tbuckley/cabot-search huggingface dataset:
Decreased Prefrontal Cortical Dopamine Transmission in Alcoholism
Authors: Rajesh Narendran, Neale Scott Mason, Jennifer Paris, Michael L. Himes, Antoine B. Douaihy, W. Gordon Frankle
Journal: American Journal of Psychiatry (2014)

Objective Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence. Method To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (BPND), was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg−1 of d-amphetamine. Results Amphetamine-induced displacement of [11C]FLB 457 binding potential (ΔBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe. Conclusions The results of this study, for the first time, unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.
One-year follow-up of a lentigo maligna: first dermoscopic signs of growth
Authors: R. Schiffner, A.M. Perusquia, W. Stolz
Journal: British Journal of Dermatology (2004)

We report a 64-year-old man with a pigmented lesion on his forehead, initially thought to be actinic lentigo. At follow-up 1 year later the lesion had increased in size and showed new areas of pigmentation. Dermoscopic observation and biopsy led to a diagnosis of lentigo maligna and the lesion was excised. The dermoscopic features indicative of early growth of lentigo maligna are identified and discussed.
A novel catestatin-induced antiadrenergic mechanism triggered by the endothelial PI3K–eNOS pathway in the myocardium
Authors: Eleonora Bassino, Sara Fornero, Maria Pia Gallo, Roberta Ramella, Sushil K. Mahata, Bruno Tota, Renzo Levi, Giuseppe Alloatti
Journal: Cardiovascular Research (2011)

Catestatin (CST) is a chromogranin A (CgA)-derived peptide (hCgA352–372) with three identified human variants (G364S/P370L/R374Q-CST) that show differential potencies towards the inhibition of catecholamine release. Although CST affects several cardiovascular parameters, the mechanisms underlying CST action in the heart have remained elusive. Therefore, we sought to determine the mechanism of action of CST and its variants on ventricular myocardium and endothelial cells. Contractile force and Ca2+ transients were measured, respectively, on rat papillary muscles and isolated cardiomyocytes (CC) under basal conditions and after β-adrenergic stimulation. Nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation (PSer1179eNOS) were studied in bovine aortic endothelial (BAE-1) cells. Under basal conditions, wild-type CST (WT-CST, 10–50 nM) transiently enhanced myocardial contractility. CST variants (G364S and P370L) exerted a comparable positive inotropic effect. The H1 histamine receptor antagonist mepyramine abolished the increase of contractile force induced by WT-CST. Moreover, WT-CST dose-dependently (5–50 nM) reduced the effect of β-adrenergic stimulation. This anti-adrenergic effect was not mediated by a direct action on CC, but involved a PI3K-dependent NO release from endocardial endothelial cells. Indeed, CST induced a wortmannin-sensitive, Ca2+-independent increase in NO production and eNOS phosphorylation on BAE-1 cells. While the anti-adrenergic and NO release effects of P370L-CST were comparable with those of WT-CST, the G364S variant was ineffective on the same parameters. Our results suggest that the anti-adrenergic action of CST depends on the endothelial PI3K–Akt–eNOS pathway and that its structural alterations entail functional features that correlate with the different anti-hypertensive potential described in humans.
Substructure of human von Willebrand factor.
Authors: W E Fowler, L J Fretto, K K Hamilton, H P Erickson, P A McKee
Journal: Journal of Clinical Investigation (1985)

Using electron microscopy, we have visualized the substructure of human von Willebrand factor (vWf) purified by two different approaches. vWf multimers, which appear as flexible strands varying in length up to 2 micron, consist of dimeric units (protomers) polymerized linearly in an end-to-end fashion through disulfide bonds. Examination of small multimers (e.g., one-mers, two-mers, and three-mers) suggests that each protomer consists of two large globular end domains (22 X 6.5 nm) connected to a small central node (6.4 X 3.4 nm) by two flexible rod domains each approximately 34 nm long and approximately 2 nm in diameter. The protomer is 120 nm in length when fully extended. These same structural features are seen both in vWf molecules that were rapidly purified from fresh plasma by a new two-step procedure and in those purified from lyophilized intermediate-purity Factor VIII/vWf concentrates. The 240,000-mol wt subunit observed by gel electrophoresis upon complete reduction of vWf apparently contains both a rod domain and a globular domain and corresponds to one half of the protomer. Two subunits are disulfide-linked, probably near their carboxyl termini, to form the protomer; disulfide bonds in the amino-terminal globular ends link promoters to form vWf multimers. The vWf multimer strands have at least two morphologically distinct types of ends, which may result from proteolytic cleavage in the globular domains after formation of large linear polymers. In addition to releasing fragments that were similar in size and shape to the repeating protomeric unit, plasmic degradation of either preparation of vWf reduced the size of multimers, but had no detectable effect on the substructure of internal protomers.
Murine model of accelerated transplant arteriosclerosis.
Authors: C Shi, M E Russell, C Bianchi, J B Newell, E Haber
Journal: Circulation Research (1994)

To define the role of specific gene deletions and mutations in the development of transplant arteriosclerosis, we generated an accelerated model of the disease in mice. Carotid arteries were transplanted between B.10A(2R) (H-2h2) donor mice and C57BL/6J (H-2b) recipients and compared with arteries isografted between H-2b mice. Immunosuppressive drugs were not used. Within 7 days, the allografted carotid artery formed a neointima composed of mononuclear leukocytes (CD45+) that were predominantly monocytes or macrophages (ie, CD11b+ cells with single-lobed nuclei). CD4+ and CD8+ cells were present as well. By 30 days, the neointima became exuberant, and mononuclear leukocytes were largely replaced by smooth muscle cells. Cells staining for proliferating-cell nuclear antigen were abundantly present in the intima at both early and late time points, indicating the proliferation of mononuclear leukocytes and smooth muscle cells. The area of the intima increased from day 7 to day 30 (P &lt; .0005), as did the number of nuclei (P = .0005), but the density of the nuclei decreased (P = .02), suggesting the formation of extracellular matrix. Six of the eight isografts formed no neointima, and in samples from the remaining two, a single layer of smooth muscle neointimal cells covered just a portion of the vessel circumference. This model, which reproduces many of the features of human transplant arteriosclerosis but at an accelerated pace, should prove useful for determining the roles in transplant arteriosclerosis of genes that code for components of immunologic and inflammatory responses.
CONTEMPORARY INCIDENCE AND PREDICTORS OF ACUTE KIDNEY INJURY IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTIONS: INSIGHTS FROM THE NCDR CATH-PCI REGISTRY
Authors: Thomas Tsai, Uptal Patel, Tara I. Chang, Kevin F. Kennedy, Frederick Masoudi, Michael Matheny, Mikhail Kosiborod, John Messenger, John Rumsfeld, John Spertus
Journal: Journal of the American College of Cardiology (2012)
Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections
Authors: Barbara Rehermann, Antonio Bertoletti
Journal: Hepatology (2014)

Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-α)-based therapy. Second, IFN-α, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-α-based and IFN-α-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens.
The Endothelial Glycocalyx Protects Against Myocardial Edema
Authors: Bernard M. van den Berg, Hans Vink, Jos A.E. Spaan
Journal: Circulation Research (2003)

Myocardial tissue edema attributable to increased microvascular fluid loss contributes to cardiac dysfunction after myocardial ischemia, cardiopulmonary bypass, hypertension, and sepsis. Recent studies suggest that carbohydrate structures on the luminal surface of microvascular endothelium are essential to prevent tissue edema. We carefully preserved these structures for visualization with electron microscopy, revealing that the rat myocardial capillary endothelial surface is coated with a 0.2- to 0.5-microm-thick carbohydrate layer and that its degradation instantly results in notable myocardial tissue edema.
Major virulence factors, VacA and CagA, are commonly positive in<i>Helicobacter pylori</i> isolates in Japan
Authors: S Maeda, K Ogura, H Yoshida, F Kanai, T Ikenoue, N Kato, Y Shiratori, M Omata
Journal: Gut (1998)

VacA and CagA proteins have been reported to be major virulence factors of Helicobacter pylori. However, antibodies against these proteins are frequently found in the sera of Japanese patients regardless of their gastroduodenal status.To evaluate the expression of VacA and CagA proteins by H pylori strains isolated in Japan.By using specific antibodies raised against recombinant VacA and CagA proteins, the expression of VacA and CagA was evaluated in 68 H pylori strains isolated from Japanese patients; a vacuolating assay and genotyping of the vacA gene were also used in the evaluation. The results in analysed in relation to the gastroduodenal diseases of the hosts.VacA and CagA proteins were expressed in 59/68 (87%) and in 61/68 (90%) isolates respectively. The vacuolating assay was positive in 57/68 (84%) isolates, indicating that most immunologically VacA positive strains produced active cytotoxin. The prevalence of infection with strains expressing CagA and positive for vacuolating activity (Type I) was very high, 54/68 (79%), irrespective of the gastroduodenal status of the host.Most H pylori isolates in Japan are positive for vacuolating cytotoxin and CagA, and thus these virulence factors cannot be used as markers to discern the risk of developing serious gastroduodenal pathologies in the hosts. However, the high prevalence of infection with strains positive for vacuolating cytotoxin and CagA may contribute to the characteristics of H pylori infection in Japan.
Desire for Information and Involvement in Treatment Decisions: Elderly Cancer Patients' Preferences and Their Physicians' Perceptions
Authors: Elena B. Elkin, Susie H.M. Kim, Ephraim S. Casper, David W. Kissane, Deborah Schrag
Journal: Journal of Clinical Oncology (2007)

Purpose Shared decision making is a tenet of contemporary medicine and oncology practice. How involved elderly patients want to be in making treatment decisions and how physicians perceive patient preferences for such involvement are uncertain. Patients and Methods In structured interviews about multiple facets of chemotherapy treatment decision making, we asked patients age 70 years and older with a recent diagnosis of metastatic colorectal cancer (CRC) about their preferences for prognostic information and for involvement in treatment decision making. We also asked treating oncologists (n = 19) to describe their perceptions of patient preferences. Information and decision-making preferences were evaluated in relation to sociodemographic and clinical characteristics. Results Seventy-three patients age 70 to 89 years completed the study interview within 16 weeks of metastatic CRC diagnosis. Most patients (n = 70; 96%) had decided to receive chemotherapy and 61 had initiated treatment. Relatively few (n = 32; 44%) wanted information about expected survival when they made a treatment decision. Preference for prognostic information was more common among men than women (56% v 29%; P &lt; .05). About half of the patients (n = 38; 52%) preferred a passive role in the treatment decision-making process. Physician perceptions were concordant with patient preferences for information in 44% of patient-physician pairs and for decision control in 41% of patient-physician pairs. Conclusion For older patients with advanced CRC, preferences for prognostic information and for an active role in treatment decision making are not easily predictable. Physicians' perceptions are often inconsistent with patients' stated preferences. Explicit discussion of preferred decision-making styles may improve patient-physician encounters.
Relationship Between Anti-Viral Antibodies and Rheumatoid Factor in Pregnant Women
Authors: M. Waller, J. Sever, N. Curry, M. R. Gilkeson
Journal: Annals of the Rheumatic Diseases (1966)

The influence of viral infections on the incidence of rheumatoid factor in a normal population was noted by Dresner and Trombly (1959).Five per cent. of 140 normal subjects gave positive latex- fixation tests for rheumatoid factor, and all seven individuals had or developed mild acute viral infec- tions of the upper respiratory tract.In all seven subjects, tests for rheumatoid factor (RF) became negative 6 days to 6 weeks after the physical mani- festations of their infection subsided.It was also noted that 83 per cent. of 35 patients with specific acute viral infections gave positive tests.In the cases followed serially, the RF activity was found to disappear in convalescence.Johnson and Hall (1958) noted positive latex- fixation tests in 65 per cent. of seventeen cases of rubella.The incidence of positive tests was higher in patients with arthritis than in those without arthritis; however, no comparison was made between the magnitude of the specific anti-viral response and the titre of RF activity.On the other hand, Bach, Grieble, and Anderson (1965) found that, in a group of 231 aged individuals, C-F, anti-viral antibody responses showed a negative correlation with the presence of RF.Failure to show antibody to influenza A and B 3 months after immunization was significantly related to the pres- ence of rheumatoid factor.Rawson, Abelson, and McCarty (1961) showed that group 0 rheumatoid arthritics have consistently lower haemagglutinin titres than do normal subjects of the same blood group.This was believed to reflect a decrease in activity associated with IgG globulins.Recently, Svec and Dingle (1965) found, in an analysis of sera from persons exposed to the 1957 influenza epidemic, that 15 per cent. of those showing a significant viral antibody response gave positive
MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors
Authors: Matthias Leisegang, Susanne Wilde, Stefani Spranger, Slavoljub Milosevic, Bernhard Frankenberger, Wolfgang Uckert, Dolores J. Schendel
Journal: Journal of Clinical Investigation (2010)

The apoptosis inhibitor protein survivin is overexpressed in many tumors, making it a candidate target molecule for various forms of immunotherapy. To explore survivin as a target antigen for adoptive T cell therapy using lymphocytes expressing survivin-specific transgenic T cell receptors (Tg-TCRs), we isolated HLA-A2–allorestricted survivin-specific T cells with high functional avidity. Lymphocytes expressing Tg-TCRs were derived from these T cells and specifically recognized HLA-A2+ survivin+ tumor cells. Surprisingly, HLA-A2+ but not HLA-A2– lymphocytes expressing Tg-TCRs underwent extensive apoptosis over time. This demise was caused by HLA-A2–restricted fratricide that occurred due to survivin expression in lymphocytes, which created ligands for Tg-TCR recognition. Therefore, survivin-specific TCR gene therapy would be limited to application in HLA-A2–mismatched stem cell transplantation. We also noted that lymphocytes that expressed survivin-specific Tg-TCRs killed T cell clones of various specificities derived from HLA-A2+ but not HLA-A2– donors. These results raise a general question regarding the development of cancer vaccines that target proteins that are also expressed in activated lymphocytes, since induction of high-avidity T cells that expand in lymph nodes following vaccination or later accumulate at tumor sites might limit themselves by self-MHC–restricted fratricide while at the same time inadvertently eliminating neighboring T cells of other specificities.
Overlapping meta-analyses on the same topic: survey of published studies
Authors: K. C. Siontis, T. Hernandez-Boussard, J. P. A. Ioannidis
Journal: BMJ (2013)

<b>Objective</b> To assess how common it is to have multiple overlapping meta-analyses of randomized trials published on the same topic. <b>Design</b> Survey of published meta-analyses. <b>Data sources</b> PubMed. <b>Study selection and methods</b> Meta-analyses published in 2010 were identified, and 5% of them were randomly selected. We further selected those that included randomized trials and examined effectiveness of any medical intervention. For eligible meta-analyses, we searched for other meta-analyses on the same topic (covering the same comparisons, indications/settings, and outcomes or overlapping subsets of them) published until February 2013. <b>Results</b> Of 73 eligible meta-analyses published in 2010, 49 (67%) had at least one other overlapping meta-analysis (median two meta-analyses per topic, interquartile range 1-4, maximum 13). In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses. <b>Conclusions</b> While some independent replication of meta-analyses by different teams is possibly useful, the overall picture suggests that there is a waste of efforts with many topics covered by multiple overlapping meta-analyses.
Targeting of HIV-1 Antigens for Rapid Intracellular Degradation Enhances Cytotoxic T Lymphocyte (CTL) Recognition and the Induction of De Novo CTL Responses In Vivo After Immunization
Authors: Timothy W. Tobery, Robert F. Siliciano
Journal: The Journal of Experimental Medicine (1997)

CD8+ cytotoxic T lymphocytes (CTLs) have the ability to recognize and eliminate virally infected cells before new virions are produced within that cell. Therefore, a rapid and vigorous CD8+ CTL response, induced by vaccination, can, in principle, prevent disseminated infection in vaccinated individuals who are exposed to the relevant virus. There has thus been interest in novel vaccine strategies that will enhance the induction of CD8+ CTLs. In this study, we have tested the hypothesis that targeting an antigen to undergo more efficient processing by the class I processing pathway will elicit a more vigorous CD8+ CTL response against that antigen. Targeting a type I transmembrane protein, the HIV-1 envelope (env) protein, for expression in the cytoplasm, rather than allowing its normal co-translational translocation into the endoplasmic reticulum, sensitized target cells expressing this mutant more rapidly for lysis by an env-specific CTL clone. Additionally, a greatly enhanced de novo env-specific CTL response was induced in vivo after immunization of mice with recombinant vaccinia vectors expressing the cytoplasmic env mutant. Similarly, targeting a cytoplasmic protein, HIV-1 nef, to undergo rapid cytoplasmic degradation induced a greatly enhanced de novo nef-specific CD8+ CTL response in vivo after immunization of mice with either recombinant vaccinia vectors or DNA expression plasmids expressing the degradation targeted nef mutant. The targeting of viral antigens for rapid cytoplasmic degradation represents a novel and highly effective vaccine strategy for the induction of enhanced de novo CTL responses in vivo.