 6p1. Conclusion Our findings suggest that independent prognostic information may be gained from cytogenetic analysis of high-grade STS.
<i>In Vivo</i> Measurement of Brain GABA Concentrations by Magnetic Resonance Spectroscopy in Smelters Occupationally Exposed to Manganese
Authors: Ulrike Dydak, Yue-Ming Jiang, Li-Ling Long, He Zhu, Jian Chen, Wen-Mei Li, Richard A.E. Edden, Shuguang Hu, Xue Fu, Zaiyang Long, Xue-An Mo, Dieter Meier, Jaroslaw Harezlak, Michael Aschner, James B. Murdoch, Wei Zheng
Journal: Environmental Health Perspectives (2010)

Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable.Our goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure.We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)].Seven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = -0.93; p < 0.001).We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.
Do Experiences Consistent With a Medical-Home Model Improve Diabetes Care Measures Reported by Adult Medicaid Patients?
Authors: Gregory D. Stevens, Leiyu Shi, Christina Vane, Anne L. Peters
Journal: Diabetes Care (2014)

The patient-centered medical home has gained much traction. Little is known about the relationship between the model and specific health care processes for chronic diseases such as diabetes. This study assesses the impact of features of a medical home on diabetes care.A cross-sectional survey of 540 patients with Medicaid (Medi-Cal) health insurance and type 2 diabetes in Los Angeles County was performed. The Primary Care Assessment Tools was used to measure seven features of medical-home performance.The response rate of the patient survey was 68.9%. Patient-reported medical-home performance averaged a score of 2.85 ± 0.29 (on a 1-4 scale, with 4 equaling the best care). Patients who received more timely and thorough diabetes care reported higher medical-home performance in every feature except for the comprehensiveness-services available. For example, the first-contact access feature score was higher among patients who had an HbA1c test in the past 6 months versus those who did not (2.38 vs. 2.25; P < 0.05). Before and after adjusting for sociodemographics and health status, total medical-home performance was positively associated with each diabetes care measure. A 1-point increase in total medical-home score was associated with 4.53 higher odds of an HbA1c test in the past 6 months and 1.88 higher odds of an eye exam in the past year.Features consistent with higher medical-home performance are associated with improvements in patient-reported diabetes care process measures, even in this low socioeconomic status setting. The patient-centered medical-home model may help in caring for people with type 2 diabetes.
Comprehensive screening of chymotrypsin C (<i>CTRC</i>) gene in tropical calcific pancreatitis identifies novel variants
Authors: Sumit Paliwal, Seema Bhaskar, K Radha Mani, D Nageshwar Reddy, G Venkat Rao, Shivaram Prasad Singh, Varghese Thomas, Giriraj Ratan Chandak
Journal: Gut (2012)

In a previous study, the authors have shown that rather than variants in trypsinogen gene(s), mutations in pancreatic secretory trypsin inhibitor (encoded by SPINK1) and cathepsin B (CTSB) are associated with tropical calcific pancreatitis (TCP). Recently, chymotrypsin C (CTRC) variants that diminish its activity or secretion were found to predict susceptibility to chronic pancreatitis (CP). The authors analysed CTRC variants in a large, ethnically matched case-control TCP cohort.The authors sequenced all eight exons and flanking regions in CTRC in 584 CP patients (497 TCP, 87 idiopathic CP) and 598 normal subjects and analysed the significance of association using χ(2) test. The authors also investigated interaction of CTRC variants with p.N34S SPINK1 and p.L26V CTSB mutations.The authors identified 14 variants in CTRC, of which non-synonymous variants were detected in 71/584 CP patients (12.2%) and 22/598 controls (3.7%; OR 3.62, 95% CI 2.21 to 5.93; p=6.2 × 10(-8)). Rather than the commonly reported p.K247_R254del variant in Caucasians, p.V235I was the most common mutation in Indian CP patients (28/575 (4.9%); OR 7.60, 95% CI 2.52 to 25.71; p=1.01 × 10(-5)). Another pathogenic variant, p.A73T was identified in 3.1% (18/584) patients compared with 0.3% (2/598) in controls (OR=9.48, 95% CI 2.19 to 41.03, p=2.5 × 10(-4)). The authors also observed significant association for the synonymous variant c.180C>T (p.(=)) with CP (OR 2.71, 95% CI 1.79 to 4.12, p=5.3 × 10(-7)). Two novel nonsense mutations, p.G242AfsX9 and p.W113X were also identified exclusively in CP patients. No interaction between CTRC variants and p.N34S SPINK1 or p.L26V CTSB mutations was observed.This study on a large cohort of TCP patients provides evidence of allelic heterogeneity and confirms that CTRC variants play a significant role in its pathogenesis.
The Kinetic and Thermodynamic Aftermath of Horizontal Gene Transfer Governs Evolutionary Recovery
Authors: Sarah M. Doore, Bentley A. Fane
Journal: Molecular Biology and Evolution (2015)

Shared host cells can serve as melting pots for viral genomes, giving many phylogenies a web-like appearance due to horizontal gene transfer. However, not all virus families exhibit web-like phylogenies. Microviruses form three distinct clades, represented by φX174, G4, and α3. Here, we investigate protein-based barriers to horizontal gene transfer between clades. We transferred gene G, which encodes a structural protein, between φX174 and G4, and monitored the evolutionary recovery of the resulting chimeras. In both cases, particle assembly was the major barrier after gene transfer. The G4φXG chimera displayed a temperature-sensitive assembly defect that could easily be corrected through single mutations that promote productive assembly. Gene transfer in the other direction was more problematic. The initial φXG4G chimera required an exogenous supply of both the φX174 major spike G and DNA pilot H proteins. Elevated DNA pilot protein levels may be required to compensate for off-pathway reactions that may have become thermodynamically and/or kinetically favored when the foreign spike protein was present. After three targeted genetic selections, the foreign spike protein was productively integrated into the φX174 background. The first adaption involved a global decrease in gene expression. This was followed by modifications affecting key protein–protein interactions that govern assembly. Finally, gene expression was re-elevated. Although the first selection suppresses nonproductive reactions, subsequent selections promote productive assembly and ultimately viability. However, viable chimeric strains exhibited reduced fitness compared with wild-type. This chimera's path to recovery may partially explain how unusual recombinant viruses could persist long enough to naturally emerge.
Sarcoplasmic reticulum Ca2+-ATPase overexpression by adenovirus mediated gene transfer and in transgenic mice
Authors: Markus Meyer, Wolfgang H Dillmann
Journal: Cardiovascular Research (1998)

The sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) is a major determinant of cardiac relaxation. It has been demonstrated that the steady state levels of the mRNA coding for this pump are reduced in human heart failure due to dilated cardiomyopathy. Although results regarding the protein level are controversial, most functional studies indicate decreased SERCA2a activity in heart failure. The extent to which a potential decrease in the calcium sequestering function of this protein could contribute to the contractile dysfunction in heart failure, and whether a reconstitution of SERCA2a could alleviate heart failure, are yet unknown. To further investigate these questions two methodological approaches were chosen. Adenovirus mediated gene transfer provides an approach to study functional consequences of SERCA2a overexpression in cardiac myocytes in vitro [1], and a transgenic mouse model allows the effects of cardiac overexpression of SERCA2a to be examined in vivo [2].
Pili of Neisseria meningitidis. Analysis of structure and investigation of structural and antigenic relationships to gonococcal pili.
Authors: D S Stephens, A M Whitney, J Rothbard, G K Schoolnik
Journal: The Journal of Experimental Medicine (1985)

To provide information useful for the design of a pilus vaccine effective for the prevention of both meningococcal and gonococcal disease, the electron microscopic morphology of meningococcal pili and the structural and antigenic relationships of meningococcal pili to gonococcal pili were investigated. Meningococcal pili were 4-6 nm in width, extended 500-6,000 nm from the organism surface, and occurred singly or in bundles composed of 8-10 pili per bundle. Meningococcal pilin varied between 17,250 and 20,600 daltons. Pilin was present in outer membrane preparations of some meningococcal isolates that were nonpiliated by electron microscopic examination. Antibodies to gonococcal pili, cyanogen bromide cleavage fragments of gonococcal pilin, or synthetic peptide analogues corresponding to regions of the gonococcal pilin sequence, were used to detect common meningococcal and gonococcal antigenic determinants that might indicate the existence of a conserved sequence beyond residue 29. Antibody to intact gonococcal pili or to the variable CNBR-3 region of gonococcal pilin detected little shared antigenicity with meningococcal pilin. However, pilin from all tested meningococcal isolates reacted with antibody to the CNBR-2 fragment of gonococcal pilin, a region highly conserved among gonococcal strains. Meningococcal pilins were also broadly crossreactive with antibody to a synthetic peptide corresponding to residues 69-84 of the gonococcal sequence, a part of the CNBR-2 region that appears to be critical for gonococcal receptor-binding function. If a sequence similar to 69-84 is also important for receptor-binding function in meningococcal pili, a peptide corresponding to this region may elicit antibodies that block the adherence function of pili elaborated by both Neisseria gonorrhoeae and N. meningitidis.
Ventilatory parameters in healthy nonsmoking adults of Adriatic islands (Yugoslavia)
Authors: N Smolej-Narancic, M Pavlovic, P Rudan
Journal: European Respiratory Journal (1991)

Forced expiratory volumes and flows (forced vital capacity (FVC), forced expiratory volume in one second (FEV1) peak expiratory flow (PEF), maximal expiratory flow at 25% (MEF25%), 50% (MEF50%) and 75% (MEF75%) of the FVC) have been measured in 909 healthy nonsmoking men and women, ranging in age from 18-86 yrs, who live on Eastern Adriatic islands (Yugoslavia). This area is essentially free from air pollution. The results have been analysed in terms of age and height and regression equations for each sex were derived. The equations for FVC and FEV1 were reliable and those for forced expiratory flows were not. Comparisons were made with prediction equations derived for other populations, especially with those which are commonly used in daily medical practice.
Notchless-dependent ribosome synthesis is required for the maintenance of adult hematopoietic stem cells
Authors: Marie Le Bouteiller, Céline Souilhol, Sarah Beck-Cormier, Aline Stedman, Odile Burlen-Defranoux, Sandrine Vandormael-Pournin, Florence Bernex, Ana Cumano, Michel Cohen-Tannoudji
Journal: The Journal of Experimental Medicine (2013)

Blood cell production relies on the coordinated activities of hematopoietic stem cells (HSCs) and multipotent and lineage-restricted progenitors. Here, we identify Notchless (Nle) as a critical factor for HSC maintenance under both homeostatic and cytopenic conditions. Nle deficiency leads to a rapid and drastic exhaustion of HSCs and immature progenitors and failure to maintain quiescence in HSCs. In contrast, Nle is dispensable for cycling-restricted progenitors and differentiated cells. In yeast, Nle/Rsa4 is essential for ribosome biogenesis, and we show that its role in pre-60S subunit maturation has been conserved in the mouse. Despite its implication in this basal cellular process, Nle deletion affects ribosome biogenesis only in HSCs and immature progenitors. Ribosome biogenesis defects are accompanied by p53 activation, which causes their rapid exhaustion. Collectively, our findings establish an essential role for Nle in HSC and immature progenitor functions and uncover previously unsuspected differences in ribosome biogenesis that distinguish stem cells from restricted progenitor populations.
Heart Failure After Myocardial Infarction
Authors: A.M. Gómez, S. Guatimosim, K.W. Dilly, G. Vassort, W.J. Lederer
Journal: Circulation (2001)

Background — Heart failure (HF) frequently follows the occurrence of myocardial infarction (MI). Questions about how HF develops and what cellular defects contribute to this dysfunction led to this study. Methods and Results — MI was induced in rats by coronary artery ligation. Clinical examination of the post-MI (PMI) surviving animals indicated that they were in overt HF by all measures. Cellular examination of the cardiomyocytes by patch-clamp and confocal [Ca 2+ ] i imaging methods indicated that cellular function was significantly compromised. At the single-cell level, [Ca 2+ ] i transient amplitudes were reduced and contractions were decreased and slowed, although Ca 2+ current ( I Ca ) remained unchanged. The excitation-contraction coupling (ECC) gain function measured as Δ[Ca 2+ ] i / I Ca was significantly decreased. Ouabain, a cardiotonic steroid that blocks the Na + ,K + -ATPase and activates Ca 2+ entry via cardiac Na + channels, largely alleviated this defect. Conclusions — After MI, I Ca becomes less able to trigger release of Ca 2+ from the sarcoplasmic reticulum. This failure of ECC is a major factor contributing to the development of contractile dysfunction and HF in PMI animals. The improved ECC gain, enhanced Ca 2+ entry, and augmented Ca 2+ signaling due to cardiotonic steroids contribute to the beneficial effects of these agents.
Progression of Lower-Extremity Disability in Older Women With Diabetes
Authors: Stefano Volpato, Luigi Ferrucci, Caroline Blaum, Glenn Ostir, Anne Cappola, Linda P. Fried, Renato Fellin, Jack M. Guralnik
Journal: Diabetes Care (2003)

OBJECTIVE—Older patients with diabetes are more likely to have a higher prevalence of multiple risk factors for physical disability, as a result of diabetic complications. We evaluated the pace of decline in lower-extremity function and the risk for progression of disability in older women with diabetes. RESEARCH DESIGN AND METHODS—We conducted a 3-year longitudinal cohort study of a random sample of 729 physically impaired older women (age ≥65 years) living in the community (Baltimore, MD). Diabetes was ascertained by standard criteria. Self-reported functional status and objective performance measures were assessed at baseline and over six semiannual follow-up visits. RESULTS—The baseline prevalence of diabetes was 14.4%. After adjustment for age and compared with women without diabetes, those with diabetes had an RR of 1.8 (95% CI 1.3–2.5) for incident mobility disability and 1.6 (1.2–2.1) for incident activity of daily living disability. The increased incidence of new disability associated with diabetes was paralleled by a greater decline in objective measures of lower-extremity function. Adjustment for multiple risk factors for disability did not significantly attenuate the risk for disability associated with diabetes. CONCLUSIONS—In older patients, impaired lower-extremity function is a long-term diabetic complication. Comprehensive assessment of older diabetic patients should include a standardized evaluation of lower-extremity performance.