tbuckley/cabot-search huggingface dataset:
Nurse Staffing and Inpatient Hospital Mortality
Authors: Jack Needleman, Peter Buerhaus, V. Shane Pankratz, Cynthia L. Leibson, Susanna R. Stevens, Marcelline Harris
Journal: New England Journal of Medicine (2011)

Cross-sectional studies of hospital-level administrative data have shown an association between lower levels of staffing of registered nurses (RNs) and increased patient mortality. However, such studies have been criticized because they have not shown a direct link between the level of staffing and individual patient experiences and have not included sufficient statistical controls.We used data from a large tertiary academic medical center involving 197,961 admissions and 176,696 nursing shifts of 8 hours each in 43 hospital units to examine the association between mortality and patient exposure to nursing shifts during which staffing by RNs was 8 hours or more below the staffing target. We also examined the association between mortality and high patient turnover owing to admissions, transfers, and discharges. We used Cox proportional-hazards models in the analyses with adjustment for characteristics of patients and hospital units.Staffing by RNs was within 8 hours of the target level for 84% of shifts, and patient turnover was within 1 SD of the day-shift mean for 93% of shifts. Overall mortality was 61% of the expected rate for similar patients on the basis of modified diagnosis-related groups. There was a significant association between increased mortality and increased exposure to unit shifts during which staffing by RNs was 8 hours or more below the target level (hazard ratio per shift 8 hours or more below target, 1.02; 95% confidence interval [CI], 1.01 to 1.03; P<0.001). The association between increased mortality and high patient turnover was also significant (hazard ratio per high-turnover shift, 1.04; 95% CI, 1.02 to 1.06; P<0.001).In this retrospective observational study, staffing of RNs below target levels was associated with increased mortality, which reinforces the need to match staffing with patients' needs for nursing care. (Funded by the Agency for Healthcare Research and Quality.).
P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model
Authors: J. R. Cirrito
Journal: Journal of Clinical Investigation (2005)

Accumulation of amyloid-beta (Abeta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Abeta production, suggesting that decreased elimination from the brain may contribute to elevated levels of Abeta and plaque formation. Efflux transport of Abeta across the blood-brain barrier (BBB) contributes to Abeta removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [I]Abeta40 and [I]Abeta42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Abeta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Abeta and enhanced Abeta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.
Isolation of novel GRO genes and a phylogenetic analysis of the CXC chemokine subfamily in mammals
Authors: W S Modi, T Yoshimura
Journal: Molecular Biology and Evolution (1999)

Approximately 15 different alpha, or CXC, chemokines have thus far been isolated from 11 species of mammals. Among the best studied chemokines are the 12 human proteins that are encoded by 11 paralogous genes. In order to better understand the evolution and function of this group of genes, we isolated and characterized six novel GRO and GRO-related cDNA sequences from the cow (Bos taurus), the sheep (Ovis aries), the rabbit (Oryctolagus cuniculus), and the guinea pig (Cavia porcellus). The amino acid sequence of the diverged guinea pig GRO or KC gene is only 50%-60% similar to presumed orthologs from other species, while the sheep and cow GRO proteins are 90%-99% similar to each other. The presence of multiple GRO genes in the cow, the rabbit, and the sheep is consistent with what has been observed for humans. Phylogenetic analyses of amino acid sequences from 44 proteins indicate that genes orthologous to many of the 11 known from humans exist in other species. One such gene, interleukin 8, or IL8, has been isolated from nine species, including the rodent guinea pig; however, this gene is absent in the rat and the mouse, indicating a unique gene loss event in the rat/mouse (muroid rodent) lineage. The KC (or MIP2) gene of rodents appears to be orthologous to the GRO gene found in other taxonomic orders. Combined evidence from different sources suggests that IP10 and MIG share sister taxon relationships on the evolutionary tree, while the remaining paralogous genes represent independent lineages, with limited evidence for kinship between them. This observation indicates that these genes originated nearly contemporaneously via a series of gene duplication events. Relative-rate tests for synonymous and nonsynonymous nucleotide substitutions in the KC and IL8 genes did not detect rate heterogeneity; however, there are several notable features regarding the IL8 genes. For example, the IL8 proteins from two Old World monkeys are as similar to one another as they are to the IL8 protein from humans, and all observed nucleotide differences between the IL8 genes of the two monkeys cause amino acid changes; in other words, there are no synonymous differences between them.
Eight Americas: Investigating Mortality Disparities across Races, Counties, and Race-Counties in the United States
Authors: Christopher J. L Murray, Sandeep C Kulkarni, Catherine Michaud, Niels Tomijima, Maria T Bulzacchelli, Terrell J Iandiorio, Majid Ezzati
Journal: PLoS Medicine (2006)

The gap between the highest and lowest life expectancies for race-county combinations in the United States is over 35 y. We divided the race-county combinations of the US population into eight distinct groups, referred to as the "eight Americas," to explore the causes of the disparities that can inform specific public health intervention policies and programs.The eight Americas were defined based on race, location of the county of residence, population density, race-specific county-level per capita income, and cumulative homicide rate. Data sources for population and mortality figures were the Bureau of the Census and the National Center for Health Statistics. We estimated life expectancy, the risk of mortality from specific diseases, health insurance, and health-care utilization for the eight Americas. The life expectancy gap between the 3.4 million high-risk urban black males and the 5.6 million Asian females was 20.7 y in 2001. Within the sexes, the life expectancy gap between the best-off and the worst-off groups was 15.4 y for males (Asians versus high-risk urban blacks) and 12.8 y for females (Asians versus low-income southern rural blacks). Mortality disparities among the eight Americas were largest for young (15-44 y) and middle-aged (45-59 y) adults, especially for men. The disparities were caused primarily by a number of chronic diseases and injuries with well-established risk factors. Between 1982 and 2001, the ordering of life expectancy among the eight Americas and the absolute difference between the advantaged and disadvantaged groups remained largely unchanged. Self-reported health plan coverage was lowest for western Native Americans and low-income southern rural blacks. Crude self-reported health-care utilization, however, was slightly higher for the more disadvantaged populations.Disparities in mortality across the eight Americas, each consisting of millions or tens of millions of Americans, are enormous by all international standards. The observed disparities in life expectancy cannot be explained by race, income, or basic health-care access and utilization alone. Because policies aimed at reducing fundamental socioeconomic inequalities are currently practically absent in the US, health disparities will have to be at least partly addressed through public health strategies that reduce risk factors for chronic diseases and injuries.
Long-term outcome following total knee arthroplasty: a controlled longitudinal study
Authors: J Cushnaghan, J Bennett, I Reading, P Croft, P Byng, K Cox, P Dieppe, D Coggon, C Cooper
Journal: Annals of the Rheumatic Diseases (2008)

To assess long-term outcome and predictors of prognosis following total knee arthroplasty (TKA) for osteoarthritis.We followed-up 325 patients from 3 English health districts approximately 6 years after TKA, along with 363 controls selected from the general population. Baseline data, collected by interview and examination, included age, sex, comorbidity, body mass index (BMI), functional status and preoperative radiographic severity of osteoarthritis. Functional status at follow-up was assessed by postal questionnaire. Predictors of change in physical function were analysed by linear regression.Between baseline and follow-up, patients reported an improvement of 6 points in median Short Form 36 Health Survey (SF-36) physical function score, whereas in controls there was a deterioration of 14 points (p<0.001). Median SF-36 vitality score declined by 10 points in patients and 5 points in controls (p = 0.005), while their median SF-36 mental health scores improved by 12 and 13 points, respectively (p = 0.2). The improvement in physical function was smaller in patients who were obese than in patients who were non-obese, but compared favourably with a substantial decline in the physical function of obese controls. Better baseline physical function and older age predicted worse changes in physical function in patients and controls. Improvement in physical function tended to be greater in patients with more severe radiological disease of the knee, and was less in those who reported pain at other joint sites at baseline.Improvements in physical function following TKA for osteoarthritis are sustained beyond 5 years. The benefits are apparent in patients who are obese as well as non-obese, and there seems no justification for withholding TKA from obese patients solely on the grounds of their body mass index.
Myocardial Ischemic Preconditioning Preserves Postischemic Function of the 26S Proteasome Through Diminished Oxidative Damage to 19S Regulatory Particle Subunits
Authors: Andras Divald, Shaye Kivity, Ping Wang, Edith Hochhauser, Beth Roberts, Saul Teichberg, Aldrin V. Gomes, Saul R. Powell
Journal: Circulation Research (2010)

Rationale : The ubiquitin proteasome system (UPS) becomes dysfunctional as a result of ischemia/reperfusion (I/R), which may lead to dysregulation of signaling pathways. Ischemic preconditioning (IPC) may prevent dysregulation by preventing UPS dysfunction through inhibition of oxidative damage. Objective : Examine the hypothesis that early IPC preserves postischemic UPS function thus facilitating prosurvival signaling events. Methods and Results : I/R decreased proteasome chymotryptic activity by 50% in isolated rat heart and an in vivo murine left anterior descending coronary artery occlusion model. Following IPC, proteasome activity was decreased 25% ( P &lt;0.05) in isolated heart and not different from baseline in the murine model. Enriched 26S proteasome was prepared and analyzed for protein carbonyl content. Increased ( P &lt;0.05) carbonylation in a 53-kDa band following I/R was diminished by IPC. Immunoprecipitation studies indicated that the 53-kDa carbonylation signal was of proteasomal origin. Two-dimensional gel electrophoresis resolved the 53-kDa band into spots analyzed by liquid chromatography/tandem mass spectrometry containing Rpt3/Rpt5 both of which could be immunoprecipitated conjugated to dinitrophenylhydrazine (DNPH). Higher amounts of DNPH-tagged Rpt5 were immunoprecipitated from the I/R samples and less from the IPC samples. I/R increased Bax levels by 63% ( P &lt;0.05) which was decreased by IPC. Lactacystin (lac) pretreatment of preconditioned hearts increased Bax by 140% ( P &lt;0.05) and also increased ubiquitinated proteins. Pretreatment of hearts with a proteasome inhibitor reversed the effects of IPC on postischemic Rpt5 carbonylation, cardiac function, morphology and morphometry, and ubiquitinated and signaling proteins. Conclusions : These studies suggest that IPC protects function of the UPS by diminishing oxidative damage to 19S regulatory particle subunits allowing this complex to facilitate degradation of proapoptotic proteins.
Skeletal complications in hairy cell leukemia: diagnosis and therapy.
Authors: B C Lembersky, M J Ratain, H M Golomb
Journal: Journal of Clinical Oncology (1988)

We identified eight patients with skeletal complications associated with hairy cell leukemia (HCL). The median time from diagnosis of HCL to the diagnosis of skeletal complications was 20 months (range, 0 to 93). All patients complained of pain and all but one lesion were located in the axial skeleton, primarily the proximal femur. Lytic lesions were seen on radiographic examination in all but one patient, and one patient additionally had multiple osteoporotic vertebral compression fractures. Radionuclide technetium bone scan was abnormal in all patients examined. Although the peripheral blood counts were variable (only two patients had a leukemic phase of the disease), all patients examined had a hypercellular bone marrow biopsy with hairy cells comprising at least 90% of the hematopoietic elements. The skeletal abnormalities responded well to local radiation therapy. Seven patients were begun on systemic therapy with interferon alpha-2b after the diagnosis of the skeletal lesion. Four of five evaluable patients had a partial hematological response and a substantial improvement in the degree of hairy cell infiltration of the bone marrow. None of these patients has had a recurrence of skeletal complications at a median follow-up time of 29 months. One patient failed to respond hematologically and developed additional bone lesions after 1 year of treatment. Another patient developed a new skeletal lesion 3 months after the cessation of interferon therapy at which time the bone marrow was essentially packed with hairy cells. This retrospective study indicates that bone involvement is a rare complication of HCL and is associated with a high tumor burden in the bone marrow. In addition to local radiation therapy, systemic treatment with interferon should be considered.
Adaptive Evolution of the Histone Fold Domain in Centromeric Histones
Authors: Jennifer L. Cooper, Steven Henikoff
Journal: Molecular Biology and Evolution (2004)

Centromeric DNA, being highly repetitive, has been refractory to molecular analysis. However, centromeric structural proteins are encoded by single-copy genes, and these can be analyzed by using standard phylogenetic tools. The centromere-specific histone, CenH3, replaces histone H3 in centromeric nucleosomes, and is required for the proper distribution of chromosomes during cell division. Whereas histone H3s are nearly identical between species, CenH3s are divergent, with an N-terminal tail that is highly variable in length and sequence. Both the N-terminal tail and histone fold domain (HFD) are subject to adaptive evolution in Drosophila. Similarly, comparisons between Arabidopsis thaliana and Arabidopsis arenosa detected adaptive evolution, but only in the N-terminal tail. We have extended our evolutionary analyses of CenH3s to other members of the Brassicaceae, which allowed the detection of positive selection in both the N-terminal tail and in the HFD. We find that adaptively evolving sites in the HFD can potentially interact with DNA, including sites in the loop 1 region of the HFD that are required for centromeric targeting in Drosophila. Other adaptively evolving sites in the HFD can be localized on the structure of the nucleosome core particle, revealing an extended surface in addition to loop 1 in which conformational changes might alter histone-DNA contacts or water bridges. The identification of adaptively evolving sites provides a structural basis for the interaction between centromeric DNA and the protein that is thought to underlie the evolution of centromeres and the accumulation of pericentric heterochromatin.
A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor
Authors: Shlomo Nedvetzki, Itshak Golan, Nathalie Assayag, Erez Gonen, Dan Caspi, Micha Gladnikoff, Avner Yayon, David Naor
Journal: Journal of Clinical Investigation (2003)

Synovial fluid cells from joints of rheumatoid arthritis (RA) patients express a novel variant of CD44 (designated CD44vRA), encoding an extra trinucleotide (CAG) transcribed from intronic sequences flanking a variant exon. The CD44vRA mutant was detected in 23 out of 30 RA patients. CD44-negative Namalwa cells transfected with CD44vRA cDNA or with CD44v3-v10 (CD44vRA wild type) cDNA bound FGF-2 to an equal extent via their associated heparan sulfate chains. However, Namalwa cells, immobilizing FGF-2 via their cell surface CD44vRA, bound substantially more soluble FGF receptor-1 (FGFR-1) than did Namalwa cells immobilizing the same amount of FGF-2 via their cell surface CD44v3-v10. The former cells stimulated the proliferation of BaF-32 cells, bearing FGFR-1, more efficiently than did the latter cells. Finally, isolated primary synovial fluid cells from RA patients expressing CD44vRA bound more soluble FGFR-1 to their cell surface–associated FGF-2 than did corresponding synovial cells expressing CD44v3-v10 or synovial cells from osteoarthritis patients. The binding of soluble FGFR-1 to RA synovial cells could be specifically reduced by their preincubation with Ab’s against the v3 exon product of CD44. Hence, FGF-2 attached to the heparan sulfate moiety expressed by the novel CD44 variant of RA synovium cells exhibits an augmented ability to stimulate FGFR-1–mediated activities. A similar mechanism may foster the destructive inflammatory cascade not only in RA, but also in other autoimmune diseases.
Mortality Among Young Black Women Using Contraceptives
Authors: Howard W. Ory
Journal: JAMA (1984)

Data on the risk of death associated with various contraceptive methods are incomplete. Therefore, we analyzed the mortality rates for young, black inner-city women who used one of four methods of contraception--oral contraceptives, depomedroxyprogesterone acetate, intrauterine (contraceptive) devices, and barrier methods. The subjects were 30,580 15- to 44-year-old women who enrolled at a family planning clinic between 1967 and 1972 and who were observed by monitoring death certificates through the end of 1977. Forty percent of the 218 deaths observed were from accidents and violence. Use of this family planning clinic greatly reduced the risk of death from childbearing; only two deaths were associated with pregnancy and childbirth, compared with the 24 deaths expected. Overall, users of the four methods died at similar, low rates. Given that this study involves considerable loss to follow-up, possible acute effects of contraceptives (eg, infections or thrombosis) are more accurately estimated than possible long-term effects (eg, cancer).
Danon Disease as an Underrecognized Cause of Hypertrophic Cardiomyopathy in Children
Authors: Zhao Yang, Colin J. McMahon, Liana R. Smith, Jeathrina Bersola, Adekunle M. Adesina, John P. Breinholt, Debra L. Kearney, William J. Dreyer, Susan W. Denfield, Jack F. Price, Michelle Grenier, Naomi J. Kertesz, Sarah K. Clunie, Susan D. Fernbach, James F. Southern, Stuart Berger, Jeffrey A. Towbin, Karla R. Bowles, Neil E. Bowles
Journal: Circulation (2005)

Background— Some patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy also present with skeletal myopathy and Wolff-Parkinson-White (WPW) syndrome; mutations in the gene encoding the lysosome-associated protein-2 (LAMP-2) have been identified in these patients, suggesting that some of these patients have Danon disease. In this study we investigated the frequency of LAMP2 mutations in an unselected pediatric HCM population. Methods and Results— LAMP2 was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing. In 2 of the 50 probands (4%), nonsense mutations were identified. In 1 family the proband initially presented with HCM as a teenager, which progressed to dilated cardiomyopathy (DCM) and heart failure. Skeletal myopathy and WPW were also noted. The teenage sister of the proband is a carrier of the same LAMP2 mutation and has HCM without skeletal myopathy or WPW. The other proband presented with HCM, WPW, and skeletal myopathy as a teenager, whereas his carrier mother developed DCM during her 40s. Skeletal and cardiac muscle sections revealed the absence of LAMP-2 on immunohistochemical staining. Conclusions— LAMP2 mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community.
Overexpression of the Oxygen Sensors PHD-1, PHD-2, PHD-3, and FIH Is Associated with Tumor Aggressiveness in Pancreatic Endocrine Tumors
Authors: Anne Couvelard, Lydia Deschamps, Vinciane Rebours, Alain Sauvanet, Kevin Gatter, Francesco Pezzella, Philippe Ruszniewski, Pierre Bedossa
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Tumor hypoxia is associated with poor prognosis and resistance to treatment. Our aim was to assess the expression of proteins that act as cellular oxygen sensors, directly regulating the hypoxia inducible factor (HIF) pathway, i.e., prolyl hydroxylase domain proteins (PHD)-1, PHD-2, PHD-3, and FIH in pancreatic endocrine tumors (PET). Experimental Design: Immunohistochemical expression of these markers was examined in 109 PET included in tissue microarrays and representing various stages of tumorigenesis. The results were correlated with histoprognostic factors including Ki-67 index, presence of a fibrotic focus, and microvascular density (MVD). Results: The cytoplasmic and nuclear expressions of the three PHD isoforms were associated, and their expression was significantly higher in aggressive PETS, malignant, with lymph node metastases or with lower MVD. High nuclear expression of the three isoforms highly correlated with HIF-1α nuclear expression (P = 0.02, 0.003, and 0.006, respectively). Moreover, high nuclear PHD-1 or PHD-3 expression was associated with a poorer survival (P = 0.01). Cytoplasmic FIH was significantly higher in malignant PETs (P = 0.05) and in PETs with lymph node metastases (P = 0.02), and its expression correlated positively with those of cytoplasmic PHD isoforms (P &amp;lt; 0001). FIH stromal expression was found in 23% of PETs and correlated with higher FIH nuclear expression (P = 0.0004) and poorer disease-free survival (P = 0.0018). Conclusion: HIF regulatory proteins are highly expressed in PET and their expression is correlated with tumor metastases, tumor recurrence, and prognosis. These molecules that play an important role in the control of hypoxia-induced genes may have a function in the regulation of cellular proliferation and differentiation during endocrine tumorigenesis.