tbuckley/cabot-search huggingface dataset:
Relation between nicotine intake and Alzheimer's disease.
Authors: C M van Duijn, A Hofman
Journal: BMJ (1991)

OBJECTIVE--To study the association between Alzheimer9s disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer9s disease, 198 controls matched for age and sex, and families of 17 patients in whom Alzheimer9s disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia, relative risk of Alzheimer9s disease. RESULTS--89 of 193 patients with Alzheimer9s disease had a history of smoking compared with 102 of 195 controls. Among the patients and controls with a family history of dementia, smoking was significantly less common in those with dementia (40/95 with dementia v 55/96 controls; relative risk 0.35; 95% confidence interval 0.16 to 0.78). The risk of Alzheimer9s disease decreased with increasing daily number of cigarettes smoked before onset of disease (relative risk 0.3 in those smoking greater than 21/day v 1 in non-smokers). In six families in which the disease was apparently inherited as an autosomal dominant disorder, the mean age of onset was 4.17 years later in smoking patients than in non-smoking patients from the same family (p = 0.03). CONCLUSIONS--These findings suggest an inverse association between smoking and Alzheimer9s disease, although smoking cannot be advocated for other health reasons. We speculate that nicotine may have a role in the aetiology of both Alzheimer9s disease and Parkinson9s disease.
Nuclear Survivin Abrogates Multiple Cell Cycle Checkpoints and Enhances Viral Oncolysis
Authors: Claire M. Connell, Sally P. Wheatley, Iain A. McNeish
Journal: Cancer Research (2008)

Abstract Survivin (BIRC5) promotes cell division and survival with roles as chromosomal passenger protein and inhibitor of apoptosis protein (IAP). It is overexpressed in many cancers and is associated with resistance to chemotherapy and radiation. Previously, we showed that expression of survivin within the nucleus of HeLa cells accelerates its degradation and blocks apoptosis inhibition without affecting localization during mitosis. Here, we have investigated the effects of survivin on cell cycle control and potential therapeutic consequences using HeLa and IGROV1 cells expressing wild-type and nuclear-targeted survivin. We show that overexpression of survivin, especially within the nucleus, increases control over G1-S checkpoint via increased nuclear accumulation of cyclin D and cyclin-dependent kinase 4 and subsequent pRb phosphorylation. We investigated the influence of survivin on the activity of the E1A CR2-deleted oncolytic adenovirus dl922-947, which depends critically on an aberrant G1-S checkpoint. Nuclear expression of survivin augments virus-induced S-phase induction and increases viral protein expression and overall viral replication. There is a consequent increase in antitumor activity both in vitro and in vivo. The increased dl922-947 activity is restricted to malignant cells and is not associated with induction of apoptosis, nor does it rely on the role of survivin as an IAP. In addition, we observe the appearance of a large ≥4N population coincident with multiple mitotic defects in dl922-947–infected cells, both of which are significantly increased by nuclear survivin. This indicates that adenoviral activity is facilitated by abrogation of multiple cell cycle checkpoints and can be enhanced by expression of survivin within the nucleus. [Cancer Res 2008;68(19):7923–31]
Molecular Imaging of the Kinetics of Vascular Endothelial Growth Factor Gene Expression in Ischemic Myocardium
Authors: Joseph C. Wu, Ian Y. Chen, Yanling Wang, Jeffrey R. Tseng, Ankush Chhabra, Mahdi Salek, Jung-Joon Min, Michael C. Fishbein, Ronald Crystal, Sanjiv S. Gambhir
Journal: Circulation (2004)

Angiogenic gene therapy is a promising treatment paradigm for patients with ischemic heart disease. In this study, we used micro-positron emission tomography (microPET) to monitor the transgene expression, function, and effects in a whole-body system.Adenovirus with cytomegalovirus promoter driving an angiogenic gene (vascular endothelial growth factor [VEGF]) linked to a PET reporter gene (herpes simplex virus type 1 mutant thymidine kinase; Ad-CMV-VEGF121-CMV-HSV1-sr39tk) was used to transfect rat embryonic cardiomyoblasts in vitro. Expression of both genes correlated strongly (r=0.98; P<0.001). Afterward, rats underwent ligation of the left anterior descending artery followed by injection of 1x10(10) pfu of Ad-CMV-VEGF121-CMV-HSV1-sr39tk (study; n=35) or Ad-null (control; n=15) at the peri-infarct region. Noninvasive microPET imaging was used to assess the uptake of 9-(4-[18F]-fluoro-hydroxymethylbutyl)guanine ([18F]-FHBG) PET reporter probe by cells expressing the HSV1-sr39tk PET reporter gene. Cardiac transgene expression peaked at day 1 and declined over the next 2 weeks. Repeat adenoviral injections at day 60 yielded no detectable signal. The in vivo reporter gene expression (% injected dose/g of [18F]-FHBG) correlated well with ex vivo gamma counting (r=0.92), myocardial tissue HSV1-sr39TK enzyme activity (r=0.95), and myocardial tissue VEGF level (r=0.94; P<0.001 for all). The VEGF121 isoform induced significant increases in capillaries and small blood vessels. However, the level of neovasculature did not translate into significant improvements in functional parameters such as myocardial contractility by echocardiography, perfusion by nitrogen-13 ammonia imaging, and metabolism by [18F]-fluorodeoxyglucose imaging.Taken together, these findings establish the feasibility of molecular imaging for monitoring angiogenic gene expression with a PET reporter gene and probe noninvasively, quantitatively, and repetitively. The principles demonstrated here can be used to evaluate other therapeutic genes of interest in animal models before future clinical trials are initiated.
Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target
Authors: Ninib Baryawno, Afsar Rahbar, Nina Wolmer-Solberg, Chato Taher, Jenny Odeberg, Anna Darabi, Zahidul Khan, Baldur Sveinbjörnsson, O.-M. FuskevÅg, Lova Segerström, Magnus Nordenskjöld, Peter Siesjö, Per Kogner, John Inge Johnsen, Cecilia Söderberg-Nauclér
Journal: Journal of Clinical Investigation (2011)

Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE2, which stimulates tumor cell proliferation. Human cytomegalovirus (HCMV) is prevalent in the human population and encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation. In particular, HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumor formation in vivo. Here, we show that a large proportion of primary medulloblastomas and medulloblastoma cell lines are infected with HCMV and that COX-2 expression, along with PGE2 levels, in tumors is directly modulated by the virus. Our analysis indicated that both HCMV immediate-early proteins and late proteins are expressed in the majority of primary medulloblastomas. Remarkably, all of the human medulloblastoma cell lines that we analyzed contained HCMV DNA and RNA and expressed HCMV proteins at various levels in vitro. When engrafted into immunocompromised mice, human medulloblastoma cells induced expression of HCMV proteins. HCMV and COX-2 expression correlated in primary tumors, cell lines, and medulloblastoma xenografts. The antiviral drug valganciclovir and the specific COX-2 inhibitor celecoxib prevented HCMV replication in vitro and inhibited PGE2 production and reduced medulloblastoma tumor cell growth both in vitro and in vivo. Ganciclovir did not affect the growth of HCMV-negative tumor cell lines. These findings imply an important role for HCMV in medulloblastoma and suggest HCMV as a novel therapeutic target for this tumor.
Role of pH in determining the cell-type-specific residual activity of glucocerebrosidase in type 1 Gaucher disease.
Authors: S van Weely, M van den Berg, J A Barranger, M C Sa Miranda, J M Tager, J M Aerts
Journal: Journal of Clinical Investigation (1993)

The properties of control and 370Asn-->Ser glucocerebrosidase, the frequently encountered mutated form of the enzyme in type 1 Gaucher disease, were studied in vitro as well as in situ. The catalytic properties of purified 370Asn-->Ser glucocerebrosidase were highly dependent on the assay conditions. The enzyme was deficient in activity towards substrate and in reactivity with the irreversible inhibitor conduritol B-epoxide (CBE) when activated by the bile salt taurocholate. In the presence of more physiological activators, the lysosomal activator protein saposin C and phosphatidylserine, the 370Asn-->Ser enzyme was near normal in kinetic properties at pH values approximately 5, but not at higher pH. In intact fibroblasts, the enzymic activity of the 370Asn-->Ser glucocerebrosidase and its reactivity with CBE were found to be clearly deficient. However, in intact lymphoblasts from the same patients, the behavior of the mutant enzyme was near normal. The catalytic efficiency of 370Asn-->Ser glucocerebrosidase in situ was also found to be highly pH dependent. When intact lymphoblasts were cultured in the presence of permeant weak bases, which increase the pH of acidic intracellular compartments, the catalytic efficiency of the mutant enzyme, as assessed by its reactivity with CBE, became markedly impaired. Our findings indicate that the intralysosomal pH in the intact cell can be expected to have a critical influence on the activation state of 370Asn-->Ser glucocerebrosidase and its ability to hydrolyse substrate. This phenomenon may partly underly the marked heterogeneity in clinical manifestation of Gaucher disease among patients with this mutated form of glucocerebrosidase.
N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Ameliorates the Progression of Renal Dysfunction and Fibrosis in WKY Rats with Established Anti–Glomerular Basement Membrane Nephritis
Authors: Mitsugu Omata, Hajime Taniguchi, Daisuke Koya, Keizo Kanasaki, Rumiko Sho, Yoshimi Kato, Ryoji Kojima, Masakazu Haneda, Norio Inomata
Journal: Journal of the American Society of Nephrology (2006)

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is hydrolyzed by angiotensin-converting enzyme, is a natural regulator of hematopoiesis. Here it is shown that Ac-SDKP inhibits TGF-beta action in mesangial cells. Because TGF-beta is thought to play a pivotal role in the development and progression of glomerulonephritis, the therapeutic effects of Ac-SDKP on an established model of renal dysfunction and histologic alteration in Wistar-Kyoto rats with anti-glomerular basement membrane nephritis was examined. Fourteen days after the induction of anti-glomerular basement membrane nephritis, the rats were treated subcutaneously with Ac-SDKP at a dose of 1 mg/kg per d for 4 wk. Treatment with Ac-SDKP significantly improved proteinuria and renal dysfunction, including increased plasma blood urea nitrogen and creatinine levels and decreased creatinine clearance. Histologic examination showed severe glomerulosclerosis and interstitial fibrosis in the vehicle-treated rats, whereas these histologic injuries were significantly ameliorated in rats that were treated with Ac-SDKP. The histologic improvements were accompanied by the suppression of gene and protein expression of fibronectin, interstitial collagen, and TGF-beta1 in the nephritic kidney. Furthermore, treatment with Ac-SDKP resulted in the inhibition of Smad2 phosphorylation, an increase in Smad7 expression in the kidney, and reduction of macrophage accumulation into the glomeruli and tubulointerstitium in nephritic rats. In conclusion, Ac-SDKP significantly ameliorated the progression of renal dysfunction and fibrosis even after the establishment of nephritis. The inhibitory effect of Ac-SDKP was mediated in part by the inhibition of TGF-beta/Smad signal transduction and the inflammatory response. These findings suggest that Ac-SDKP treatment may be a novel and useful therapeutic strategy for the treatment of progressive renal diseases.
Daclizumab versus Antithymocyte Globulin in High-Immunological-Risk Renal Transplant Recipients
Authors: Christian Noe[Combining Diaeresis]l, Daniel Abramowicz, Dominique Durand, Georges Mourad, Philippe Lang, Miche[Combining Grave Accent]le Kessler, Bernard Charpentier, Guy Touchard, Franc[COMBINING CEDILLA]ois Berthoux, Pierre Merville, Nacera Ouali, Jean-Paul Squifflet, Franc[COMBINING CEDILLA]ois Bayle, Karl Martin Wissing, Marc Hazzan
Journal: Journal of the American Society of Nephrology (2009)

Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these therapies have not been directly compared in a high-risk, HLA-sensitized renal transplant population. We randomly assigned 227 patients, who were about to receive a kidney graft from a deceased donor, to either Thymoglobulin or daclizumab if they met one of the following risk factors: current panel reactive antibodies (PRA) >30%; peak PRA >50%; loss of a first kidney graft from rejection within 2 yr of transplantation; or two or three previous grafts. Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and steroids. Compared with the daclizumab group, patients treated with Thymoglobulin had a lower incidence of both biopsy-proven acute rejection (15.0% versus 27.2%; P = 0.016) and steroid-resistant rejection (2.7% versus 14.9%; P = 0.002) at one year. One-year graft and patient survival rates were similar between the two groups. In a comparison of rejectors and nonrejectors, overall graft survival was significantly higher in the rejection-free group (87.2% versus 75.0%; P = 0.037). In conclusion, among high-immunological-risk renal transplant recipients, Thymoglobulin is superior to daclizumab for the prevention of biopsy-proven acute rejection, but there is no significant benefit to one-year graft or patient survival.
Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis
Authors: Mora Murri, Manuel Luque-Ramírez, María Insenser, Miriam Ojeda-Ojeda, Hector F. Escobar-Morreale
Journal: Human Reproduction Update (2013)

BACKGROUND Oxidative stress might be associated with polycystic ovary syndrome (PCOS), but relatively small studies published to date do not permit reaching a definitive conclusion. We aimed at conducting a systematic review and meta-analysis of studies evaluating circulating markers of oxidative stress in patients with PCOS. METHODS We conducted a systematic review of studies reporting circulating markers of oxidative stress in women with PCOS and controls published up to June 2012, using Entrez PubMed and EMBASE online facilities. Meta-analysis calculated standardized mean differences (SMDs) and 95% confidence intervals (95CI). RESULTS From 1633 potential studies identified electronically, 68 studies, including 4933 PCOS patients and 3671 controls, were selected. For each of nine circulating markers of oxidative stress, an individual meta-analysis was conducted. Compared with control women, patients with PCOS presented higher circulating concentrations of homocysteine (23% increase, SMD 0.6, 95CI, 0.4-0.8), malondialdehyde (47% increase, SMD 1.9, 95CI 1.2-2.6) and asymmetric dimethylarginine (36% increase, SMD 1.1, 95CI 0.6-1.6), and increased superoxide dismutase activity (34% increase, SMD 1.0, 95CI 0.5-1.4) and decreased glutathione levels (50% decrease, SMD -3.7, 95CI -6.2 to -1.2) and paraoxonase-1 activity (32% decrease, SMD -0.9, 95CI -1.3 to -0.4). Similar results were found when restricting the analyses to studies in which patients and controls were matched for age and body mass index. CONCLUSIONS Circulating markers of oxidative stress are abnormal in women with PCOS independent of weight excess. This finding suggests that oxidative stress may participate in the pathophysiology of this common disorder.
Risk of Subsequent Neoplasms During the Fifth and Sixth Decades of Life in the Childhood Cancer Survivor Study Cohort
Authors: Lucie M. Turcotte, John A. Whitton, Debra L. Friedman, Sue Hammond, Gregory T. Armstrong, Wendy Leisenring, Leslie L. Robison, Joseph P. Neglia
Journal: Journal of Clinical Oncology (2015)

Purpose Survivors of childhood cancer have an increased risk for subsequent neoplasms (SNs), but the incidence beyond the age of 40 years and associations with therapeutic exposures have not been well described. Patients and Methods Among 14,364 survivors of childhood cancer diagnosed between 1970 and 1986, 3,171 had an attained age of 40 years or older at the time of last contact. Cumulative incidence of SNs, standardized incidence ratios (SIRs), excess absolute risk of subsequent malignant neoplasms (SMNs), and relative risks (RRs) for SMNs and nonmelanoma skin cancers were calculated. Results In total, 679 SNs were diagnosed in patients age 40 years or older. These included 196 SMNs, 419 nonmelanoma skin cancers, 21 nonmalignant meningiomas, and 43 other benign neoplasms. At age 55 years, the cumulative incidence of new SNs and SMNs occurring after age 40 years was 34.6% (95% CI, 28.7 to 40.6) and 16.3% (95% CI, 11.7 to 20.9), respectively. Survivors were four times as likely as the general population to receive a diagnosis of SMN after age 40 years (SIR, 4.4; 95% CI 3.8 to 5.0). Among SMNs, risk was most increased for soft tissue sarcoma (SIR, 12.3; 95% CI, 7.2 to 21.0), breast cancer (SIR, 8.3; 95% CI, 6.9 to 10.0), renal cancer (SIR, 6.1; 95% CI, 3.2 to 11.6), and thyroid cancer (SIR, 5.1; 95% CI, 2.8 to 9.4). Female sex (RR, 1.5; 95% CI, 1.1 to 2.1; P = .008), platinum chemotherapy (RR, 3.4; 95% CI, 1.5 to 7.7; P = .003), epipodophyllotoxins (RR, 2.4; 95% CI, 1.0 to 5.8; P = .05), and therapeutic radiation exposure (RR, 2.0; 95% CI, 1.4 to 3.1; P &lt; .001) were associated with higher risk for SMN in multivariable analysis. Conclusion Even after age 40 years, survivors of childhood cancer remain at increased risk for treatment-related SNs. These data suggest the need for life-long monitoring and should inform anticipatory guidance provided to survivors of childhood cancer.
Effects of nebulized heparin in a rat-model of endotoxemia-induced lung injury
Authors: Laura Chimenti, Raquel Guillamat, Maria Nieves Gomez, Jessica Tijero, Thomas Lebouvier, Lluis Blanch, Antonio Artigas
Journal: European Respiratory Journal (2014)

BACKGROUND. Sepsis is a mayor cause of acute lung injury (ALI) and pulmonary coagulopathy is intrinsic to ALI. In sepsis, anticoagulant system is impaired, due to consumption and downregulation by inflammatory mediators. Several studies, in ALI patients and in ALI experimental models, inconsistently suggest beneficial effects of systemic anticoagulants which affect systemic coagulation. Nebulization of anticoagulants might allow for higher pulmonary concentration and reduce the risk of systemic bleeding. METHODS. Adult male Sprague-Dawley rats (250-300 g; n=6/group) were anesthetized with isofluorane and subjected to intratracheal administration (IA) of LPS (10 μg/g b.w.) and IA of saline in control animals. Saline or heparin (1000 IU/kg) were nebulized at 4 and 8h after LPS instillation. Animals were sacrificed 24h after the injury. Inflammatory cells and total proteins were assessed in bronchoalveaolar lavage fluid (BALF). Data are reported as mean±SD. One-way ANOVA was used for multigroup comparisons. RESULTS. Total neutrophil counts were significantly higher in rats instilled with LPS (18.1±6.1x10 7 cells/ml, p 7 cells/ml). Nebulized heparin significantly reduced neutrophils in animals instilled with LPS (12.4±4.3x10 7 cells/ml, p  Grant acknowledgment: FIS-PI12/02548, CIBERES and Fundacio Parc Tauli.
Is there a link between malignant hyperthermia and exertional heat illness?
Authors: P M Hopkins
Journal: British Journal of Sports Medicine (2007)

There is a link between malignant hyperthermia and exertional heat illness

Malignant hyperthermia is a relatively rare pharmacogenetic disorder inherited in an autosomal dominant fashion.1 It is triggered in previously healthy susceptible individuals by exposure to potent inhalational anaesthetic agents and the muscle relaxant suxamethonium (succinylcholine). The clinical features of a malignant hyperthermia reaction have many similarities to those of heat illness.2 These include a mixed respiratory and metabolic acidosis, tachycardia, rhabdomyolysis and muscle rigidity with progressive hyperthermia. The condition acquired its name because of the high mortality of the early cases.

Exertional heat illness occurs mainly in previously healthy young men during exercise, often in hot and humid climates to which the victim is not properly acclimatised.3 Typical scenarios include military exercises undertaken by personnel recently arrived in a hot country, and long-distance races that happen to coincide with one of the first hot days of the year. In these situations, multiple cases are common. Exertional heat illness is also more likely in the obese, in the physically unfit, in the presence of concurrent viral infection, after recent alcohol consumption, in those with skin diseases preventing sweating, in those with thyrotoxicosis and in those taking a variety of prescribed or non-prescribed medicines.4 There are, however, sporadic cases that occur in individuals, with no obvious predisposing factors, exercising in unremarkable weather conditions. Again, these often occur in the context of military exercises or running races, but it is notable that the victim is the only person out of tens, hundreds or even thousands of others taking part to be so affected. It is these cases that arouse particular suspicion of an underlying, relatively rare, predisposing factor.

Malignant hyperthermia is caused by a defect in skeletal muscle intracellular calcium homoeostasis. Clinical diagnosis of susceptibility to malignant hyperthermia …
Does Elevated Plasma Triglyceride Level Independently Predict Impaired Fasting Glucose?
Authors: Susan X. Lin, Ivan Berlin, Richard Younge, Zhezhen Jin, Christopher T. Sibley, Pamela Schreiner, Moyses Szklo, Alain G. Bertoni
Journal: Diabetes Care (2012)

Elevated plasma triglycerides (TGs) have been included in diabetes risk prediction models. This study examined whether elevated TGs predict risk for impaired fasting glucose (IFG).