tbuckley/cabot-search huggingface dataset:
Large-Scale Brain Network Coupling Predicts Acute Nicotine Abstinence Effects on Craving and Cognitive Function
Authors: Caryn Lerman, Hong Gu, James Loughead, Kosha Ruparel, Yihong Yang, Elliot A. Stein
Journal: JAMA Psychiatry (2014)

<h3>Importance</h3> Interactions of large-scale brain networks may underlie cognitive dysfunctions in psychiatric and addictive disorders. <h3>Objectives</h3> To test the hypothesis that the strength of coupling among 3 large-scale brain networks—salience, executive control, and default mode—will reflect the state of nicotine withdrawal (vs smoking satiety) and will predict abstinence-induced craving and cognitive deficits and to develop a resource allocation index (RAI) that reflects the combined strength of interactions among the 3 large-scale networks. <h3>Design, Setting, and Participants</h3> A within-subject functional magnetic resonance imaging study in an academic medical center compared resting-state functional connectivity coherence strength after 24 hours of abstinence and after smoking satiety. We examined the relationship of abstinence-induced changes in the RAI with alterations in subjective, behavioral, and neural functions. We included 37 healthy smoking volunteers, aged 19 to 61 years, for analyses. <h3>Interventions</h3> Twenty-four hours of abstinence vs smoking satiety. <h3>Main Outcomes and Measures</h3> Inter-network connectivity strength (primary) and the relationship with subjective, behavioral, and neural measures of nicotine withdrawal during abstinence vs smoking satiety states (secondary). <h3>Results</h3> The RAI was significantly lower in the abstinent compared with the smoking satiety states (left RAI,<i>P</i> = .002; right RAI,<i>P</i> = .04), suggesting weaker inhibition between the default mode and salience networks. Weaker inter-network connectivity (reduced RAI) predicted abstinence-induced cravings to smoke (<i>r</i> = −0.59;<i>P</i> = .007) and less suppression of default mode activity during performance of a subsequent working memory task (ventromedial prefrontal cortex,<i>r</i> = −0.66,<i>P</i> = .003; posterior cingulate cortex,<i>r</i> = −0.65,<i>P</i> = .001). <h3>Conclusions and Relevance</h3> Alterations in coupling of the salience and default mode networks and the inability to disengage from the default mode network may be critical in cognitive/affective alterations that underlie nicotine dependence.
Homocysteine and the Renal Epithelial Transport and Toxicity of Inorganic Mercury
Authors: Rudolfs K. Zalups, Sarfaraz Ahmad
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The epithelial cells that line the renal proximal tubule have been shown to be the primary cellular targets where mercuric ions gain entry, accumulate, and induce pathologic effects in vivo. Recent data have implicated at least one of the organic anion transport systems in the basolateral uptake of inorganic mercury (Hg). With the use of a line of type II MDCK cells transfected stably with the human organic anion transporter 1 (hOAT1), the hypothesis that hOAT1 can transport mercuric conjugates of homocysteine (Hcy) was tested. Indeed, MDCK II cells expressing a functional form of hOAT1 gained the ability to transport the mercuric conjugate 2-amino-4-(3-amino-3-carboxy-propylsulfanylmercuricsulfanyl) butyric acid (Hcy-S-Hg-S-Hcy). In addition, p-aminohippurate and the dicarboxylates adipate and glutarate (but not succinate or malonate) inhibited individually the uptake of Hcy-S-Hg-S-Hcy in a concentration-dependent manner. Furthermore, a direct relationship between the uptake of Hcy-S-Hg-S-Hcy and the induction of cellular injury and death was demonstrated in the hOAT1-expressing MDCK II cells only. These data represent the first line of direct evidence implicating one of the organic anion transporters in the uptake of a mercuric conjugate of Hcy in a mammalian cell. Thus, mercuric conjugates of Hcy are potential transportable substrates of OAT1. More important, the findings from the present study implicate the activity of OAT1 in the uptake and toxicity of Hg (when in the form of Hcy-S-Hg-S-Hcy in the extracellular compartment) in proximal tubular epithelial cells in vivo.
Variation in nebulizer aerosol output and weight output from the Mefar dosimeter: implications for multicentre studies
Authors: S Chinn, WA Arossa, DL Jarvis, CM Luczynska, PG Burney
Journal: European Respiratory Journal (1997)

The active aerosol component of nebulizers is less than 100% of output by weight, and may vary between nebulizers in different batches from the same manufacturer. A measure of bronchial responsiveness to methacholine, which can overcome this problem, is required. One hundred and sixty nebulizers from 21 centres in the European Community Respiratory Health Survey (ECRHS) were calibrated for aerosol and weight output. Methacholine challenge data were obtained for 1,021 subjects in three English centres of the ECRHS. The dose producing a 20% fall in forced expiratory volume in one second (PD20), and log-slope, the regression slope of percentage decline in FEV1 with log (dose), were calculated, with and without calibration of nebulizers by weight. Within-centre variation in nebulizer percentage aerosol output had a coefficient of variation of less than 10%. Unlike PD20, log-slope is unaffected by constant percentage overestimation of nebulizer output. Variation in output by weight of nebulizers of 10% had little affect on log-slope. It is, however, affected by the scheduled range of doses. Log-slope shows advantages in analysis, and is less affected by variation in nebulizer output. It can be used for multicentre comparisons, with restriction to a common dose protocol.
Antitumor effects of systemic and local immunization with a CTL-directed peptide in combination with a local injection of OK-432.
Authors: Takeharu Ono, Mamoru Harada, Akira Yamada, Masahiro Tanaka, Yukari Takao, Yasuaki Tanaka, Takashi Mine, Kikuo Sakamoto, Tadashi Nakashima, Kyogo Itoh
Journal: Clinical Cancer Research (2006)

The accumulation of T cells into the tumor site is crucial for the elicitation of in vivo antitumor effects after cancer vaccination. In this study, we investigated the antitumor effects and associated mechanisms of action that were induced by systemic and local immunization with a CTL-directed peptide in combination with a peritumoral injection of a streptococcal preparation, OK-432.The human SART3(315-323) peptide, which has the potential to induce human leukocyte antigen-A24-restricted CTLs, not only has the same amino acid sequence as the mouse SART3, but also has the capacity for binding to H-2K(d) molecules. Therefore, the SART3(315-323) peptide could be used as a tumor antigen-derived peptide in H-2(d) mice. Systemic immunization with the SART3(315-323) peptide and the subsequent peritumoral injection of both the SART3(315-323) peptide and OK-432 effectively induced peptide-specific and colon26 carcinoma-reactive CTLs in BALB/c mice. The combination therapy suppressed the growth of s.c. established colon26 carcinoma. The accumulation of both CD8(+) and CD4(+) T cells into the tumor site was more apparent in mice treated with the combination therapy than in those treated with other protocols. In addition, the level of IgG reactive to the administered SART3(315-323) peptide increased in mice that were treated with the combination therapy.These results indicate that antitumor effects could be efficiently induced by a combination therapy that included systemic and local immunization with a CTL-directed peptide together with a local injection of OK-432.
Circulating Growth Differentiation Factor 11/8 Levels Decline With Age
Authors: Tommaso Poggioli, Ana Vujic, Peiguo Yang, Claudio Macias-Trevino, Aysu Uygur, Francesco S. Loffredo, James R. Pancoast, Miook Cho, Jill Goldstein, Rachel M. Tandias, Emilia Gonzalez, Ryan G. Walker, Thomas B. Thompson, Amy J. Wagers, Yick W. Fong, Richard T. Lee
Journal: Circulation Research (2015)

Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum.
Thirty-Day Postoperative Mortality Among Individuals With HIV Infection Receiving Antiretroviral Therapy and Procedure-Matched, Uninfected Comparators
Authors: Joseph T. King, Melissa F. Perkal, Ronnie A. Rosenthal, Adam J. Gordon, Stephen Crystal, Maria C. Rodriguez-Barradas, Adeel A. Butt, Cynthia L. Gibert, David Rimland, Michael S. Simberkoff, Amy C. Justice
Journal: JAMA Surgery (2015)

Antiretroviral therapy (ART) has converted human immunodeficiency virus (HIV) infection into a chronic condition, and patients now undergo a variety of surgical procedures, but current surgical outcomes are inadequately characterized.To compare 30-day postoperative mortality in patients with HIV infection receiving ART with the rates in uninfected individuals.Retrospective analysis of nationwide electronic medical record data from the US Veterans Health Administration Healthcare System, October 1, 1996, to September 30, 2010. Common inpatient surgical procedures were grouped using the Healthcare Cost and Utilization Project Clinical Classification System to match HIV-infected and uninfected patients in a 1:2 ratio. Data on 1641 patients with HIV infection receiving combination ART who were undergoing inpatient surgery were compared with data on 3282 procedure-matched, uninfected comparators. Poisson regression models of 30-day postoperative mortality were adjusted for procedure year, age, Charlson Comorbidity Index score, hemoglobin level, albumin level, HIV infection, CD4 cell count, and HIV-1 RNA level.All-cause 30-day postoperative mortality.The most common procedures in both groups were cholecystectomy (10.5%), hip arthroplasty (10.5%), spine surgery (9.8%), herniorrhaphy (7.4%), and coronary artery bypass grafting (7.0%). In patients with HIV infection, CD4 cell distributions were 80.0% with 200/μL or more, 16.3% with 50/μL to 199/μL, and 3.7% with less than 50/μL; 74.1% of patients with HIV infection had undetectable HIV-1 RNA. Human immunodeficiency virus infection was associated with higher 30-day postoperative mortality compared with the mortality in uninfected patients (3.4% [56 patients]) vs 1.6% [53]); incidence rate ratio [IRR], 2.11; 95% CI, 1.41-3.17; P < .001). CD4 cell count was inversely associated with mortality, but HIV-1 RNA provided no additional information. After adjustment, patients with HIV infection had increased mortality compared with uninfected patients at all CD4 cell count strata (≥500/μL: IRR, 1.92; 95% CI, 1.02-3.60; P = .04; 200-499/μL: IRR, 1.89; 95% CI, 1.20-2.98; P = .01; 50-199/μL: IRR, 2.66; 95% CI, 1.29-5.47; P = .01; and <50/μL: IRR, 6.21; 95% CI, 3.55-10.85; P < .001). Hypoalbuminemia (IRR, 4.35; 95% CI, 2.78-6.81; P < .001) and age in decades (IRR, 1.47; 95% CI, 1.23-1.76; P < .001) were also strongly associated with mortality.Current postoperative mortality rates among individuals with HIV infection who are receiving ART are low and are influenced as much by hypoalbuminemia and age as by CD4 cell status. Human immunodeficiency virus infection and CD4 cell count are only 2 of many factors associated with surgical outcomes that should be incorporated into surgical decision making.
Psychological Outcomes and Health Beliefs in Adolescent and Young Adult Survivors of Childhood Cancer and Controls
Authors: Anne E. Kazak, Branlyn Werba DeRosa, Lisa A. Schwartz, Wendy Hobbie, Claire Carlson, Richard F. Ittenbach, Jun J. Mao, Jill P. Ginsberg
Journal: Journal of Clinical Oncology (2010)

PURPOSE The purpose of this study was to compare adolescent and young adult (AYA) pediatric cancer survivors and peers without a history of serious illness on psychological distress, health-related quality of life (HRQOL), health beliefs; examine age at diagnosis and cancer treatment intensity on these outcomes; and examine relationships between number of health problems and the outcomes. PATIENTS AND METHODS AYA cancer survivors (n = 167) and controls (n = 170), recruited during visits to a cancer survivorship clinic and primary care, completed self-report questionnaires of distress, health problems, and health beliefs. For survivors, providers rated treatment intensity and health problems. Results There were no statistically significant differences between survivors and controls in psychological distress or HRQOL. Cancer survivors had less positive health beliefs. Survivors diagnosed as adolescents had significantly greater psychological distress and fewer positive health beliefs than those diagnosed earlier. Survivors with the highest level of treatment intensity had greater anxiety and fewer positive health beliefs than those with less intense treatments. Provider report of current health problems related to survivors' beliefs and mental HRQOL only, whereas patient report of health problems correlated significantly with most psychosocial outcomes and beliefs. CONCLUSION AYA cancer survivors did not differ from peers in psychological adjustment but did endorse less adaptive health beliefs. Survivors diagnosed during adolescence and who had more intensive cancer treatments evidenced poorer psychosocial outcomes. Beliefs about health may be identified and targeted for intervention to improve quality of life, particularly when patient perceptions of current health problems are considered.
The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells.
Authors: L Koulova, E A Clark, G Shu, B Dupont
Journal: The Journal of Experimental Medicine (1991)

Activation via the T lymphocyte cell surface molecule CD28 provides a potent amplification signal for interleukin 2 (IL-2) production in several in vitro systems. The B lymphocyte activation antigen, B7/BB1, is a natural ligand for CD28. Here we investigate the role of CD28 and B7/BB1 in primary activation of CD4+ T lymphocytes stimulated with allogeneic B lymphoblastoid cell lines. A subset of peripheral CD4+ T cells that is unresponsive to crosslinking of CD3/T cell receptor (TCR) with CD3 monoclonal antibody (mAb) does proliferate in response to allogeneic B lymphoblasts. TCR binding to allogeneic major histocompatibility complex antigens was an absolute requirement for activation of these cells because mAbs to either CD3 or human histocompatibility leukocyte antigen (HLA) class II completely inhibited activation. CD28 and B7/BB1 antibodies inhibited T cell proliferation 90% and 84%, respectively. Similar results were obtained with the total CD4+ T lymphocyte population. Crosslinking of HLA-DR antigens on small, resting B cells induced rapid expression of B7/BB1, which peaked at 6 h and returned to baseline levels within 18 h. These data demonstrate that CD28-B7/BB1 binding provides an important early second signal for alloactivation of CD4+ T lymphocyte by B lymphoblasts. The results also suggest that T cells interacting with allogeneic resting B cells may induce B7/BB1 expression in the alloantigen-presenting cell as a consequence of interaction between the TCR and class II molecules.
Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation
Authors: Marc Lütgehetmann, Lida V. Mancke, Tassilo Volz, Martina Helbig, Lena Allweiss, Till Bornscheuer, Joerg M. Pollok, Ansgar W. Lohse, J. Petersen, Stephan Urban, Maura Dandri
Journal: Hepatology (2011)

No specific drugs are currently available against hepatitis delta virus (HDV), a defective virus leading to the most severe form of chronic viral hepatitis in man. The lack of convenient HDV infection models has hampered the development of effective therapeutics. In this study, naïve and hepatitis B virus (HBV) chronically infected humanized uPA/SCID mice were employed to establish a small animal model of HBV/HDV coinfection and superinfection. For preclinical antiviral drug evaluation, the GMP version of the myristoylated preS-peptide (Myrcludex-B), a lipopeptide derived from the pre-S1 domain of the HBV envelope, was applied to prevent de novo HBV/HDV coinfection in vivo . Virological parameters were determined at serological and intrahepatic level both by real-time polymerase chain reaction (PCR) and by immunohistochemistry. Establishment of HDV infection was highly efficient in both HBV-infected and naïve chimeric mice with HDV titers rising up to 1 × 10E9 copies/mL. Notably, HDV superinfection led to a median 0.6log reduction of HBV viremia, which although not statistically significant suggests that HDV may hinder HBV replication. In the setting of HBV/HDV simultaneous infection, a majority of human hepatocytes stained HDAg-positive long before HBV spreading was completed, confirming that HDV can replicate intrahepatically also in the absence of HBV infection. Furthermore, the increase of HBV viremia and intrahepatic cccDNA loads was significantly slower than in HBV mono-infected mice. Treatment with the HBV entry inhibitor Myrcludex-B, efficiently hindered the establishment of HDV infection in vivo . Conclusion : We established an efficient model of HBV/HDV infection to exploit mechanisms of viral interference in human hepatocytes and to test the efficacy of an HDV-entry inhibitor in vivo .
Accumulation of acidic renin isoforms in kidneys of cyclosporine-A-treated rats.
Authors: L L Norling, A Tufro-McReddie, R Ariel Gomez, L C Moore, F J Kaskel
Journal: Journal of the American Society of Nephrology (1996)

Chronic cyclosporin A (CsA) treatment results in major hemodynamic changes in the renal microvasculature and in expression of the intrarenal renin angiotensin system. Changes in renin expression in kidneys of CsA-treated rats include the recruitment of immunoreactive renin in afferent arterioles and in the juxtaglomerular apparatus. This study presents evidence that an acidic isoform of renin is increased in kidneys of CsA-treated rats. Immunoblots of rat kidney homogenate separated by polyacrylamide-gel electrophoresis and also by isoelectric focusing demonstrate the presence of an acidic isoform (pl 5.5 and estimated molecular weight of approximately 32 to 36 kd) seen in increased amounts in kidney homogenate from CsA-treated rats. Silver-stained two-dimensional gels of renin separated from kidney homogenate with pepstatin agarose confirm the presence of an acidic renin isoform in CsA-treated rats. In rats that received CsA for varied intervals of 1, 3, 5, and 8 wk, this acidic isoform is shown to significantly accumulate relative to duration of treatment with CsA when immunoreactive bands are analyzed by densitometric scanning (r2 = 0.90, P < 0.001). Renin enzymatic activity also increased in kidney homogenate of CsA-treated rats relative to duration of treatment with CsA (r2 = 0.486, P < 0.001). Prorenin in these same samples was significantly decreased compared with controls. The acidic renin isoform identified in kidney homogenate of CsA-treated rats may be involved in the vascular changes that are seen in this model.
Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer.
Authors: A W Tolcher, K H Cowan, D Solomon, F Ognibene, B Goldspiel, R Chang, M H Noone, A M Denicoff, C S Barnes, M R Gossard, P A Fetsch, S L Berg, F M Balis, D J Venzon, J A O'Shaughnessy
Journal: Journal of Clinical Oncology (1996)

PURPOSE We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer. PATIENTS AND METHODS Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy. RESULTS The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations. CONCLUSION r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.
Not a slippery slope or sudden subversion: German medicine and National Socialism in 1933
Authors: H. M Hanauske-Abel
Journal: BMJ (1996)

The history of medicine this century is darkened by the downfall of the German medical profession, exposed during the doctors' trial at Nuremberg in 1946. Relying largely on documents published during 1933 in German medical journals, this paper examines two widely accepted notions of those events, metaphorically termed "slippery slope" and "sudden subversion." The first connotes a gradual slide over infinitesimal steps until, suddenly, all footing is lost; the second conveys forced take over of the profession's leadership and values. Both concepts imply that the medical profession itself became the victim of circumstances. The slippery slope concept is a prominent figure of argument in the current debate on bioethics. The evidence presented here, however, strongly suggests that the German medical community set its own course in 1933. In some respects this course even outpaced the new government, which had to rein in the profession's eager pursuit of enforced eugenic sterilizations. In 1933 the convergence of political, scientific, and economic forces dramatically changed the relationship between the medical community and the government. That same convergence is occurring again and must be approached with great caution if medicine is to remain focused on the preservation of physical and medical integrity.