tbuckley/cabot-search huggingface dataset:
Global Impairment of Cardiac Autonomic Nervous Activity Late After the Fontan Operation
Authors: Constantinos H. Davos, Darrel P. Francis, Marjolein F.E. Leenarts, Sing-Chien Yap, Wei Li, Periklis A. Davlouros, Roland Wensel, Andrew J.S. Coats, Massimo Piepoli, Narayanswami Sreeram, Michael A. Gatzoulis
Journal: Circulation (2003)

Atrial tachyarrhythmia is a common cause of morbidity and mortality in patients with univentricular physiology undergoing the Fontan operation. We examined cardiac autonomic nervous activity, a predictor of arrhythmia and sudden death in other cardiovascular disease, in patients late after the Fontan operation, employing heart rate variability (HRV) and baroreflex sensitivity.We measured HRV and baroreflex sensitivity in 22 consecutive patients (8 male, age 26+/-9 years) who had undergone the Fontan operation 13+/-6 years previously, and 22 age- and sex-matched healthy controls. Fontan patients had significantly lower HRV (P<0.0001). Baroreflex sensitivity was measured by the alpha-index method (square root of ratio of RR interval spectral power to systolic blood pressure (SBP) spectral power, in the LF and the HF band) and was also significantly depressed in the Fontan group (P<0.0001 for both). Both low frequency (LF) and high frequency (HF) components of HRV were reduced in the Fontan patients (P<0.0001), but there was interindividual variation so that the LF/(LF+HF) ratio may be high, normal, or low, and decreased with increasing right atrial dimensions (r=-0.62, P=0.006). Patients with a history of sustained atrial arrhythmia had a stronger baroreflex than those without (P=0.005).Autonomic nervous control of the heart is markedly deranged in patients late after the Fontan operation, with reduced HRV and baroreflex sensitivity. A relative suppression of the sympathetic-compared with the parasympathetic-system was observed in patients with marked right atrial dilation within the Fontan group. Furthermore, stronger baroreflexes were seen in Fontan patients in association with a higher incidence of sustained atrial tachyarrhythmia, implying that sinus node dysfunction is unlikely to be the dominant mechanism. Additional studies are clearly required to examine the prognostic importance of impaired BRS and HRV in these patients.
Rosiglitazone and Cognitive Stability in Older Individuals With Type 2 Diabetes and Mild Cognitive Impairment
Authors: Angela M. Abbatecola, Fabrizia Lattanzio, Anna M. Molinari, Michele Cioffi, Luigi Mansi, Pierfrancesco Rambaldi, Luigi DiCioccio, Federico Cacciapuoti, Raffaele Canonico, Giuseppe Paolisso
Journal: Diabetes Care (2010)

OBJECTIVE Studies have suggested that insulin resistance plays a role in cognitive impairment in individuals with type 2 diabetes. We aimed to determine whether an improvement in insulin resistance could explain cognitive performance variations over 36 weeks in older individuals with mild cognitive impairment (MCI) and type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 97 older individuals (mean ± SD age 76 ± 6 years) who had recently (&amp;lt;2 months) started an antidiabetes treatment of metformin (500 mg twice a day) (n = 30) or metformin (500 mg/day)+rosiglitazone (4 mg/day) (n = 32) or diet (n = 35) volunteered. The neuropsychological test battery consisted of the Mini-Mental State Examination (MMSE), Rey Verbal Auditory Learning Test (RAVLT) total recall, and Trail Making Tests (TMT-A and TMT-B) performed at baseline and every 12 weeks for 36 weeks along with clinical testing. RESULTS At baseline, no significant differences were found between groups in clinical or neuropsychological parameters. Mean ± SD values in the entire population were as follows: A1C 7.5 ± 0.5%, fasting plasma glucose (FPG) 8.6 ± 1.3 mmol/l, fasting plasma insulin (FPI) 148 ± 74 pmol/l, MMSE 24.9 ± 2.4, TMT-A 61.6 ± 42.0, TMT-B 162.8 ± 78.7, the difference between TMT-B and TMT-A [DIFFBA] 101.2 ± 58.1, and RAVLT 24.3 ± 2.1. At follow-up, ANOVA models tested changes in metabolic control parameters (FPI, FPG, and A1C). Such parameters improved in the metformin and metformin/rosiglitazone groups (Ptrend &amp;lt; 0.05 in both groups). ANCOVA repeated models showed that results for the metformin/rosiglitazone group remained stable for all neuropsychological tests, and results for the diet group remained stable for the MMSE and TMT-A and declined for the TMT-B (Ptrend = 0.024), executive efficiency (DIFFBA) (Ptrend = 0.026), and RAVLT memory test (Ptrend = 0.011). Results for the metformin group remained stable for the MMSE and TMTs but declined for the RAVLT (Ptrend = 0.011). With use of linear mixed-effects models, the interaction term, FPI × time, correlated with cognitive stability on the RAVLT in the metformin/rosiglitazone group (β = −1.899; P = 0.009). CONCLUSIONS Rosiglitazone may protect against cognitive decline in older individuals with type 2 diabetes and MCI.
Flotillin-1 Regulates Oncogenic Signaling in Neuroblastoma Cells by Regulating ALK Membrane Association
Authors: Arata Tomiyama, Takamasa Uekita, Reiko Kamata, Kazuki Sasaki, Junko Takita, Miki Ohira, Akira Nakagawara, Chifumi Kitanaka, Kentaro Mori, Hideki Yamaguchi, Ryuichi Sakai
Journal: Cancer Research (2014)

Neuroblastomas harbor mutations in the nonreceptor anaplastic lymphoma kinase (ALK) in 8% to 9% of cases where they serve as oncogenic drivers. Strategies to reduce ALK activity offer clinical interest based on initial findings with ALK kinase inhibitors. In this study, we characterized phosphotyrosine-containing proteins associated with ALK to gain mechanistic insights in this setting. Flotillin-1 (FLOT1), a plasma membrane protein involved in endocytosis, was identified as a binding partner of ALK. RNAi-mediated attenuation of FLOT1 expression in neuroblastoma cells caused ALK dissociation from endosomes along with membrane accumulation of ALK, thereby triggering activation of ALK and downstream effector signals. These features enhanced the malignant properties of neuroblastoma cells in vitro and in vivo. Conversely, oncogenic ALK mutants showed less binding affinity to FLOT1 than wild-type ALK. Clinically, lower expression levels of FLOT1 were documented in highly malignant subgroups of human neuroblastoma specimens. Taken together, our findings suggest that attenuation of FLOT1-ALK binding drives malignant phenotypes of neuroblastoma by activating ALK signaling.
Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort
Authors: Dalia L. Rotstein, Brian C. Healy, Muhammad T. Malik, Tanuja Chitnis, Howard L. Weiner
Journal: JAMA Neurology (2014)

With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown.To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI).Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset).NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes.A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years.NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.
Infectious diseases: an ecological perspective
Authors: M. E Wilson
Journal: BMJ (1995)

Microbes have played a decisive role in human history.Between 1348 and 1352 in many European countries plague was estimated to have killed a third to a half of the population.'2It was not swords and guns but imported microbes, carried by explorers over oceans, that defeated native populations in the Americas,3 and in Australia and southern Africa the arrival of Europeans killed off local populations by introducing infectious diseases.Local flora and fauna were also irreversibly altered.Many of these fertile, temperate, and now less populated lands were subsequently settled by Europeans.3By the middle of the 20th century, infectious diseases were no longer the major causes of mortality in developed countries.The eradication of smallpox reinforced the perception that infectious diseases could be eliminated.Improved sanitation, clean water, and better living conditions, along with vaccines and antimicrobial agents, brought many infectious diseases under control in industrialised countries, but infections continued to kill millions each year in the developing world.Infectious diseases remain the most common single cause of death in the world today.Of the 51 million deaths worldwide in 1993, an estimated 16-4 million resulted from infectious and parasitic diseases.4In sub-Saharan Africa, communicable diseases account for more than 70% of the burden of ill health (as measured by disability adjusted life years), in contrast to about 10% in industrialised countries.'Increasingly humans have changed the earth in ways that make it easier for microbes to move and to reach vulnerable populations.Widespread use of anti- microbial agents and chemicals produces selective pressure for the survival and persistence of more resistant populations of microbes, and also of more
Deregulated GSK3 Sustains Gastrointestinal Cancer Cells Survival by Modulating Human Telomerase Reverse Transcriptase and Telomerase
Authors: Wei Mai, Kazuyuki Kawakami, Abbas Shakoori, Satoru Kyo, Katsuyoshi Miyashita, Kenji Yokoi, Mingji Jin, Takeo Shimasaki, Yoshiharu Motoo, Toshinari Minamoto
Journal: Clinical Cancer Research (2009)

Glycogen synthase kinase-3beta (GSK3beta) regulates multiple cell signaling pathways and has been implicated in glucose intolerance, neurodegenerative disorders, and inflammation. We investigated the expression, activity, and putative pathologic role of GSK3beta in gastrointestinal, pancreatic, and liver cancers.Colon, stomach, pancreatic, and liver cancer cell lines; nonneoplastic HEK293 cells; and matched pairs of normal and tumor tissues of stomach and colon cancer patients were examined for GSK3beta expression and its phosphorylation at serine 9 (inactive form) and tyrosine 216 (active form) by Western immunoblotting and for GSK3beta activity by in vitro kinase assay. The effects of small-molecule GSK3beta inhibitors and of RNA interference on cell survival, proliferation, and apoptosis were examined in vitro and on human colon cancer cell xenografts in athymic mice. The effects of GSK3beta inhibition on human telomerase reverse transcriptase (hTERT) expression and telomerase activity were compared between colon cancer and HEK293 cells.Cancer cell lines and most cancer tissues showed increased GSK3beta expression and increased tyrosine 216 phosphorylation and activity but decreased serine 9 phosphorylation compared with HEK293 cells and nonneoplastic tissues. Inhibition of GSK3beta resulted in attenuated cell survival and proliferation and increased apoptosis in most cancer cell lines and in HT-29 xenografts in rodents but not in HEK293 cells. GSK3beta inhibition in colon cancer cells was associated with decreased hTERT expression and telomerase activity.The results indicate that deregulated GSK3beta sustains gastrointestinal cancer cells survival through modulation of hTERT and telomerase.
Defective Interleukin (IL)-18–mediated Natural Killer and T Helper Cell Type 1 Responses in IL-1 Receptor–associated Kinase (IRAK)-deficient Mice
Authors: Palanisamy Kanakaraj, Karen Ngo, Ying Wu, Ana Angulo, Peter Ghazal, Crafford A. Harris, John J. Siekierka, Per A. Peterson, Wai-Ping Fung-Leung
Journal: The Journal of Experimental Medicine (1999)

Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor–associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB. The role of IRAK in IL-18–induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-κB activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-γ mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-γ production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-γ production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18–induced signaling and function.
TEMPORAL EEG ABNORMALTIES IN ACUTE SCHIZOPHRENIA
Authors: JOYCE C. SMALL, IVER F. SMALL, WILLIAM R. P. SURPHLIS
Journal: American Journal of Psychiatry (1964)

The incidence of EEG temporal focal sharp or spike abnormalities in a representative sample of acutely ill schizophrenic patients was found to be 10%. The clinical implications of these findings were investigated by a comparison of these patients with other acutely ill schizophrenics who had normal EEG's, using a matched pair design. Although the groups are too small to draw firm conclusions, our patients with EEG temporal foci differed from the controls in terms of 1) lower ratings of severity of illness on admission, 2) later age of onset of symptoms, 3) fewer previous hospitalizations, and 4) a slightly better clinical status after 6 months. Further studies with larger numbers of patients over a longer period are necessary to substantiate these results.
Significant Improvement in Survival After Allogeneic Hematopoietic Cell Transplantation During a Period of Significantly Increased Use, Older Recipient Age, and Use of Unrelated Donors
Authors: Theresa Hahn, Philip L. McCarthy, Anna Hassebroek, Christopher Bredeson, James L. Gajewski, Gregory A. Hale, Luis M. Isola, Hillard M. Lazarus, Stephanie J. Lee, Charles F. LeMaistre, Fausto Loberiza, Richard T. Maziarz, J. Douglas Rizzo, Steven Joffe, Susan Parsons, Navneet S. Majhail
Journal: Journal of Clinical Oncology (2013)

Over the past four decades, allogeneic hematopoietic cell transplantation (alloHCT) has evolved as a curative modality for patients with hematologic diseases. This study describes changes in use, technique, and survival in a population-based cohort.The study included 38,060 patients with hematologic malignancies or disorders who underwent first alloHCT in a US or Canadian center from 1994 to 2005 and were reported to the Center for International Blood and Marrow Transplant Research.AlloHCT as treatment for acute lymphoblastic (ALL) and myeloid leukemias (AML), myelodysplastic syndrome (MDS), and Hodgkin and non-Hodgkin lymphomas increased by 45%, from 2,520 to 3,668 patients annually. From 1994 to 2005, use of both peripheral (7% to 63%) [corrected] and cord blood increased (2% to 10%), whereas use of marrow decreased (90% to 27%). Despite a median age increase from 33 to 40 years and 165% [corrected] increase in unrelated donors for alloHCT, overall survival (OS) at day 100 significantly improved for patients with AML in first complete remission after myeloablative sibling alloHCT (85% to 94%; P < .001) and unrelated alloHCT (63% to 86%; P < .001); 1-year OS improved among those undergoing unrelated alloHCT (48% to 63%; P = .003) but not among those undergoing sibling alloHCT. Similar results were seen for ALL and MDS. Day-100 OS after cord blood alloHCT improved significantly from 60% to 78% (P < .001) for AML, ALL, MDS, and chronic myeloid leukemia. Use of reduced-intensity regimens increased, yielding OS rates similar to those of myeloablative regimens.Survival for those undergoing alloHCT has significantly improved over time. However, new approaches are needed to further improve 1-year OS.
Asthma and pulmonary embolism: bringing airways and vessels closer together
Authors: Stavros V. Konstantinides
Journal: European Respiratory Journal (2014)

In the present issue of the European Respiratory Journal , Chung et al. [1] report the results of a longitudinal epidemiological study in Taiwan which adds significant evidence for the existence of a link between asthma and the risk of developing pulmonary embolism (PE). The authors are to be congratulated for following 31 356 asthmatic patients for a total of 186 182 patient-years and matching them with 125 157 non-asthmatic individuals (743 374 person-years). This is relevant, truly representative epidemiological work, as it appears to include the entire (99%) population diagnosed with asthma in this country. Its results will hopefully have far reaching implications, helping to finally eliminate the distance between the airways and the (pulmonary) vessels, which is still astronomical in the minds of many pulmonologists and vascular specialists.

Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and acute PE, is the third most frequent cardiovascular disease with an overall annual incidence of 1–2 per 1000 population [2, 3]. Its most threatening clinical manifestation, acute PE, is a major cause of mortality, morbidity, and hospitalisation in Europe. The magnitude of the problem is supported by an epidemiological model which estimated that up to 317 000 deaths were related to VTE in six countries of the European Union (with a total population of 454.4 million) in 2004 [3]. It is important to emphasise that, in the vast majority …
High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group
Authors: M.D. Caballero, J.A. Pérez-Simón, A. Iriondo, J.J. Lahuerta, J. Sierra, J. Marín, M. Gandarillas, R. Arranz, J. Zuazu, V. Rubio, A. Fernández de Sevilla, E. Carreras, J. García-Conde, J. García-Laraña, C. Grande, A. Sureda, M.J. Vidal, J. Rifón, C. Pérez-Equiza, R. Varela, J.M. Moraleda, J.C. García Ruíz, C. Albó, R. Cabrera, J.F. San Miguel, E. Conde
Journal: Annals of Oncology (2002)
Associations of Serum Concentrations of 25-Hydroxyvitamin D and Parathyroid Hormone With Surrogate Markers of Insulin Resistance Among U.S. Adults Without Physician-Diagnosed Diabetes: NHANES, 2003–2006
Authors: Guixiang Zhao, Earl S. Ford, Chaoyang Li
Journal: Diabetes Care (2009)

OBJECTIVE To examine whether concentrations of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) are associated with surrogate markers of insulin resistance (IR) in U.S. adults without physician-diagnosed diabetes. RESEARCH DESIGN AND METHODS Cross-sectional data (n = 3,206) from the National Health and Nutrition Examination Survey (NHANES) 2003–2006 were analyzed. RESULTS The age-adjusted prevalence of hyperinsulinemia, high homeostasis model assessment-IR, high GHb, and fasting and 2-h hyperglycemia decreased linearly across quintiles of 25(OH)D but increased linearly across quintiles of PTH (except for a quadratic trend for fasting hyperglycemia). After extensive adjustment for potential confounders, the relationships between 25(OH)D and the markers of IR and 2-h hyperglycemia persisted. Only hyperinsulinemia was positively associated with PTH (P &amp;lt; 0.05). CONCLUSIONS Among U.S. adults without physician-diagnosed diabetes, low concentrations of serum 25(OH)D were associated with markers of IR. The role of PTH in IR deserves further investigation.
Testing for Differences in Rates-Across-Sites Distributions in Phylogenetic Subtrees
Authors: Edward Susko, Yuji Inagaki, Chris Field, Michael E. Holder, Andrew J. Roger
Journal: Molecular Biology and Evolution (2002)

It has long been recognized that the rates of molecular evolution vary amongst sites in proteins. The usual model for rate heterogeneity assumes independent rate variation according to a rate distribution. In such models the rate at a site, although random, is assumed fixed throughout the evolutionary tree. Recent work by several groups has suggested that rates at sites often vary across subtrees of the larger tree as well as across sites. This phenomenon is not captured by most phylogenetic models but instead is more similar to the covarion model of Fitch and coworkers. In this article we present methods that can be useful in detecting whether different rates occur in two different subtrees of the larger tree and where these differences occur. Parametric bootstrapping and orthogonal regression methodologies are used to test for rate differences and to make statements about the general differences in the rates at sites. Confidence intervals based on the conditional distributions of rates at sites are then used to detect where the rate differences occur. Such methods will be helpful in studying the phylogenetic, structural, and functional bases of changes in evolutionary rates at sites, a phenomenon that has important consequences for deep phylogenetic inference.
Giant bathing trunk naevus with lymphadenopathy and unusual pathology
Authors: E.A. West, J.L. McPartland, H. Rigby, R.A.G. Parslew
Journal: British Journal of Dermatology (2007)

Giant congenital melanocytic naevi remain a challenge to clinicians and histopathologists with respect to observation for malignant change and interpretation of histology findings, respectively. We report a 5-year-old boy with a giant bathing trunk naevus who, after multiple previous skin biopsies, developed lymphadenopathy. Biopsy from the lymph nodes demonstrated collections of naevomelanocytes within the lymph node. Interpretation of these findings and subsequent management is discussed.