tbuckley/cabot-search huggingface dataset:
Vasoconstrictor effect of aldosterone via angiotensin II type 1 (AT1) receptor: possible role of AT1 receptor dimerization
Authors: M. Yamada, M. Kushibiki, T. Osanai, H. Tomita, K. Okumura
Journal: Cardiovascular Research (2008)

We recently demonstrated that aldosterone induces a non-genomic vasoconstrictor effect on rat coronary arterioles and that this effect was blocked by angiotensin II type 1 receptor (AT1) blockers. Intracellular transglutaminase enhances AT1 signalling by cross-linking AT1 homodimers. The purpose of this study was to confirm the AT1-dependency of the vasoconstrictor effect of aldosterone using AT1a knockout (AT1aKO) mice and to investigate the role of intracellular transglutaminase and AT1 dimerization in this effect.The mesenteric arterioles (60-160 microm) were isolated from C57BL/6J (wild-type, WT) and AT1aKO mice, and the internal diameter was measured by video microscopy. Aldosterone (10(-13) to 10(-6) M), but not hydrocortisone, produced a dose-dependent vasoconstriction in WT mice; the maximal diameter change was -8.6 +/- 0.3% from the baseline (P < 0.001). This vasoconstrictor effect was unaffected by the mineralocorticoid receptor antagonist spironolactone or eplerenone, the AT2 antagonist PD123319, the glucocorticoid receptor antagonist RU486, or endothelium denudation. Aldosterone's vasoconstrictor effect was negligible in AT1aKO mice. The AT1 blockers valsartan or candesartan suppressed aldosterone-induced vasoconstriction in WT mice. The transglutaminase inhibitors cystamine and monodansyl cadaverine also suppressed the vasoconstrictor effect of aldosterone, without affecting the vasoconstrictor effect of angiotensin II in WT mice. AT1 dimer protein levels were increased in WT mesenteric arterioles treated with 10(-7) M aldosterone, and the transglutaminase inhibitor and AT1 blocker blocked this aldosterone-induced formation of AT1 dimer. Treatment with 10(-7) M aldosterone for 10 min increased the transglutaminase activity by 2.5 +/- 0.2-fold in cultured vascular smooth muscle cells and by 1.2 +/- 0.1-fold in the mesenteric arterioles. These increases were abolished by transglutaminase inhibitors.Aldosterone produces a non-genomic, endothelium-independent vasoconstrictor effect by enhancing intracellular transglutaminase activity and presumably inducing AT1 dimer formation in mesenteric arterioles.
The Diagnosis and Treatment of Panic Disorder
Authors: W. Stewart Agras
Journal: Annual Review of Medicine (1993)

Panic attacks and panic disorder often first present in the emergency room or to the family practitioner. The presentation and differential diagnosis of this disabling disorder are described in this review, together with the etiology and health effects of the syndrome. Both medication and psychological treatments are described, as are the indications, side effects, and expected outcome for each therapy alone and in combination.
700. Intradermal Injection, as Opposed to Subcutaneous Injection, Enhances Immunogenicity and Suppresses Tumorigenicity of Tumor Cells
Authors: Bernard Bonnotte, Michael Gough, Vy Phan, Atique Ahmed, Heung Chong, François Martin, Richard G. Vile
Journal: Molecular Therapy (2003)

Tumor cell immunogenicity depends heavily upon the microenvironment in which the cells grow. We have compared the tumorigenicity and immunogenicity of the same tumor cells when injected either into the dermis, a tissue containing numerous dendritic cells (DCs), or s.c., at a site which contains only few DCs. After s.c. injection, progressive tumors were constantly obtained, whereas most intradermal injections did not give rise to tumor and immunized animals against additional challenge. We present evidence that the high density of DCs at dermal sites facilitates the capture of tumor antigens and that local inflammation induces maturation of the DCs and their migration into draining lymph nodes.
Impaired pneumococcal antibody response in bronchiectasis of unknown aetiology
Authors: D. A. van Kessel, H. van Velzen-Blad, J. M. M. van den Bosch, G. T. Rijkers
Journal: European Respiratory Journal (2005)

As a defective anti-polysaccharide response can exist in the absence of an immunoglobulin deficiency, a series of 26 patients with bronchiectasis of unknown aetiology was vaccinated with a 23-valent pneumococcal polysaccharide vaccine. All patients suffered from recurrent respiratory tract infections. When measuring total antibody levels to pneumococcal serotypes 3, 4 and 9, a normal polysaccharide antibody response was found in 22 patients. However, only 11 of these subjects showed a normal pneumococcal antibody response within the IgA and/or IgG2 subclass, and thus could be classified as true responders, while 15 patients did not respond in either the IgA class or in the IgG2 subclass. When analysing differences between the responder (n = 11) and nonresponder (n = 15) groups, the latter demonstrated higher frequencies of respiratory tract infections and more severe lung pathology, as revealed by the presence of more bronchi visualised in the peripheral third of the lung by high-resolution computed tomography scanning. Moreover, nonresponders needed extensive lung surgery more often in order to control their disease (number of resected segments eight versus five). In conclusion, an important fraction of patients presenting with idiopathic bronchiectasis is associated with a selective anti-polysaccharide response deficiency and this subgroup appears to represent a more severe clinical phenotype. Therefore, it can be regarded as a separate clinical entity with possible therapeutic targets. In order to identify IgA and IgG2 anti-polysaccharide nonresponders, all patients presenting with bronchiectasis of unkown aetiology should be immunised with a pneumococcal polysaccharide vaccine, and IgA and IgG2 isotype responses should be evaluated as well as the total antibody response.
The Sequential Administration of XELOX and XELIRI Was Effective, Feasible and Manageable for Patients with MCRC
Authors: Fukui Taro, Suzuki Koichi, Kato Takaharu, Muto Yuta, Ichida Kosuke, Takayama Yuji, Watanabe Fumiaki, Tsujinaka Shingo, Sasaki Junichi, Noda HIroshi, Horie Hisanaga, Rikiyama Toshiki
Journal: Annals of Oncology (2014)
Fitness effects of grandparental investments in contemporary low-risk societies
Authors: Ralf Kaptijn, Fleur Thomese
Journal: Behavioral and Brain Sciences (2010)

Abstract Coall &amp; Hertwig (C&amp;H) suggest that, because grandparental investments do not impact on child mortality in low-risk societies, fitness effects are not plausible any more. We found that grandparental investments could very well alleviate contemporary constraints on fertility. Cultural factors may influence both the occurrence and impact of grandparental investments.
Tobacco Use in Human Papillomavirus–Positive Advanced Oropharynx Cancer Patients Related to Increased Risk of Distant Metastases and Tumor Recurrence
Authors: Jessica H. Maxwell, Bhavna Kumar, Felix Y. Feng, Francis P. Worden, Julia S. Lee, Avraham Eisbruch, Gregory T. Wolf, Mark E. Prince, Jeffrey S. Moyer, Theodoros N. Teknos, Douglas B. Chepeha, Jonathan B. McHugh, Susan G. Urba, Jay Stoerker, Heather M. Walline, David M. Kurnit, Kitrina G. Cordell, Samantha J. Davis, Preston D. Ward, Carol R. Bradford, Thomas E. Carey
Journal: Clinical Cancer Research (2010)

The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy.Between 1999 and 2007, 124 patients with advanced SCCOP (86% with stage IV) and adequate tumor tissue for HPV analysis who were enrolled in one of two consecutive University of Michigan treatment protocols were prospectively included in this study. Patients were categorized as never-, former, or current tobacco users. The primary end points were risk of disease recurrence and time to recurrence; secondary end points were disease-specific survival and overall survival.One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2; confidence interval, 1.1-24.4; P = 0.038). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence (P = 0.002), and had reduced disease-specific survival (P = 0.004) and overall survival (P < 0.001) compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival (P = 0.064) but not overall survival (P = 0.221).Current tobacco users with advanced, HPV-positive SCCOP are at higher risk of disease recurrence compared with never-tobacco users.
Managed Care in Workers' Compensation Plans
Authors: Pamela B Peele, David J Tollerud
Journal: Annual Review of Public Health (2001)

▪ Abstract Workers' compensation plans have lagged behind most public and private health care plans in the adoption of managed care techniques. This is largely attributable to the underlying differences between workers' compensation and group health plans. Managed care techniques were developed within group health plans with the objective of health at the lowest cost. In workers' compensation, managed care must address a different objective—restoring a worker to health and productivity at the lowest cost. It is this fundamental difference that makes the application of managed care techniques to workers' compensation plans contentious and at times inappropriate. Research on the impact of managed care on the health and welfare of injured workers is sparse, and important questions remain about the appropriateness of care delivered under workers' compensation managed care plans. In this paper, we discuss the application of managed care to workers' compensation, and highlight the barriers to effective implementation.
Using Metabolic Syndrome Traits for Efficient Detection of Impaired Glucose Tolerance
Authors: James B. Meigs, Ken Williams, Lisa M. Sullivan, Kelly J. Hunt, Steven M. Haffner, Michael P. Stern, Clicerio González Villalpando, Jessica S. Perhanidis, David M. Nathan, Ralph B. D’Agostino, Ralph B. D’Agostino, Peter W.F. Wilson
Journal: Diabetes Care (2004)

Efficient detection of impaired glucose tolerance (IGT) is needed to implement type 2 diabetes prevention interventions.We assessed the capacity of the metabolic syndrome (MetS) to identify IGT in a cross-sectional analysis of 3,326 Caucasian Framingham Offspring Study (FOS), 1,168 Caucasian and 1,812 Mexican-American San Antonio Heart Study (SAHS), 1,983 Mexico City Diabetes Study (MCDS), and 452 Caucasian, 407 Mexican-American, and 290 African-American Insulin Resistance Atherosclerosis Study (IRAS) men and women aged 30-79 years who had a clinical examination and an oral glucose tolerance test (OGTT) during 1987-1996. Those with diabetes treatment or fasting plasma glucose > or =7.0 mmol/l were excluded (MetS was defined by Third Report of the National Cholesterol Education Program's Adult Treatment Panel criteria and IGT as 2-h postchallenge glucose [2hPG] > or =7.8 mmol/l). We calculated positive (PPV) and negative predictive values (NPV), population attributable risk percentages (PAR%), age- and sex-adjusted odds ratios (ORs), and areas under the receiver operating characteristic curve (AROCs) associated with MetS traits.Among FOS, SAHS, and MCDS subjects, 24-43% had MetS and 15-23% had IGT (including 2-5% with 2hPG > or =11.1 mmol/l). Among those with MetS, OR for IGT were 3-4, PPV were 0.24-0.41, NPV were 0.84-0.91, and PAR% were 30-40%. Among subjects with MetS defined by impaired fasting glucose (IFG) and any two other traits, OR for IGT were 9-24, PPV were 0.62-0.89, NPV were 0.78-0.87, and PAR% were 3-12%. Among IRAS subjects, 24-34% had MetS and 37-41% had IGT. Among those with MetS, ORs for IGT were 3-6, PPVs were 0.57-0.73, and NPVs were 0.67-0.72. In logistic regression models, IFG, large waist, and high triglycerides were independently associated with IGT (AROC 0.71-0.83) in all study populations.The MetS, especially defined by IFG, large waist, and high triglycerides, efficiently identifies subjects likely to have IGT on OGTT and thus be eligible for diabetes prevention interventions.
The relationship between overdrive suppression and overdrive excitation in ventricular pacemakers in dogs.
Authors: M Vassalle, M Cummins, C Castro, J H Stuckey
Journal: Circulation Research (1976)

We studied the excitatory and inhibitory effects of overdrive on idioventricular pacemakers in anesthetized dogs with recently induced complete atrioventricular block. The following results were obtained: (1) a slow driving rate may induce a temporary rhythm which may be reinstituted with additional stimuli; (2) the induced rhythm may appear as coupled extrasystoles which, on interruption of the drive, are found to be self-sustaining; (3) during continued slow driving, extrasystoles may appear and disappear in a cyclical manner; (4) a short period of fast driving may be followed by a fast new rhythm, the rate and duration of which are a function of the rate and duration of drive; (5) fast driving may induce a new rhythm at a rate below predrive control; (6) after a long period fast driving, only suppression follows; and (7) intermittent periods of fast driving lead to a summation of inhibition with each successive period. These results suggest the following conclusions: (1) under certain conditions, electrical driving instead of inducing suppression may induce a rhythm ("overdrive excitation") at a rate similar to, faster then, or slower ("inhibited excitation") than control; (2) the duration of diastole and the number of driven beats are major factors in the induction of new rhythms; and (3) overdrive excitation is counteracted by overdrive inhibition, with development of the former requiring fewer beats than the latter.
CD38 deficiency in the tumor microenvironment attenuates glioma progression and modulates features of tumor-associated microglia/macrophages
Authors: Ayelet Levy, Eran Blacher, Hananya Vaknine, Frances E. Lund, Reuven Stein, Lior Mayo
Journal: Neuro-Oncology (2012)

Gliomas are the most frequent primary tumors of the brain, and for highly malignant gliomas there is no successful treatment. The tumor microenvironment contains large numbers of infiltrating microglia and macrophages (MM). There is increasing evidence that the tumor-associated MM support glioma expansion. CD38 is a multifunctional ectoenzyme that uses nicotinamide adenine dinucleotide as a substrate to generate second messengers. Previously we showed that CD38 deficiency modulates microglial "activation" and impaired recovery from head trauma by a microglia-associated mechanism. In view of the supportive role of MM in glioma progression and the role of CD38 in microglia activation, we hypothesize that deficiency of CD38 in the tumor microenvironment would inhibit glioma progression. Using the syngeneic GL261 model of glioma progression in wild-type and CD38 null mice, we show here that CD38 deficiency significantly attenuates glioma expansion and prolongs the life span of the glioma-bearing mice. The CD38 deficiency effect was associated with increased cell death and decreased metalloproteinase-12 expression in the tumor mass, as well as modulation of the tumor-induced MM properties, as indicated by a reduction in the expression of the MM marker F4/80 and matrix metalloproteinases. Our results thus suggest that CD38 participates in the tumor-supporting action of MM and that targeting CD38 might be a potential therapeutic approach for glioma treatment.
Association Between BMI Measured Within a Year After Diagnosis of Type 2 Diabetes and Mortality
Authors: Jennifer Logue, Jeremy J. Walker, Graham Leese, Robert Lindsay, John McKnight, Andrew Morris, Sam Philip, Sarah Wild, Naveed Sattar
Journal: Diabetes Care (2012)

To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes.Using records of 106,640 patients in Scotland, we investigated the association between BMI recorded around the diagnosis of type 2 diabetes mellitus (T2DM) and mortality using Cox proportional hazards regression adjusted for age and smoking status, with BMI 25 to <30 kg/m(2) as a referent group. Deaths within 2 years of BMI determination were excluded. Mean follow-up to death or the end of 2007 was 4.7 years.A total of 9,631 deaths occurred between 2001 and 2007. Compared with the reference group, mortality risk was higher in patients with BMI 20 to <25 kg/m(2) (hazard ratio 1.22 [95% CI 1.13-1.32] in men, 1.32 [1.22-1.44] in women) and patients with BMI ≥35 kg/m(2) (for example, 1.70 [1.24-2.34] in men and 1.81 [1.46-2.24] in women for BMI 45 to <50 kg/m(2)). Vascular mortality was higher for each 5-kg/m(2) increase in BMI >30 kg/m(2) by 24% (15-35%) in men and 23% (14-32%) in women, but was lower below this threshold. The results were similar after further adjustment for HbA1c, year of diagnosis, lipids, blood pressure, and socioeconomic status.Patients categorized as normal weight or obese with T2DM within a year of diagnosis of T2DM exhibit variably higher mortality outcomes compared with the overweight group, confirming a U-shaped association of BMI with mortality. Whether weight loss interventions reduce mortality in all T2DM patients requires study.
Behavioral Counseling Interventions in Primary Care To Reduce Risky/Harmful Alcohol Use by Adults: A Summary of the Evidence for the U.S. Preventive Services Task Force
Authors: Evelyn P. Whitlock, Michael R. Polen, Carla A. Green, Tracy Orleans, Jonathan Klein
Journal: Annals of Internal Medicine (2004)

Background: Primary health care visits offer opportunities to identify and intervene with risky or harmful drinkers to reduce alcohol consumption. Purpose: To systematically review evidence for the efficacy of brief behavioral counseling interventions in primary care settings to reduce risky and harmful alcohol consumption. Data Sources: Cochrane Database of Systematic Reviews, Database of Research Effectiveness (DARE), MEDLINE, Cochrane Controlled Clinical Trials, PsycINFO, HealthSTAR, CINAHL databases, bibliographies of reviews and included trials from 1994 through April 2002; update search through February 2003. Study Selection: An inclusive search strategy (alcohol* or drink*) identified English-language systematic reviews or trials of primary care interventions to reduce risky/harmful alcohol use. Twelve controlled trials with general adult patients met our quality and relevance inclusion criteria. Data Extraction: Investigators abstracted study design and setting, participant characteristics, screening and assessment procedures, intervention components, alcohol consumption and other outcomes, and quality-related study details. Data Synthesis: Six to 12 months after good-quality, brief, multicontact behavioral counseling interventions (those with up to 15 minutes of initial contact and at least 1 follow-up), participants reduced the average number of drinks per week by 13% to 34% more than controls did, and the proportion of participants drinking at moderate or safe levels was 10% to 19% greater compared with controls. One study reported maintenance of improved drinking patterns for 48 months. Conclusions: Behavioral counseling interventions for risky/harmful alcohol use among adult primary care patients could provide an effective component of a public health approach to reducing risky/harmful alcohol use. Future research should focus on implementation strategies to facilitate adoption of these practices into routine health care.
Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition
Authors: Paramita Chakrabarty, Li Tianbai, Amanda Herring, Carolina Ceballos-Diaz, Pritam Das, Todd E Golde
Journal: Molecular Neurodegeneration (2012)

Abstract Background Pro-inflammatory stimuli, including cytokines like Interleukin-1β, Interleukin-6 and Interferon-γ, in the brain have been proposed to exacerbate existing Alzheimer’s disease (AD) neuropathology by increasing amyloidogenic processing of APP and promoting further Aβ accumulation in AD. On the other hand, anti-inflammatory cytokines have been suggested to be neuroprotective by reducing neuroinflammation and clearing Aβ. To test this hypothesis, we used adeno-associated virus serotype 1 (AAV2/1) to express an anti-inflammatory cytokine, murine Interleukin-4 (mIL-4), in the hippocampus of APP transgenic TgCRND8 mice with pre-existing plaques. Results mIL-4 expression resulted in establishment of an “M2-like” phenotype in the brain and was accompanied by exacerbated Aβ deposition in TgCRND8 mice brains. No change in holo APP or APP C terminal fragment or phosphorylated tau levels were detected in mIL-4 expressing CRND8 cohorts. Biochemical analysis shows increases in both SDS soluble and insoluble Aβ. mIL-4 treatment attenuates soluble Aβ40 uptake by microglia but does not affect aggregated Aβ42 internalization by microglia or soluble Aβ40 internalization by astrocytes. Conclusions Short term focal mIL-4 expression in the hippocampus leads to exacerbation of amyloid deposition in vivo, possibly mediated by acute suppression of glial clearance mechanisms. Given that recent preclinical data from independent groups indicate engagement of the innate immune system early on during disease pathogenesis may be beneficial, our present study strongly argues for a cautious re-examination of unwarranted side–effects of anti-inflammatory therapies for neurodegenerative diseases, including AD.
LSP1
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Endothelial cells use an actin-binding protein to retract and allow neutrophils to crawl out of blood vessels, according to a new study by Liu et al. (page 409).






Figure 

LSP1 (red) expression in mouse endothelial cells is required for neutrophil transmigration.




Neutrophils must traverse the endothelial cell barrier to migrate out of blood vessels into inflamed or injured tissue. Transendothelial migration, once thought to be controlled primarily by the neutrophil, is now known to be a two-way street that requires active participation by both cell types. Endothelial cells respond to neutrophil adhesion by increasing their intracellular calcium levels and rearranging proteins that maintain the tight junctions between neighboring cells. The rearrangement of junctional proteins in endothelial cells ultimately causes them to retract from one another and allows the neutrophils to pass, although the signaling pathways involved are not completely understood.Leukocyte-specific protein 1 (LSP1) is an intracellular actin-binding protein that is expressed in many white blood cells, including neutrophils. LSP1 is a downstream target of kinases that are essential for neutrophil motility and chemotaxis, but the function of LSP1 in neutrophil transmigration remains unclear, as studies using LSP1-deficient mice have produced conflicting results.

Liu et al. now show that LSP1 expression is required for neutrophils to traverse the vascular endothelial cell barrier in muscle, as fewer cells were able to cross the endothelium in LSP1-deficient mice. Surprisingly, however, the neutrophils themselves did not need LSP1. Neutrophils lacking LSP1 migrated across wild-type endothelium with the ease of wild-type neutrophils. Wild-type neutrophils, by contrast, could not squeeze through LSP1-deficient endothelial cells.

LSP1-deficient mice are resistant to histamine-induced blood vessel leakage which is caused by endothelial cell retraction, suggesting that LSP1 is an indispensable component of the retraction machinery. Exactly how LSP1 links cell surface signals to the cytoskeletal changes that allow retraction remains to be determined.