tbuckley/cabot-search huggingface dataset:
Calmodulin Kinase II Inhibition Shortens Action Potential Duration by Upregulation of K <sup>+</sup> Currents
Authors: Jingdong Li, Céline Marionneau, Rong Zhang, Vaibhavi Shah, Johannes W. Hell, Jeanne M. Nerbonne, Mark E. Anderson
Journal: Circulation Research (2006)

The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated by elevated intracellular Ca(2+) (Ca(2+)(i)), and mice with chronic myocardial CaMKII inhibition (Inh) resulting from transgenic expression of a CaMKII inhibitory peptide (AC3-I) unexpectedly showed action potential duration (APD) shortening. Inh mice exhibit increased L-type Ca(2+) current (I(Ca)), because of upregulation of protein kinase A (PKA) activity, and decreased CaMKII-dependent phosphorylation of phospholamban (PLN). We hypothesized that CaMKII is a molecular signal linking Ca(2+)(i) to repolarization. Whole cell voltage-clamp recordings revealed that the fast transient outward current (I(to,f)) and the inward rectifier current (I(K1)) were selectively upregulated in Inh, compared with wild-type (WT) and transgenic control, mice. Breeding Inh mice with mice lacking PLN returned I(to,f) and I(K1) to control levels and equalized the APD and QT intervals in Inh mice to control and WT levels. Dialysis of AC3-I into WT cells did not result in increased I(to,f) or I(K1), suggesting that enhanced cardiac repolarization in Inh mice is an adaptive response to chronic CaMKII inhibition rather than an acute effect of reduced CaMKII activity. Increasing PKA activity, by cell dialysis with cAMP, or inhibition of PKA did not affect I(K1) in WT cells. Dialysis of WT cells with cAMP also reduced I(to,f), suggesting that PKA upregulation does not increase repolarizing K(+) currents in Inh mice. These findings provide novel in vivo and cellular evidence that CaMKII links Ca(2+)(i) to cardiac repolarization and suggest that PLN may be a critical CaMKII target for feedback regulation of APD in ventricular myocytes.
Loss of Expression of the β Subunit of Soluble Guanylyl Cyclase Prevents Nitric Oxide–Mediated Inhibition of DNA Synthesis in Smooth Muscle Cells of Old Rats
Authors: Lihua Chen, Günter Daum, Jens W. Fischer, Suzanne Hawkins, Marie-Luce Bochaton-Piallat, Giulio Gabbiani, Alexander W. Clowes
Journal: Circulation Research (2000)

Abstract —We compared the effects of NO donors and cGMP analogues on the growth of aortic smooth muscle cells (SMCs) derived from newborn, adult (aged 3 months), and old (aged 2 years) rats. We found that the NO donor S -nitroso- N -acetylpenicillamine failed to block DNA synthesis in SMCs from old rats but was effective in SMCs from newborn and adult rats. However, cGMP analogues were inhibitory in all 3 SMC types. We demonstrated that in SMCs from old rats, NO was unable to increase the concentration of intracellular cGMP, suggesting that either cGMP synthesis was defective or cGMP degradation was enhanced. Western blot analysis revealed that SMCs from old rats do not express the β subunit of soluble guanylyl cyclase. To confirm the importance of this observation in vivo, we balloon-injured the carotid arteries of adult and old rats. Whereas soluble guanylyl cyclase was expressed at the same level in the media of injured vessels and uninjured vessels of both groups, its expression in the intimas of old rats was reduced by 70% compared with intimas from adult animals. Furthermore, N ω -nitro- l -arginine, an inhibitor of NO synthesis, enhanced the intimal thickening in injured vessels in adult rats but not in old rats. We conclude that the loss of NO responsiveness in aged rats is due to the lack of the β subunit of soluble guanylyl cyclase, and we speculate that this defect contributes to the enhanced intimal thickening in response to injury in old animals.
Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism
Authors: Subhash C. Pandey, Huaibo Zhang, Adip Roy, Tiejun Xu
Journal: Journal of Clinical Investigation (2005)

We investigated the role of cAMP-responsive element–binding protein (CREB) in genetic predisposition to anxiety and alcohol-drinking behaviors using alcohol-preferring (P) and -nonpreferring (NP) rats. The levels of CREB, phosphorylated CREB, and neuropeptide Y (NPY) were innately lower in the central amygdala (CeA) and medial amygdala (MeA), but not in the basolateral amygdala (BLA), of P rats compared with NP rats. P rats displayed higher baseline anxiety-like behaviors and consumed higher amounts of alcohol compared with NP rats. Ethanol injection or voluntary intake reduced the higher anxiety levels in P rats. Ethanol also increased CREB function in the CeA and MeA, but not in the BLA, of P rats. Infusion of the PKA activator Sp-cAMP or NPY into the CeA decreased the alcohol intake and anxiety-like behaviors of P rats. PKA activator infusion also increased CREB function in the CeA of P rats. On the other hand, ethanol injection or voluntary intake did not produce any changes either in anxiety levels or on CREB function in the amygdaloid structures of NP rats. Interestingly, infusion of the PKA inhibitor Rp-cAMP into the CeA provoked anxiety-like behaviors and increased alcohol intake in NP rats. PKA inhibitor decreased CREB function in the CeA of NP rats. These novel results provide the first evidence to our knowledge that decreased CREB function in the CeA may be operative in maintaining the high anxiety and excessive alcohol-drinking behaviors of P rats.
Paclitaxel Enhances Thrombin-Induced Endothelial Tissue Factor Expression via c-Jun Terminal NH <sub>2</sub> Kinase Activation
Authors: Barbara E. Stähli, Giovanni G. Camici, Jan Steffel, Alexander Akhmedov, Kushiar Shojaati, Michelle Graber, Thomas F. Lüscher, Felix C. Tanner
Journal: Circulation Research (2006)

Paclitaxel is used on drug-eluting stents because it inhibits proliferation of vascular cells. Stent thrombosis remains a concern with this compound, particularly with higher dosages. This study investigates the effect of paclitaxel on tissue factor (TF) expression in human endothelial cells. Paclitaxel enhanced thrombin-induced endothelial TF protein expression in a concentration- and time-dependent manner. A concentration of 10 −5 mol/L elicited a 2.1-fold increase in TF protein and a 1.6-fold increase in TF surface activity. The effect was similar after a 1 hour as compared with a 25-hour pretreatment period. Real-time polymerase chain reaction revealed that paclitaxel increased thrombin-induced TF mRNA expression. Paclitaxel potently activated c-Jun terminal NH 2 kinase (JNK) as compared with thrombin alone, whereas the thrombin-mediated phosphorylation of p38 and extracellular signal-regulated kinase remained unaffected. Similar to paclitaxel, docetaxel enhanced both TF expression and JNK activation as compared with thrombin alone. The JNK inhibitor SP600125 reduced thrombin-induced TF expression by 35%. Moreover, SP600125 blunted the effect of paclitaxel and docetaxel on thrombin-induced TF expression. Paclitaxel increases endothelial TF expression via its stabilizing effect on microtubules and selective activation of JNK. This observation provides novel insights into the pathogenesis of thrombus formation after paclitaxel-eluting stent deployment and may have an impact on drug-eluting stent design.
Decreased Poly(ADP-Ribosyl)ation of CTCF, a Transcription Factor, Is Associated with Breast Cancer Phenotype and Cell Proliferation
Authors: France Docquier, Georgia-Xanthi Kita, Dawn Farrar, Parmjit Jat, Michael O'Hare, Igor Chernukhin, Svetlana Gretton, Adhip Mandal, Louise Alldridge, Elena Klenova
Journal: Clinical Cancer Research (2009)

There is compelling evidence of a relationship between poly(ADP-ribosyl)ation and tumorigenesis; however, much less is known about the role of specific targets of poly(ADP-ribosyl)ation in tumor development. Two forms of the multifunctional transcription factor, CTCF, were previously identified: a 130-kDa protein (CTCF-130), characteristic for cell lines, and a 180-kDa protein (CTCF-180), modified by poly(ADP-ribosyl)ation. This study was aimed to investigate differential poly(ADP-ribosyl)ation of CTCF in normal and tumor breast tissues.Western blot analysis, mass spectrometry, and immunohistochemical and immunofluorescent stainings were used to characterize CTCF-130 and CTCF-180 in breast cell lines, primary cultures, and normal and tumor breast tissues. The immunoreactivity score was used for CTCF-130 quantification in tissues.We discovered that only CTCF-180 is detected in the normal breast tissues, whereas both CTCF-130 and CTCF-180 are present in breast tumors. Using an antibody specific for CTCF-130, we observed that 87.7% of breast tumors were positive for CTCF-130. A negative correlation existed between the levels of CTCF-130, tumor stage, and tumor size. Significantly, a transition from CTCF-180 to CTCF-130 was discovered in primary cultures generated from normal breast tissues, indicating a link between CTCF-130 and proliferation. Conversely, the appearance of CTCF-180 was observed following growth arrest in breast cell lines.Collectively, our data suggest that the loss of CTCF poly(ADP-ribosyl)ation is associated with cell proliferation and breast tumor development. We propose the use of CTCF-130 as a marker for tumor breast cells and lower levels of CTCF-130 as an indicator of unfavorable prognosis.
A Randomized Comparison of Print and Web Communication on Colorectal Cancer Screening
Authors: David S. Weinberg, Eileen Keenan, Karen Ruth, Karthik Devarajan, Michelle Rodoletz, Eric J. Bieber
Journal: JAMA Internal Medicine (2012)

New methods to enhance colorectal cancer (CRC) screening rates are needed. The web offers novel possibilities to educate patients and to improve health behaviors, such as cancer screening. Evidence supports the efficacy of health communications that are targeted and tailored to improve the uptake of recommendations.We identified unscreened women at average risk for CRC from the scheduling databases of obstetrics and gynecology practices in 2 large health care systems. Participants consented to a randomized controlled trial that compared CRC screening uptake after receipt of CRC screening information delivered via the web or in print form. Participants could also be assigned to a control (usual care) group. Women in the interventional arms received tailored information in a high- or low-monitoring Cognitive Social Information Processing model-defined attentional style. The primary outcome was CRC screening participation at 4 months.A total of 904 women were randomized to the interventional or control group. At 4 months, CRC screening uptake was not significantly different in the web (12.2%), print (12.0%), or control (12.9%) group. Attentional style had no effect on screening uptake for any group. Some baseline participant factors were associated with greater screening, including higher income (P = .03), stage of change (P < .001), and physician recommendation to screen (P < .001).A web-based educational intervention was no more effective than a print-based one or control (no educational intervention) in increasing CRC screening rates in women at average risk of CRC. Risk messages tailored to attentional style had no effect on screening uptake. In average-risk populations, use of the Internet for health communication without additional enhancement is unlikely to improve screening participation.clinicaltrials.gov Identifier: NCT00459030.
Sclerosing skin disorders in association with multiple sclerosis. Coincidence, underlying autoimmune pathology or interferon induced?: Table 1
Authors: T Hügle, S Gratzl, T Daikeler, D Frey, A Tyndall, U A Walker
Journal: Annals of the Rheumatic Diseases (2008)

Objectives: To describe and analyse the manifestation of sclerosing skin disorders in patients with multiple sclerosis (MS). Case reports: We describe three patients with relapsing-remitting MS who developed skin sclerosis while receiving interferon (IFN)-β treatment and review nine further cases of systemic sclerosis (SSc) in MS from the literature. Of all 12 patients reported, eight had limited cutaneous SSc, three had diffuse cutaneous SSc and one patient had an antisynthetase syndrome. Localised scleroderma such as morphoea was not described. The mean age at diagnosis was 25.2 years for MS (range 12 to 51) and 38.3 years for SSc (range 16 to 66). Eleven patients developed SSc after the onset of MS and manifested with skin sclerosis after a mean of 14.9 years (range 1 to 45). In five patients IFN-β was commenced before the development of skin sclerosis (mean 4.6 years, range 1 to 8 years). There was no relationship between the onset of skin sclerosis and MS activity. With the exception of one individual, all patients had antinuclear antibodies. Conclusions: Sclerosing skin disorders may develop in the course of MS. The relatively early age of SSc onset in patients with MS suggests a genetic predisposition and/or an IFN-associated trigger.
Dithionite Increases Radical Formation and Decreases Vasoconstriction in the Lung
Authors: Stephen L. Archer, Václav Hampl, Daniel P. Nelson, Erika Sidney, Douglas A. Peterson, E. Kenneth Weir
Journal: Circulation Research (1995)

Abstract Dithionite is a powerful reducing agent used to deoxygenate hemoglobin and create anaerobic conditions in vitro. Recently, dithionite has been used as a convenient means of creating “hypoxia” in experiments studying the O 2 sensor in the pulmonary circulation and carotid body. We evaluated the hypothesis that hypoxia created by hypoxic ventilation and that created by dithionite have different effects on the pulmonary circulation. In vitro, dithionite (10 −5 to 10 −3 mol/L), added to oxygenated Krebs’ solution, rapidly created superoxide anion in a dose-dependent manner. Dithionite consumed O 2 in parallel with the generation of superoxide radical, with both processes peaking within seconds. Anoxia was sustained only if resupply of O 2 was prevented. In isolated rat lungs (whether perfused with autologous blood or Krebs’ solution), hypoxic ventilation alone lowered perfusate P o 2 from ≈140 to 40 mm Hg and decreased lung levels of activated oxygen species (AOS), measured by luminol-enhanced chemiluminescence, before the onset of hypoxic pulmonary vasoconstriction. Constrictor responses to angiotensin II and KCl were not impaired by intermittent hypoxic challenges, and lung weight did not increase. In contrast, dithionite impaired constrictor responses of the Krebs’ solution–perfused lungs to all vasoconstrictors tested and increased lung weight. When given as a bolus (5×10 −3 mol/L) into the pulmonary artery during normoxic ventilation, dithionite caused no vasoconstriction and only briefly lowered P o 2 (because of constant resupply of O 2 from the alveoli). When superimposed on hypoxic ventilation, dithionite further lowered P o 2 from ≈40 to ≈0 mm Hg and caused additional constriction. Unlike hypoxic ventilation, dithionite increased AOS production. Antioxidant enzymes diminished dithionite-induced radical production and diminished the loss of vascular reactivity and lung edema. In conclusion, unlike hypoxic ventilation, dithionite causes edema and loss of vascular reactivity in the lung by generating superoxide anion and hydrogen peroxide. Hypoxia elicited by dithionite is not equivalent to authentic hypoxia because of the obligatory associated generation of AOS. Dithionite usage should not be substituted for authentic hypoxia in studies of O 2 sensing.
The promotion of neural progenitor cells proliferation by aligned and randomly oriented collagen nanofibers through β1 integrin/MAPK signaling pathway
Authors: Yansong Wang, Meng Yao, Jihui Zhou, Wei Zheng, Changwei Zhou, Daming Dong, Yugang Liu, Zhaowei Teng, Yongqing Jiang, Guojun Wei, Xiaoying Cui
Journal: Biomaterials (2011)
HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice
Authors: Louise R. Howe, Sung-Hee Chang, Kelly C. Tolle, Rachelle Dillon, Lawrence J.T. Young, Robert D. Cardiff, Robert A. Newman, Peiying Yang, Howard T. Thaler, William J. Muller, Clifford Hudis, Anthony M.C. Brown, Timothy Hla, Kotha Subbaramaiah, Andrew J. Dannenberg
Journal: Cancer Research (2005)

Abstract The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in ∼40% of human breast cancers and at higher frequencies in preinvasive ductal carcinoma in situ (DCIS). Cox-2 expression is particularly associated with overexpression of human epidermal growth factor receptor 2 (HER2/neu). To definitively interrogate the role of Cox-2 in mammary neoplasia, we have used a genetic approach, crossing Cox-2-deficient mice with a HER2/neu transgenic strain, MMTV/NDL. At 20 weeks of age, mammary glands from virgin MMTV/NDL females contained multiple focal tumors, or mammary intraepithelial neoplasias, which histologically resembled human DCIS. Mammary tumor multiplicity and prostaglandin E2 (PGE2) levels were significantly decreased in Cox-2 heterozygous and knockout animals relative to Cox-2 wild-type controls. Notably, the proportion of larger tumors was decreased in Cox-2-deficient mice. HER2/neu-induced mammary hyperplasia was also substantially reduced in Cox-2 null mice. Additionally, mammary glands from Cox-2 knockout mice exhibited a striking reduction in vascularization, and expression of proangiogenic genes was correspondingly reduced. Decreased vascularization was observed both in dysplastic and normal-appearing regions of Cox-2-null mammary glands. Our data provide the first genetic evidence that Cox-2 contributes to HER2/neu-induced mammary tumorigenesis. This finding may help to explain the reduced risk of breast cancer associated with regular use of nonsteroidal anti-inflammatory drugs.
The enhanced characteristics of osteoblast adhesion to photofunctionalized nanoscale TiO2 layers on biomaterials surfaces
Authors: Tomohiko Miyauchi, Masahiro Yamada, Akiko Yamamoto, Fuminori Iwasa, Tetsuo Suzawa, Ryutaro Kamijo, Kazuyoshi Baba, Takahiro Ogawa
Journal: Biomaterials (2010)
Alteration in regulatory T cells and programmed cell death 1-expressing regulatory T cells in active generalized vitiligo and their clinical correlation
Authors: M.K. Tembhre, A.S. Parihar, V.K. Sharma, A. Sharma, P. Chattopadhyay, S. Gupta
Journal: British Journal of Dermatology (2014)

Vitiligo is an autoimmune depigmentation disease, and defects in regulatory T cells (Tregs) have been proposed in the pathogenesis of generalized vitiligo (GV). However, the role of programmed cell death (PD)1(+) Tregs has not been studied.To investigate the status of Tregs, PD1(+) Tregs and associated parameters in active GV (aGV) during the first episode of disease attack and to establish the clinical correlation.The percentages of circulating Tregs, PD1(+) Tregs and CD3(+) CD4(+) PD1(+) T cells were evaluated in 50 patients with aGV and 51 controls. Expression levels of FOXP3, TGFB1, CTLA4 and genes for chemokine receptors (CCR4, CCR7) and their ligands (CCL21, CCL22) were quantified in peripheral blood and in lesional, perilesional, nonlesional and normal skin sections. The corresponding proteins were immunolocalized in tissue of aGV.The percentage of Tregs was decreased (P = 0·001) and that of PD1(+) Tregs increased (P = 0·001) in peripheral blood of patients with aGV compared with controls. The abundance of TGFB1 and CCL21 mRNA was significantly decreased in the peripheral blood of patients with aGV. Significant differences in forkhead box P3, transforming growth factor-β and CCL21 protein expression were found in skin sections.Deficiency in Treg frequency and decreased expression of Treg-associated parameters (TGFB and CCL21) suggested a possible defect in Tregs that may alter their suppression function and skin homing in aGV. The increased PD1(+) Tregs suggests that the PD1/PD ligand pathway may be involved in aGV and may have a role in Treg exhaustion. Further study is required to delineate the effect of PD1 in regulating Treg function in aGV.
Portable monitoring in sleep apnoea: the way forward?
Authors: W.T. McNicholas, P. Lévy
Journal: European Respiratory Journal (2011)

Population-based epidemiological studies estimate the prevalence of obstructive sleep apnoea syndrome (OSAS) to be at least 2% of adult females and 4% of adult males in the developed world based on an apnoea/hypopnoea frequency (AHI) of >5 events·h−1 associated with excessive daytime sleepiness. However, a substantial proportion of these individuals are undiagnosed 1–3. Furthermore, it is very likely that these epidemiological data, now dating back many years, underestimate the current prevalence of OSAS given the dramatic increase in obesity over recent decades 4. Existing evidence points to OSAS as an independent risk factor for motor vehicle accidents, neurocognitive deficits, and cardiovascular morbidity and mortality 5–8. Substantial evidence also supports the argument that appropriate treatment of OSAS reduces the risk of these consequences 9–11. Since the diagnosis of OSAS requires both clinical assessment and objective monitoring of sleep-disordered breathing 12, there are major resource implications for the management of patients with suspected sleep apnoea. However, the perceived need in many healthcare systems to perform costly and labour-intensive polysomnography (PSG) in a sleep laboratory limits patient access to diagnosis and treatment 13. Commercially available and relatively inexpensive portable monitors might facilitate earlier recognition of disease and faster initiation of treatment, thereby reducing the healthcare burden associated with OSAS 14. Interest in the clinical application of portable monitoring devices is growing rapidly, and is being used as a mainstay approach to the management of OSAS in some settings. This interest is also supported by the lack of obvious clinical benefit when using full PSG rather than simplified monitoring, as evidenced in a US health technology assessment 15.

An international workshop to determine the research priorities in ambulatory management of adults with OSAS was held on October 15–16, 2007, …
Endemic tropical sprue in Rhodesia.
Authors: G Thomas, D J Clain
Journal: Gut (1976)

The existence of tropical sprue in Africa is controversial. In this paper we present 31 cases seen in Rhodesia over a 15 month period. They have the clinical features, small intestinal morphology, malabsorption pattern, and treatment response of tropical sprue. Other causes of malabsorption, and primary malnutrition, have been excluded. The severity of the clinical state and intestinal malabsorption distinguish these patients from those we have described with tropical enteropathy. The previous work on tropical sprue in Africa is reviewed and it is apparent that, when it has been adequately looked for, it has been found. It is clear that the question of tropical sprue in Africa must be re-examined and that it existence may have hitherto been concealed by the assumption that primary malnutrition is responsible for the high prevalence of deficiency states.
An oxygen enrichment attachment for use with humidified air
Authors: P. Jebson, J. Dewar, J. White
Journal: Thorax (1974)

<b>Jebson, P., Dewar, J., and White, J. (1974).</b><i>Thorax</i>, <b>29</b>, 371-376. <b>An oxygen enrichment attachment for use with humidified air.</b> An oxygen enrichment attachment is described which fulfils the basic requirements for intubated patients. Using values for tidal volume and inspiratory time found in the type of patients for whom the attachment is intended, a range of mean inspired oxygen concentration has been given for 2, 4, 6, 8, and 10 1/min oxygen flow.