tbuckley/cabot-search huggingface dataset:
Biological effects of nanostructured lipid carriers
Authors: Matina Kardara, Nikolaos Maniatis, Aggeliki Sfika, Anastasia Kotanidou, Charalambos Roussos, Apostolos Armaganidis, Sophia Hatziantoniou, Stylianos Orthanos
Journal: European Respiratory Journal (2012)

Nanostructured lipid carriers (NLC) are a type of drug delivery system offering improved performance in terms of drug loading and long-term stability. Our aims were to test mechanisms of NLC uptake into endothelial cells (EC) and evaluate possible biologic effects of these compounds.  NLC were prepared with triglycerides Miglyol and Softisan and egg-phosphatidylcholine (1:1 by weight) by the double emulsion technique. Cultured mouse lung microvascular endothelial cells (LMVEC) were incubated with curcumin-loaded NLC and uptake was quantified as fluorescence detected in the cell homogenate or by FACS. To test biologic effects, we challenged human LMVEC with thrombin with or without NLC and measured endothelial permeability as flux rate of fluorescent albumin across endothelial monolayers grown on transwell inserts. Alterations were tested in thrombin-induced Extracellular-Regulated Kinase (ERK) activation by immunoblotting and endothelial actin remodelling by fluorescence microscopy. Finally, NLC were delivered intravenously as pre-treatment in a mouse model of hydrochloric acid (HCl) aspiration lung injury.  Using cultured mouse LMVEC we observed that NLC are incorporated into cells more efficiently when caveolin-1, the structural protein of caveolar vesicles, is expressed. Upon challenge of cultured EC with thrombin, NLC attenuated the permeability increase, activation of ERK, cytokine production and actin stress fiber formation. In the HCl-aspiration model, NLC attenuated the increase in bronchoalveolar lavage protein content, inflammatory cells and histological alterations.  Conclusion: systemically delivered NLC are taken up by EC via caveolae and have endothelial-protective effects of potential relevance to acute lung injury.
Exercise in preventing falls and fall related injuries in older people: a review of randomised controlled trials
Authors: Melinda M Gardner, M Clare Robertson, A John Campbell
Journal: British Journal of Sports Medicine (2000)

Objective —To assess the effectiveness of exercise programmes in preventing falls (and/or lowering the risk of falls and fall related injuries) in older people. Design —A review of controlled clinical trials designed with the aim of lowering the risk of falling and/or fall injuries through an exercise only intervention or an intervention that included an exercise component Main outcome measures —Falls, fall related injuries, time between falls, costs, cost effectiveness. Subjects —A total of 4933 men and women aged 60 years and older. Results —Eleven trials meeting the criteria for inclusion were reviewed. Eight of these trials had separate exercise interventions, and three used interventions with an exercise programme component. Five trials showed a significant reduction in the rate of falls or the risk of falling in the intervention group. Conclusions —Exercise is effective in lowering falls risk in selected groups and should form part of falls prevention programmes. Lowering fall related injuries will reduce health care costs but there is little available information on the costs associated with programme replication or the cost effectiveness of exercise programmes aimed at preventing falls in older people.
Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin
Authors: Nichole M. Danzl, Laura T. Donlin, Konstantina Alexandropoulos
Journal: The Journal of Experimental Medicine (2010)

Medullary thymic epithelial cells (mTECs) play an important role in T cell tolerance and prevention of autoimmunity. Mice deficient in expression of the signaling protein Sin exhibit exaggerated immune responses and multitissue inflammation. Here, we show that Sin is expressed in the thymic stroma, specifically in mTECs. Sin deficiency led to thymic stroma–dependent autoimmune manifestations shown by radiation chimeras and thymic transplants in nude mice, and associated with defective mTEC-mediated elimination of thymocytes in a T cell receptor transgenic model of negative selection. Lack of Sin expression correlated with a disorganized medullary architecture and fewer functionally mature mTECs under steady–state conditions. Additionally, Sin deficiency inhibited the expansion of mTECs in response to in vivo administration of keratinocyte growth factor (KGF). These results identify Sin as a novel regulator of mTEC development and T cell tolerance, and suggest that Sin is important for homeostatic maintenance of the medullary epithelium in the adult thymus.
Nasal Carriage of and Infection with Staphylococcus aureus in HIV-Infected Patients
Authors: M H Nguyen, C A Kauffman, R P Goodman, C Squier, R D Arbeit, N Singh, M M Wagener, V L Yu
Journal: Annals of Internal Medicine (1999)

Background: Staphylococcus aureus is a common cause of serious infection in patients infected with HIV. Objectives: To evaluate risk factors for and quantitative effect of S. aureus infection in HIV-infected patients, with special attention to nasal carriage. Design: Prospective, multihospital cohort study. Setting: Three tertiary care Veterans Affairs Medical Centers. Participants: 231 ambulatory HIV-infected patients. Results: Thirty-four percent of patients were nasal carriers of S. aureus. Of these patients, 38% were persistent carriers and 62% were intermittent carriers. Twenty-one episodes of infection occurred in 13 patients: Ten were bacteremias (including 2 cases of endocarditis), 1 was pneumonia, and 10 were cutaneous or subcutaneous infections. Seventeen (85%) of these episodes occurred in patients with CD4 counts less than 100 cells/mm3. Recurrent infections occurred in 3 of 7 patients who survived an initial S. aureus infection. The mortality rate was higher among patients with S. aureus infection than among those without infection (P = 0.03). Factors significantly associated with S. aureus infection were nasal carriage, presence of a vascular catheter, low CD4 count, and neutropenia. Molecular strain typing indicated that for 6 of 7 infected patients, the strain of S. aureus isolated from the infected sites was the same as that previously cultured from the nares. Conclusion: Nasal carriage is an important risk factor for S. aureus infection in HIV-infected patients. Controlled studies are indicated to determine whether eradication of nasal carriage in a selected subset of patients (for example, those with a low CD4 cell count) might prevent invasive S. aureus infection in patients with HIV infection.
Nephron Function in Transgenic Mice with Selective Vascular or Tubular Expression of Angiotensin-Converting Enzyme
Authors: Sean P. Kessler, Seiji Hashimoto, Preenie S. Senanayake, Christina Gaughan, Ganes C. Sen, Jurgen Schnermann
Journal: Journal of the American Society of Nephrology (2005)

Angiotensin-converting enzyme (ACE) null mice display aberrant renal pathology. Inadequate formation of angiotensin II (Ang II) results in hypotension, loss of fluid homeostasis, lack of urine concentration, and failure to regulate GFR through the tubuloglomerular feedback (TGF) mechanism. For examining the tissue-specific role of ACE in renal structure and regulation of renal filtrate formation, single-nephron GFR, proximal tubular fluid reabsorption, and TGF responsiveness were determined in mice that expressed ACE in only one tissue. Maximum TGF responses in mice that expressed somatic ACE (sACE) in proximal tubule cells (Gs strain) or germinal ACE in the serum (Pg strain) were reduced significantly compared with wild-type (WT) mice. In contrast, TGF responses in mice that expressed sACE in vascular endothelial cells (Ts strain) were not different from control. Single-nephron GFR was reduced in Ts compared with WT mice, but fractional reabsorption and therefore glomerulotubular balance were not distinguishable. BP responses to exogenous Ang I were diminished in Ts, Gs, and Pg mice, whereas those to Ang II were the same in the different strains. Plasma and renal tissue Ang I of all transgenic mouse strains was significantly higher than WT, whereas Ang II levels were generally lower; aldosterone levels were significantly lower than WT in Ts mice but not in the two other transgenic strains. Our results demonstrate that vascular expression of sACE can largely but not completely restore TGF regulation of GFR. Proximal fluid reabsorption in the chronic absence of proximal tubule ACE is normal.
Role of Bile Acid Sequestrants in the Treatment of Type 2 Diabetes
Authors: Yehuda Handelsman
Journal: Diabetes Care (2011)

Type 2 diabetes is a complex disease that requires lifestyle modification and often pharmacological therapy. There are a variety of effective oral antidiabetes agents to help control type 2 diabetes, thereby providing the opportunity for clinicians to select specific treatment(s) that meet the individual needs of a patient. This is particularly important for patients with type 2 diabetes, who often have comorbidities that can complicate the management and limit the pharmacological options for treatment. This review discusses the rationale for using a bile acid sequestrant (BAS) for the treatment of type 2 diabetes, the clinical effects of the only BAS approved for both glycemic and lipid control in the U.S. (colesevelam hydrochloride), and the appropriate place in type 2 diabetes therapy for a BAS.

Treatment strategies for type 2 diabetes evolve as new agents are approved, and evidence from clinical trials provides additional insight into the benefits and risks of existing treatments. The classes of oral antidiabetes agents include α-glucosidase inhibitors, biguanides, BASs, dipeptidyl peptidase-4 inhibitors, meglitinides, sulfonylureas, and thiazolidinediones (reviewed by Campbell [1]). This multitude of effective antidiabetes agents allows clinicians to individualize a treatment strategy to meet the needs of each patient. Although most antidiabetes agents are routinely used, each class is associated with specific safety concerns; for example, sulfonylureas have been associated with hypoglycemia, edema, and weight gain (2–4), whereas thiazolidinediones have been associated with edema, congestive heart failure, and peripheral fractures (5,6). In addition, patients with type 2 diabetes often develop comorbidities as the disease progresses, including kidney disease, congestive heart failure, and coronary heart disease, which may be exacerbated by certain medications; for example, metformin should not be used in patients with renal insufficiency because of the risk of lactic acidosis (7), and thiazolidinediones are contraindicated in patients with …
Aneurysm of the left aortic sinus causing acute myocardial infarction.
Authors: K Hiyamuta, T Ohtsuki, M Shimamatsu, Y Ohkita, M Terasawa, H Bekki, H Toshima, F Utsu, K Ohishi, M Koga, K Nagayama
Journal: Circulation (1983)

A 30-year-old female had an acute myocardial infarction complicated by congestive heart failure. Angiography demonstrated an aneurysm in the area of the left aortic sinus. The aneurysm compressed and displaced the main trunk of the left coronary artery and the proximal portion of the left anterior descending artery. This aneurysm was considered to be the cause of the infarction. Aortic valve replacement and removal of the aneurysm were performed. Postoperative studies revealed good function of the replaced valve, good antegrade filling of the left coronary artery, and improved left ventricular function.
Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis
Authors: J. Cortes, V. Calvo, N. Ramírez-Merino, J. O'Shaughnessy, A. Brufsky, N. Robert, M. Vidal, E. Muñoz, J. Perez, S. Dawood, C. Saura, S. Di Cosimo, A. González-Martín, M. Bellet, O.E. Silva, D. Miles, A. Llombart, J. Baselga
Journal: Annals of Oncology (2011)
Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomised controlled trial
Authors: Manel Sabate, Angel Cequier, Andrés Iñiguez, Antonio Serra, Rosana Hernandez-Antolin, Vicente Mainar, Marco Valgimigli, Maurizio Tespili, Pieter den Heijer, Armando Bethencourt, Nicolás Vazquez, Joan Antoni Gómez-Hospital, José Antonio Baz, Victoria Martin-Yuste, Robert-Jan van Geuns, Fernando Alfonso, Pascual Bordes, Matteo Tebaldi, Monica Masotti, Antonio Silvestro, Bianca Backx, Salvatore Brugaletta, Gerrit Anne van Es, Patrick W Serruys
Journal: The Lancet (2012)
Epstein-Barr Virus Latent Membrane Protein 1 (CAO) Up-regulates VEGF and TGFα Concomitant with Hyperlasia, with Subsequent Up-regulation of p16 and MMP9
Authors: David Stevenson, Chrystalla Charalambous, Joanna B. Wilson
Journal: Cancer Research (2005)

Abstract EBV latent membrane protein 1 (LMP1) is an oncoprotein frequently expressed in nasopharyngeal carcinoma. We have generated transgenic mice expressing the nasopharyngeal carcinoma–derived CAO strain of LMP1 and LMP1 of the B95-8 strain, using the viral ED-L2 promoter for epithelial expression. LMP1CAO and LMP1B95-8 induce transforming growth factor α expression and epidermal hyperplasia. However, levels of total epidermal growth factor receptor (EGFR) decline with the appearance of phosphorylated EGFR products, suggesting that the negative feedback loop upon EGFR expression is intact or that there is faster turnover at these early stages of carcinogenesis. In the L2LMP1CAO mice, increased levels of vascular endothelial growth factor are also seen at an early stage in the skin. As the phenotype worsens, with increasing hyperplasia and vascularization leading to keratoacanthoma, p16INK4a and matrix metalloproteinase 9 expression is induced. The lesions can progress spontaneously to carcinoma. Carcinoma cell lines developed from these mice show high levels of total and phosphorylated EGFR. These data show that the induction of signaling through EGFR by LMP1 is an early event in carcinogenesis and that any inhibition upon EGFR expression is lifted during progression. Furthermore, expression of LMP1 is not sufficient to inhibit induction of p16INK4a in response to abnormal proliferation. These data are consistent with the cooperative effects seen between LMP1 and loss of the INK4a locus in transgenic mice and with the frequency of loss of this locus in EBV-associated nasopharyngeal carcinoma.
Learning to tolerate ourselves
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2008)

On page 139, Duty et al. find self-reactive B cells in healthy adults that might harm their own body if given the chance.






Figure 1

A population of mature B cells from healthy people produce autoreactive antibodies that bind to DNA (green).




Checkpoints during B cell development ensure that immune cells won't confuse the self for an intruder. At birth, many B cells express self-reactive receptors. Most of these potentially harmful cells are either set straight by rearranging new receptors or are eliminated before leaving the bone marrow. Yet a minority manages to escape, slipping into the periphery as mature B cells with a propensity for self-attack.

In healthy mice, autoimmunity is avoided because most self-reactive escapees, which classically express high levels of IgD and reduced IgM, are arrested in an anergic state. But until now, a similar population of anergic, autoreactive B cells hadn't been found in humans.

Duty et al. have now spotted these cells in the blood of healthy adults, where they accounted for 2.5% of peripheral B cells. These cells turned out to be mature and autoreactive, bearing no signs of antigen encounter in vivo. The cells were also anergic, as they had faulty signaling in response to BCR ligation. These defects were overcome, however, when the authors gave cells a strong enough signal.

Autoreactive B cells are common in patients with autoimmune diseases, such as lupus or rheumatoid arthritis (RA). And the authors suspect that the new population may contain the precursors of these troublemaking cells. Lapses in early steps of self-tolerance have been shown to contribute to disease in patients with lupus or RA. Alternatively, suggests author Patrick Wilson, anergy may fail in these patients, allowing self-sabotaging cells to run free.

Why the body silences these potentially mutinous cells after they escape rather than putting them to death is unclear. Perhaps, suggests Wilson, a limited amount of autoimmunity isn't such a bad thing, as long as it's not chronic. For example, anergic cells might help attack pathogens disguised as self-antigens.
Chronic effects of early started angiotensin converting enzyme inhibition and angiotensin AT1-receptor subtype blockade in rats with myocardial infarction: role of bradykinin
Authors: K Hu
Journal: Cardiovascular Research (1998)

Objective: The long-term effects and mechanisms of early started angiotensin converting enzyme (ACE) inhibition post myocardial infarction (MI) are not well understood. Chronic effects of early ACE inhibition on hemodynamics, left ventricular diastolic wall stress and remodeling were, therefore, compared to that of angiotensin AT1-receptor subtype blockade in rats with experimental myocardial infarction. The contribution of bradykinin potentiation to both ACE inhibitor and angiotensin AT1-receptor subtype blockade was assessed by cotreatment of rats with a bradykinin B2-receptor antagonist. Methods: MI was produced by coronary artery ligation in adult male Wistar rats. The ACE inhibitor, quinapril (6 mg/kg per day), or the angiotensin AT1-receptor subtype blocker, losartan (10 mg/kg per day), administered by gavage, and the bradykinin B2-receptor antagonist, Hoe-140 (500 μg/kg per day s.c.), administered either alone or in combination with quinapril or losartan, were started 30 min after MI and continued for eight weeks. Results: Quinapril and losartan reduced left ventricular end-diastolic pressure and global left ventricular diastolic wall stress only in rats with large MI. Pressure volume curves showed a rightward shift in proportion to MI size that was not prevented by quinapril or losartan treatment. Only the ACE inhibitor reduced left ventricular weight and this effect was prevented by cotreatment with the bradykinin antagonist. Baseline and peak cardiac index and stroke volume index, as determined using an electromagnetic flowmeter before and after an acute intravenous volume load, were restored by quinapril, whereas losartan had no effects. Conclusion: Treatments starting 30 min after coronary artery ligation, with either quinapril or losartan, reduced preload only in rats with large MI. Despite this unloading of the heart, structural dilatation was not prevented by this early treatment. Only quinapril improved cardiac performance and reduced left ventricular weight and this effect was abolished by cotreatment with Hoe-140, suggesting an angiotensin II blockade-independent, but bradykinin potentiation-dependent, mechanism.
Domestic Radon Exposure and Risk of Childhood Cancer: A Prospective Census-Based Cohort Study
Authors: Dimitri Hauri, Ben Spycher, Anke Huss, Frank Zimmermann, Michael Grotzer, Nicolas von der Weid, Damien Weber, Adrian Spoerri, Claudia E. Kuehni, Martin Röösli
Journal: Environmental Health Perspectives (2013)

Background: In contrast with established evidence linking high doses of ionizing radiation with childhood cancer, research on low-dose ionizing radiation and childhood cancer has produced inconsistent results.Objective: We investigated the association between domestic radon exposure and childhood cancers, particularly leukemia and central nervous system (CNS) tumors.Methods: We conducted a nationwide census-based cohort study including all children < 16 years of age living in Switzerland on 5 December 2000, the date of the 2000 census. Follow-up lasted until the date of diagnosis, death, emigration, a child's 16th birthday, or 31 December 2008. Domestic radon levels were estimated for each individual home address using a model developed and validated based on approximately 45,000 measurements taken throughout Switzerland. Data were analyzed with Cox proportional hazard models adjusted for child age, child sex, birth order, parents' socioeconomic status, environmental gamma radiation, and period effects.Results: In total, 997 childhood cancer cases were included in the study. Compared with children exposed to a radon concentration below the median (< 77.7 Bq/m3), adjusted hazard ratios for children with exposure ≥ the 90th percentile (≥ 139.9 Bq/m3) were 0.93 (95% CI: 0.74, 1.16) for all cancers, 0.95 (95% CI: 0.63, 1.43) for all leukemias, 0.90 (95% CI: 0.56, 1.43) for acute lymphoblastic leukemia, and 1.05 (95% CI: 0.68, 1.61) for CNS tumors.Conclusions: We did not find evidence that domestic radon exposure is associated with childhood cancer, despite relatively high radon levels in Switzerland.Citation: Hauri D, Spycher B, Huss A, Zimmermann F, Grotzer M, von der Weid N, Weber D, Spoerri A, Kuehni C, Röösli M, for the Swiss National Cohort and the Swiss Paediatric Oncology Group (SPOG). 2013. Domestic radon exposure and risk of childhood cancer: a prospective census-based cohort study. Environ Health Perspect 121:1239–1244; http://dx.doi.org/10.1289/ehp.1306500
Enhanced activation of p21-activated kinase 1 in heart failure contributes to dephosphorylation of connexin 43
Authors: Xun Ai, Aiyang Jiang, Yunbo Ke, R. John Solaro, Steven M. Pogwizd
Journal: Cardiovascular Research (2011)

We previously showed decreased cellular coupling and dephosphorylation of the gap junctional protein connexin 43 (Cx43) in left ventricular (LV) myocytes from an arrhythmogenic rabbit model of non-ischaemic heart failure (HF) that was associated with a 2.5-fold increase in the amount of protein phosphatase type 2A (PP2A) co-localized with Cx43. Here, we further explore the molecular mechanisms of enhanced dephosphorylation of Cx43 in HF. p21-activated kinase 1 (PAK1) is a serine–threonine protein kinase that has been shown to activate PP2A. We found that total PAK1 and activated PAK1 (PAK1-PThr423) were both increased in HF rabbit LV (vs. controls). PAK1 co-immunoprecipitated (co-IP'd) with Cx43 protein and, with HF, co-IP'd PAK1 and PAK1-PThr423 were increased. With failing human LV, PAK1 total protein and PAK1-PThr423 were also increased globally and locally (co-IP'd with Cx43). To further explore the role of PAK1 in modulating Cx43 dephosphorylation and intercellular coupling, we overexpressed active PAK1 in isolated LV myocytes from control rabbits and in HEK293 cells with genetically modified overexpression of Cx43 (HEK293-Cx43). PAK1 overexpression in both rabbit myocytes and HEK293-Cx43 cells significantly increased PP2A activity (globally and at the level of Cx43), increased dephosphorylated Cx43, and markedly reduced intercellular dye coupling. These effects were attenuated with PP2A inhibition using okadaic acid (10 nM). PAK1 and PP2A are integral components of a macromolecular complex with cardiac Cx43, and increased activation of associated PAK1 can contribute to enhanced Cx43 dephosphorylation and impaired intercellular coupling that may underlie slow conduction in HF.