tbuckley/cabot-search huggingface dataset:
HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells
Authors: H NARUMIYA, S SASAKI, N KUWAHARA, H IRIE, T KUSABA, H KAMEYAMA, K TAMAGAKI, T HATTA, K TAKEDA, H MATSUBARA
Journal: Cardiovascular Research (2004)

Klotho is thought to play a critical role in the development of age-related disorders including arteriosclerosis. Statins may exert vascular protective effects, independent of the lowering of plasma cholesterol levels. We investigated the impact of statins on mRNA expression of the age-suppressor gene, klotho in mIMCD3 cells.Klotho mRNA levels were evaluated with real-time RT-PCR. Atorvastatin and pitavastatin increased the expression of klotho mRNA in a dose-dependent manner. This stimulatory effect was abolished by the addition of mevalonate, GGPP and FPP, essential molecules for isoprenylation of the small GTPase Rho. As was the case with the statin treatment, inhibition of Rho-kinase by Y27632 up-regulated klotho mRNA. In contrast to the statin treatment, stimulation with angiotensin II down-regulated klotho mRNA expression without obvious morphological changes. Furthermore, pretreatment with atorvastatin blunted the angiotensin II-induced response and ameliorated the decrease in klotho mRNA expression towards basal levels. RhoA activity was further evaluated by detection of its translocation. Angiotensin II activated RhoA, whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II.Statins inactivate the RhoA pathway, resulting in over-expression of klotho mRNA, which may contribute to the novel pleiotropic effects of statins towards vascular protection.
Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine
Authors: Graeme Eisenhofer, Irwin J. Kopin, David S. Goldstein
Journal: Pharmacological Reviews (2004)

This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal <i>O</i>-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal <i>O</i>-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states.
Long-Term Effects of Neonatal Exposure to Hydroxylated Polychlorinated Biphenyls in the BALB/cCrgl Mouse
Authors: Jeanelle M. Martinez, L. Clifton Stephens, Lovell A. Jones
Journal: Environmental Health Perspectives (2005)

The neonatal mouse model has been a valuable tool in determining the long-term effects of early exposure to estrogenic agents in mammals. Using this model, we compared the effects of 2′,4′,6′-trichloro-4-biphenylol (OH-PCB-30) and 2′,3′,4′,5′-tetrachloro-4-biphenylol (OH-PCB-61) as prototype estrogenic hydroxylated PCBs (OH-PCBs) because they are reported to exhibit relatively high estrogenic activity both in vivo and in vitro. The purpose of this study was to examine the relationship between estrogenicity and carcinogenicity of OH-PCB congeners. The OH-PCBs were tested individually and in combination to determine whether effects of combined OH-PCBs differed from those of these OH-PCBs alone. We evaluated the long-term effects of neonatal exposure to OH-PCBs with treatment doses that were based on the reported binding affinity of specific OH-PCB congeners to estrogen receptor α. BALB/cCrgl female mice were treated within 16 hr after birth by subcutaneous injections every 24 hr, for 5 days. The mice treated with OH-PCB-30 (200 μg/day) or 17β-estradiol (5 μg/day) showed similar increased incidences of cervicovaginal (CV) tract carcinomas (43% and 47%, respectively). In addition, when mice were treated with OH-PCBs as a mixture, a change in the type of CV tract tumor was observed, shifting from predominantly squamous cell carcinomas to adenosquamous cell carcinoma. From our results, we conclude that the individual OH-PCBs tested were estrogenic and tumorigenic in mice when exposed during development of the reproductive tract. These data support the hypothesis that mixtures may act differently and unexpectedly than do individual compounds.
Effect of aerosol challenge with sensitising antigen on the permeability of the surface of the rat trachea in life.
Authors: S Mukherjee, P Heap, F Carswell
Journal: Thorax (1988)

A rat model of immediate pulmonary hypersensitivity was used to investigate the permeability changes in the tracheal epithelium produced by aerosol challenge with antigen. The rats were sensitised by the intraperitoneal injection of antigen (dinitrophenyl (DNP19) ovalbumin). Sensitised and control animals were then challenged for 60 minutes with an aerosol of the same antigen, which also contained the electron dense pore marker lanthanum. Histological examination and x ray probe microanalysis showed a greater intercellular concentration of lanthanum in the tracheal epithelium in sensitised than in control animals. The results show that in sensitised rats increased intercellular penetrance of antigen can occur after antigen challenge.
Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation-Negative Hereditary Breast Cancer Families
Authors: Noah D. Kauff, Nandita Mitra, Mark E. Robson, Karen E. Hurley, Shaokun Chuai, Deborah Goldfrank, Eve Wadsworth, Johanna Lee, Tessa Cigler, Patrick I. Borgen, Larry Norton, Richard R. Barakat, Kenneth Offit
Journal: JNCI Journal of the National Cancer Institute (2005)

Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.
A Clinical Score to Predict Acute Renal Failure after Cardiac Surgery
Authors: Charuhas V. Thakar, Susana Arrigain, Sarah Worley, Jean-Pierre Yared, Emil P. Paganini
Journal: Journal of the American Society of Nephrology (2004)

The risk of mortality associated with acute renal failure (ARF) after open-heart surgery continues to be distressingly high. Accurate prediction of ARF provides an opportunity to develop strategies for early diagnosis and treatment. The aim of this study was to develop a clinical score to predict postoperative ARF by incorporating the effect of all of its major risk factors. A total of 33,217 patients underwent open-heart surgery at the Cleveland Clinic Foundation (1993 to 2002). The primary outcome was ARF that required dialysis. The scoring model was developed in a randomly selected test set (n = 15,838) and was validated on the remaining patients. Its predictive accuracy was compared by area under the receiver operating characteristic curve. The score ranges between 0 and 17 points. The ARF frequency at each score level in the validation set fell within the 95% confidence intervals (CI) of the corresponding frequency in the test set. Four risk categories of increasing severity (scores 0 to 2, 3 to 5, 6 to 8, and 9 to 13) were formed arbitrarily. The frequency of ARF across these categories in the test set ranged between 0.5 and 22.1%. The score was also valid in predicting ARF across all risk categories. The area under the receiver operating characteristic curve for the score in the test set was 0.81 (95% CI 0.78 to 0.83) and was similar to that in the validation set (0.82; 95% CI 0.80 to 0.85; P = 0.39). In conclusion, a score is valid and accurate in predicting ARF after open-heart surgery; along with increasing its clinical utility, the score can help in planning future clinical trials of ARF.
Action of Low Calcemic 1 ,25-Dihydroxyvitamin D3 Analogue EB1089 in Head and Neck Squamous Cell Carcinoma
Authors: J. Prudencio, N. Akutsu, N. Benlimame, T. Wang, Y. Bastien, R. Lin, M. J. Black, M. A. Alaoui-Jamali, J. H. White
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] and its analogues inhibit growth of various types of cancer cells. Although the therapeutic potential of 1,25(OH)2D3 is limited by its tendency to induce hypercalcemia, analogues such as EB1089 are potent inhibitors of cell growth and exhibit reduced calcemic effects. We analyzed the antiproliferative and calcemic effects of EB1089 in tissue culture and animal models of head and neck squamous cell carcinoma (SCC) to investigate its potential as a chemotherapeutic/chemopreventive agent. Methods: The effects of 1,25(OH)2D3 and EB1089 on cell growth and expression of p21WAF1/CIP1 and p27KIP1, which encode cyclin-dependent kinase inhibitors, and a novel target, gadd45α, a growth-arrest and DNA-damage gene, were monitored in cultured murine AT-84 SCC cells. The effects of these agents on AT-84 cell growth in vitro and on growth of AT-84 tumors in syngeneic C3H mice were monitored; treatment started at the time of tumor implantation (early tumor model) or after 12 days (late tumor model). Weight and serum calcium levels were also monitored in these animals. All P values were two-sided. Results: Both 1,25(OH)2D3 and EB1089 arrested proliferation of AT-84 cells in G0/G1 phase, inhibited p21WAF1/CIP1 expression, and induced expression of p27KIP1 protein. 1,25(OH)2D3 also enhanced the expression of gadd45α, apparently by a p53-independent mechanism. There was a statistically significant decrease in tumor growth for 1,25(OH)2D3-treated mice (P<.001 for early tumor model) and EB1089-treated mice (P<.001 and P = .001 for early and late tumor models, respectively). Unlike 1,25(OH)2D3, EB1089 did not induce cachexia or hypercalcemia. The effects of 1,25(OH)2D3 and EB1089 on expression of p21WAF1/CIP1 and GADD45α were similar in tumors and in vitro. Conclusions: EB1089 completely inhibited growth of AT-84 SCC cells at nanomolar concentrations, reduced tumor growth, and did not have calcemic effects. Our results support continued investigation of EB1089 as a chemopreventive/chemotherapeutic agent for head and neck SCC.
Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo controlled trial
Authors: S. Drew
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To determine whether <i>Ginkgo biloba</i> is effective in treating tinnitus. <b>Design:</b> Double blind, placebo controlled trial using postal questionnaires. <b>Participants:</b> 1121 healthy people aged between 18 and 70 years with tinnitus that was comparatively stable; 978 participants were matched (489 pairs). <b>Intervention:</b> 12 weeks9 treatment with either 50 mg <i>Ginkgo biloba</i> extract LI 1370 three times daily or placebo. <b>Main outcome measures:</b> Participants9 assessment of tinnitus before, during, and after treatment. Questionnaires included items assessing perception of how loud and how troublesome tinnitus was. Changes in loudness were rated on a six point scale. Changes in how troublesome were rated on a five point scale. <b>Results:</b> There were no significant differences in primary or secondary outcome measures between the groups. 34 of 360 participants receiving active treatment reported that their tinnitus was less troublesome after 12 weeks of treatment compared with 35 of 360 participants who took placebo. <b>Conclusions:</b> 50 mg <i>Ginkgo biloba</i> extract LI 1370 given 3 times daily for 12 weeks is no more effective than placebo in treating tinnitus.
Deep vein thrombosis in a 13‐year‐old boy with hereditary protein S deficiency and a review of the pediatric literature
Authors: A. Blanco, M. Bonduel, L. Peñalva, M. Hepner, M. Lazzari
Journal: American Journal of Hematology (1994)

Abstract We report a 13‐year‐old boy with hereditary deficiency of protein S, who developed a deep vein thrombosis of the lower limb after a varicella with severe cutaneous lesions. Hereditary protein S deficiency is an established cause of thrombophllia; however thrombotic events are seldom described in pediatric patients. A review of previous literature revealed 35 cases, 16 girls and 19 boys, with a first episode below of the age of 18 years old (x = 10y). The 57% of the patients had venous thrombosis, 20% arterial thrombosis, and 14% both and in 9% the type of thrombosis was not reported. Predisposing factors were referred In only 12 cases. The deficiencies can be classified as type 1 in 25 patients and type III in 8. © 1994 Wiley‐Liss, Inc.
Lipid and Blood Pressure Treatment Goals for Type 1 Diabetes
Authors: Trevor J. Orchard, Kimberly Y.-Z. Forrest, Lewis H. Kuller, Dorothy J. Becker
Journal: Diabetes Care (2001)

OBJECTIVE—Subjects with type 1 diabetes are at high risk for many long-term complications, including early mortality and coronary artery disease (CAD). Few data are available on which to base goal levels for two major risk factors, namely blood pressure and lipid/lipoproteins. The objective of this study was to determine at which levels of LDL and HDL cholesterol, triglycerides, and blood pressure the relative risks of type 1 diabetic complications increase significantly. RESEARCH DESIGN AND METHODS—Observational prospective study of 589 patients with childhood-onset type 1 diabetes (&amp;lt;17 years) aged ≥18 years at baseline; 10-year incidence of mortality, CAD, lower-extremity arterial disease, proliferative retinopathy, distal symmetric polyneuropathy, and overt nephropathy. Relative risks were determined using traditional groupings of blood pressure and lipid/lipoproteins, measured at baseline, using the lowest groupings (&amp;lt;100 mg/dl [2.6 mmol/l] LDL cholesterol, &amp;lt;45 mg/dl [1.1 mmol/l] HDL cholesterol, &amp;lt;100 mg/dl [1.1 mmol/l] triglycerides, &amp;lt;110 mmHg systolic blood pressure, and &amp;lt;80 mmHg diastolic blood pressure) as reference. Adjustments for age, sex, and glycemic control were examined. RESULTS—Driven mainly by strong relationships (RR range 1.8–12.1) with mortality, CAD, and overt nephropathy, suggested goal levels are as follows: LDL cholesterol &amp;lt;100 mg/dl (2.6 mmol/l), HDL cholesterol &amp;gt;45 mg/dl (1.1 mmol/l), triglycerides &amp;lt;150 mg/dl (1.7 mmol/l), systolic blood pressure &amp;lt;120 mmHg, and diastolic blood pressure &amp;lt;80 mmHg. Age, sex, and glycemic control had little influence on these goals. CONCLUSIONS—Although observational in nature, these data strongly support the case for vigorous control of lipid levels and blood pressure in patients with type 1 diabetes.
Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy
Authors: Livia Casciola-Rosen, Kanneboyina Nagaraju, Paul Plotz, Kondi Wang, Stuart Levine, Edward Gabrielson, Andrea Corse, Antony Rosen
Journal: The Journal of Experimental Medicine (2005)

Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.
HIGH-DOSE DELAY OF THE IMMUNE RESPONSE
Authors: J. Iványi, M. Maler, L. Wudl, E. Sercarz
Journal: The Journal of Experimental Medicine (1968)

The continuation of the primary and secondary antibody response to human serum albumin (HSA), induced in vivo, was followed in explanted chicken spleen fragments. The effect of actinomycin D (AMD) on the in vitro response was studied in spleens from chickens injected with various doses of HSA and removed at differing intervals after injection. The antibody response of "early spleen" cultures was AMD-sensitive, while cultures of spleens removed later were AMD-resistant. It was suggested that this shift represented the development of cells with in vivo preformed RNA involved in specific immunoglobulin synthesis. With increasing doses of HSA, the AMD-sensitive phase was prolonged, suggesting the delay of mRNA formation or some other AMD-inhibitable process in vivo. With large doses of HSA, the immune response in vitro was decreased, starting after a 1–2 day delay and not occurring in the presence of AMD. Massive doses of HSA completely inhibited the continuation of the response in vitro by spleen fragments removed between the 2nd and 5th day after injection. The results point to the controlling role of antigen dose in determining the onset of macromolecular synthesis during immunocyte maturation.
Reversibility of the monocrotaline pulmonary hypertension rat model
Authors: Gerrina Ruiter, Frances S. de Man, Ingrid Schalij, Shellice Sairras, Katrien Grünberg, Nico Westerhof, Willem J. van der Laarse, Anton Vonk-Noordegraaf
Journal: European Respiratory Journal (2013)

To the Editor :

Pulmonary hypertension (PH) is a disease characterised by progressive remodelling of the pulmonary vasculature eventually leading to right heart failure. Various animal models have been used to mimic the disease, involving pigs, dogs, rats and mice [1]. The most commonly used model is the monocrotaline (MCT) rat model. In this model MCT is injected subcutaneously and becomes metabolically activated, as a pyrrolizidine alkaloid, by hepatic cytochrome P450 3A [2, 3]. The active MCT pyrrole is pneumotoxic and damages the pulmonary artery endothelial cells (PAECs), which leads to a disturbed barrier function [4]. Other features of MCT-induced pulmonary vascular remodelling are arterial medial hyperplasia of axial arteries, interstitial oedema, adventitial inflammation, haemorrhage and, eventually, fibrosis [1, 2, 5, 6]. As a result, pulmonary vascular resistance (PVR) increases and the right ventricle compensates by hypertrophy and eventually fails [7, 8].

Besides the MCT PH rat model, chronic hypoxia with or without Sugen 5416 and pulmonary artery banding are used to study experimental PH [1]. The PH animal model of choice is mostly dependent on the research question that needs to be answered. Ideally, an animal model would recapitulate the progressive and irreversible pulmonary vascular remodelling, which is the hallmark of human PH [1, 4, 9]. However, none of the animal models fulfil this criterion. Concerns have been raised about the MCT rat model since many therapies were successful in MCT rats but not in humans with PH [4].

We, therefore, investigated the long-term progression and reversibility of MCT-induced PH in rats over 12 weeks, using a dose of 40 mg·kg−1 in a randomised placebo-controlled study design. Since it is known that a high dose …
Circadian regulation of allergic reactions by the mast cell clock in mice
Authors: Yuki Nakamura, Nobuhiro Nakano, Kayoko Ishimaru, Mutsuko Hara, Takako Ikegami, Yu Tahara, Ryohei Katoh, Hideoki Ogawa, Ko Okumura, Shigenobu Shibata, Chiharu Nishiyama, Atsuhito Nakao
Journal: Journal of Allergy and Clinical Immunology (2013)
Linguistics, cognitive psychology, and the Now-or-Never bottleneck
Authors: Ansgar D. Endress, Roni Katzir
Journal: Behavioral and Brain Sciences (2016)

Abstract Christiansen &amp; Chater (C&amp;C)'s key premise is that “if linguistic information is not processed rapidly, that information is lost for good” (sect. 1, para. 1). From this “Now-or-Never bottleneck” (NNB), C&amp;C derive “wide-reaching and fundamental implications for language processing, acquisition and change as well as for the structure of language itself” (sect. 2, para. 10). We question both the premise and the consequentiality of its purported implications.