tbuckley/cabot-search huggingface dataset:
Current pathophysiological views on vibration-induced Raynaud's phenomenon
Authors: Z Stoyneva
Journal: Cardiovascular Research (2003)

This review attempts to summarize and discuss contemporary pathogenetic views on vibration-induced Raynaud's phenomenon assuming its multifactorial etiology. An increase in central and peripheral sympathetic nervous activity is discussed based on different physiological indicators of autonomic dysfunction and sympathetic hyperactivity. Local acral vasodysregulation is considered. Receptor and nerve endings dysfunction presented with predominance of α2-receptor function in the digital arteries and neuronal loss in those digital cutaneous perivascular nerves containing calcitonin gene-related peptide result in deficiency of endogenous release of this powerful vasodilator. Endothelial damage and dysregulation induced by vibration and increased shear stresses are demonstrated by the elevated plasma level of thrombomodulin and of von Willebrand factor and reduced endothelium-dependent vasodilator responses. The concentrations of endothelin-1 are high, the highest being in most advanced stages. Decreased plasma thiol level, indicating increased production and activity of free radicals, contribute to vasospastic paroxysms in vibration white finger patients. Dysbalance of local vasoactive factors with opposing effects on vascular smooth muscle like endothelin and nitric oxide, endothelin and calcitonin gene-related peptide, nitric oxide and superoxide anion are discussed. Disturbed smooth muscle response is supposed. Changes in hemostasis, fibrinolysis and hemorrheology, activation of blood cells with erythrocyte hyperaggregation and red cell hypodeformability, platelet aggregation with increased release of vasoconstricting thromboxane A2 and serotonin as well as leukocyte activation, entrapment within capillaries and post-capillary venules and increased reactive oxygen species and lysosomal lytic enzymes release might also contribute to digital vasospasms and tissue damage. Elevated soluble intercellular adhesion molecule-1 levels involved in the adherence of leukocytes to endothelium and to other leukocytes have been found in patients with hand–arm vibration syndrome.
Impact of Androgen Deprivation Therapy on Cardiovascular Disease and Diabetes
Authors: Shabbir M.H. Alibhai, Minh Duong-Hua, Rinku Sutradhar, Neil E. Fleshner, Padraig Warde, Angela M. Cheung, Lawrence F. Paszat
Journal: Journal of Clinical Oncology (2009)

PURPOSE Use of androgen deprivation therapy (ADT) may be associated with an increased risk of diabetes mellitus but the risk of both acute myocardial infarction (AMI) and cardiovascular mortality remain controversial because few outcomes and conflicting findings have been reported. We sought to clarify whether ADT is associated with these outcomes in a large, representative cohort. METHODS Using linked administrative databases in Ontario, Canada, men age 66 years or older with prostate cancer given continuous ADT for at least 6 months or who underwent bilateral orchiectomy (n = 19,079) were matched with men with prostate cancer who had never received ADT. Treated and untreated groups were matched 1:1 (ie, hard-matched) on age, prior cancer treatment, and year of diagnosis and propensity-matched on comorbidities, medications, cardiovascular risk factors, prior fractures, and socioeconomic variables. Primary outcomes were development of AMI, sudden cardiac death, and diabetes. Fragility fracture was also examined. Results The cohort was observed for a mean of 6.47 years. In time-to-event analyses, ADT use was associated with an increased risk of diabetes (hazard ratio [HR], 1.16; 95% CI, 1.11 to 1.21) and fragility fracture (HR, 1.65; 95% CI, 1.53 to 1.77) but not with AMI (HR, 0.91; 95% CI, 0.84 to 1.00) or sudden cardiac death (HR, 0.96; 95% CI, 0.83 to 1.10). Increasing duration of ADT was associated with an excess risk of fragility fractures and diabetes but not cardiac outcomes. CONCLUSION Continuous ADT use for at least 6 months in older men is associated with an increased risk of diabetes and fragility fracture but not AMI or sudden cardiac death.
Allosteric modifiers of neuronal nicotinic acetylcholine receptors: New methods, new opportunities
Authors: Ruin Moaddel, Krzysztof Jozwiak, Irving W. Wainer
Journal: Medicinal Research Reviews (2007)

Allosteric, non-competitive inhibitors (NCIs) of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to produce a wide variety of clinically relevant responses. Many of the observed effects are desired as the nAChR is the therapeutic target, while others are undesired consequences due to off-target binding at the nAChR. Thus, the determination of whether or not a lead drug candidate is an NCI should play an important role in drug discovery programs. However, the current experimental techniques used to identify NCIs are challenging, expensive, and time consuming. This review focuses on an alternative approach to the investigation of interactions between test compounds and nAChRs based upon liquid chromatographic stationary phases containing cellular fragments from cell lines expressing nAChRs. The development and validation of these phases as well as their use in drug discovery and pharmacophore modeling are discussed.
A Genetic Variant of Aurora Kinase A Promotes Genomic Instability Leading to Highly Malignant Skin Tumors
Authors: Enrique C. Torchia, Yiyun Chen, Hong Sheng, Hiroshi Katayama, James Fitzpatrick, William R. Brinkley, Carlos Caulin, Subrata Sen, Dennis R. Roop
Journal: Cancer Research (2009)

Aurora kinase A (Aurora-A) belongs to a highly conserved family of mitotis-regulating serine/threonine kinases implicated in epithelial cancers. Initially we examined Aurora-A expression levels at different stages of human skin cancer. Nuclear Aurora-A was detected in benign lesions and became more diffused but broadly expressed in well and poorly differentiated squamous cell carcinomas (SCC), indicating that Aurora-A deregulation may contribute to SCC development. To mimic the overexpression of Aurora-A observed in human skin cancers, we established a gene-switch mouse model in which the human variant of Aurora-A (Phe31Ile) was expressed in the epidermis upon topical application of the inducer RU486 (Aurora-AGS). Overexpression of Aurora-A alone or in combination with the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), did not result in SCC formation in Aurora-AGS mice. Moreover, Aurora-A overexpression in naive keratinocytes resulted in spindle defects in vitro and marked cell death in vivo, suggesting that the failure of Aurora-A to initiate tumorigenesis was due to induction of catastrophic cell death. However, Aurora-A overexpression combined with exposure to TPA and the mutagen 7,12-dimethylbenz(a)anthracene accelerated SCC development with greater metastatic activity than control mice, indicating that Aurora-A cannot initiate skin carcinogenesis but rather promotes the malignant conversion of skin papillomas. Further characterization of SCCs revealed centrosome amplification and genomic alterations by array CGH analysis, indicating that Aurora-A overexpression induces a high level of genomic instability that favors the development of aggressive and metastatic tumors. Our findings strongly implicate Aurora-A overexpression in the malignant progression of skin tumors and suggest that Aurora-A may be an important therapeutic target.
What is the best management strategy for high grade dysplasia in Barrett's oesophagus? A cost effectiveness analysis
Authors: N J Shaheen, J M Inadomi, B F Overholt, P Sharma
Journal: Gut (2004)

<b>Background:</b> Multiple treatment strategies for subjects with high grade dysplasia (HGD) in Barrett's oesophagus (BO) have been suggested. However, it is unclear which of these strategies provides the greatest life expectancy, and the costs associated with the management strategies are unknown. <b>Aim:</b> To compare the efficacy and cost effectiveness of competing management strategies for BO with HGD. <b>Methods:</b> We created a decision analysis model in Data 4.0 to assess possible treatment strategies for BO with HGD. The strategies included: (1) no preventative strategy, (2) elective surgical oesophagectomy, (3) endoscopic ablation, and (4) surveillance endoscopy. The base case was a healthy 50 year old White male with an initial diagnosis of BO with HGD. The model allowed for complications of surgery, including death. Ablative therapy could cause stricture or perforation. Pathological misinterpretation was allowed, and modelled after reported rates. Estimates were derived from the literature for the rate of progression of HGD to cancer and for complication rates for the various treatment modalities. The endoscopic ablation arm was modelled as photodynamic therapy. Sensitivity analyses were performed over a wide range of cancer incidences, complication rates, and procedure costs. <b>Results:</b> Endoscopic ablation was the most effective strategy, yielding 15.5 discounted quality adjusted life years (dQALY), compared with 15.0 for endoscopic surveillance and 14.9 for oesophagectomy. No preventative strategy was the most inexpensive option, yielding an average cost per quality adjusted life year of $54 (€44) per dQALY, but resulted in high rates of cancer. Endoscopic surveillance dominated oesophagectomy, being both less costly and more effective. The condition of extended dominance occurred when comparing endoscopic ablation to endoscopic surveillance because, although the total costs of ablation were greater than those of surveillance, it was less expensive to buy an additional life year using endoscopic ablation than endoscopic surveillance. The incremental cost effectiveness ratio when moving from no therapy to ablative therapy was a reasonable $25 621/dQALY (€21 009/dQALY). Sensitivity analysis demonstrated that when yearly rates of progression to cancer from HGD exceeded 30%, oesophagectomy became the most cost effective option. <b>Conclusions:</b> A strategy of endoscopic ablation provided the longest quality adjusted life expectancy for BO with HGD. Although endoscopic surveillance was less expensive than endoscopic ablation, it was associated with shorter survival. Optimal utilisation of healthcare resources may be achieved with endoscopic ablative therapy for BO with HGD.
RAD001 Inhibits Human Ovarian Cancer Cell Proliferation, Enhances Cisplatin-Induced Apoptosis, and Prolongs Survival in an Ovarian Cancer Model
Authors: Seiji Mabuchi, Deborah A. Altomare, Mitchell Cheung, Lili Zhang, Poulikos I. Poulikakos, Harvey H. Hensley, Russell J. Schilder, Robert F. Ozols, Joseph R. Testa
Journal: Clinical Cancer Research (2007)

Abstract Purpose: mTOR (mammalian target of rapamycin) plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether mTOR inhibition by RAD001 (everolimus) is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with cisplatin. Experimental Design: Using four human ovarian cancer cell lines, we determined the effect of RAD001 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Western blot, and apoptosis assays. We evaluated the association between phospho-AKT/mTOR activity and RAD001 sensitivity. We also determined the effect of RAD001 on tumor growth and malignancy using mice inoculated with human ovarian cancer cells. Results: RAD001 markedly inhibited cell proliferation of human ovarian carcinoma cells with high AKT activity (OVCAR10 and SKOV-3), but the effect was minimal in cells with low AKT activity (OVCAR4 and OVCAR5). Sensitivity to RAD001 was independent of p53 expression. RAD001 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase and attenuated the expression of Myc. RAD001 also attenuated the expression of HIF-1α and vascular endothelial growth factor, important factors in angiogenesis and tumor invasiveness. RAD001 enhanced cisplatin-induced apoptosis in cells with high AKT/mTOR activity, with minimal effect in cells with low AKT-mTOR activity. Mouse xenografts of SKOV-3 cells revealed that RAD001 inhibits tumor growth, angiogenesis, and i.p. dissemination and ascites production and prolongs survival. Moreover, treatment with RAD001 significantly enhanced the therapeutic efficacy of cisplatin in vivo. Conclusion: These results indicate that RAD001 could have therapeutic efficacy in human ovarian cancers with hyperactivated AKT/mTOR signaling.
Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p
Authors: S. Nagafuchi, H. Yanagisawa, K. Sato, T. Shirayama, E. Ohsaki, M. Bundo, T. Takeda, K. Tadokoro, I. Kondo, N. Murayama, Y. Tanaka, H. Kikushima, K. Umino, H. Kurosawa, T. Furukawa, K. Nihei, T. Inoue, A. Sano, O. Komure, M. Takahashi, T. Yoshizawa, I. Kanazawa, M. Yamada
Journal: Nature Genetics (1994)
Practical phenotyping of difficult asthma
Authors: Angela Thomas, Ruth H Green, Robert M Niven, Shiron Saha, Ian Hall, Liam G Heaney, Ian Sabroe
Journal: Thorax (2013)

### Key messages

Asthma comprises multiple but incompletely understood and characterised clinical phenotypes. We created two imaginary but typical cases and presented them to asthma specialists. This text summarises responses, which are presented in greater length in the online supplement.

AT: What should I do with a 40-year-old woman, body mass index (BMI) 32, ex-smoker with 10 pack-year history, asthma as a child, with a 4-year history of episodic breathlessness, cough and wheeze? Exercise tolerance has become progressively more limited. She has received several courses of oral prednisolone with only temporary improvement and currently on combined inhaled corticosteroid (ICS) and long-acting β-agonist (LABA). Spirometry shows forced expiratory volume in the first second (FEV1) 2.08 (65%), forced vital capacity (FVC) 3.15 (80%), ratio 66%. Predicted values were 3.21/3.94. Her FeNO was 42 ppb.

RG, RN, LH, IH: The most important thing to determine is if this is eosinophilic or non-eosinophilic asthma. These asthma phenotypes are discussed in the Commentary section below. To determine if eosinophilic disease is or has been present, we would look at historical blood counts in stable state and during exacerbations, induced sputum where available, and perhaps gain support from tests for atopy. We all suspect this first case is probably one of non-eosinophilic asthma. The measurement of FeNO is probably not …
Role of TNF-a in ventilator-induced lung injury in the developing murine lung
Authors: Tina Gimm, Melina Kossert, Christina M. Alvira, Harald Ehrhardt, Anne Hilgendorff
Journal: European Respiratory Journal (2013)

Rationale:  Chronic lung disease in the premature infant is characterized by impaired alveolar and vascular development preceded by an increase in lung inflammation and apoptosis. The disease mainly occurs after mechanical ventilation with oxygen rich gas (MV-O2). As the presence of Tumor necrosis factor (TNF)-a has been described in association with disease development, we hypothesized, that its absence will ameliorate changes induced by MV-O2 in a model of the disease in newborn mice.   Objective and Methods:  5-6 days old TNF-a knock-out (TNF-a -/- ) and wild type (WT, TNF-a +/+ ) mice received MV with 40%O 2  at 180 breaths/min; controls received 40%O 2  without MV respectively. After 8h, lungs (n=10-12/group) were harvested for histologic, mRNA and protein analysis. Primary myofibroblasts (MFB) from unventilated newborn TNF-a -/-  and WT mouse lungs were subjected to mechanical stretch (Flexcell®) and cytokine incubation.   Results:  Contrary to our expectations, pulmonary chemokine (MCP-1, CXCL-1) and cytokine (IL-1b) expression as well as influx of monocytes was significantly elevated in ventilated TNF-a -/-  mice, accompanied by an increase in apoptosis (TUNEL, caspase 3, 8 and 9) when compared to WT mice. These differences potentially resulted from a significant increase in TGF-b signaling in TNF -/-  mice after MV-O2 confirmed by an elevated response to TGF-β in MFB from TNF-a -/-  mice  in vitro  in contrast to WT pups. Histological changes were similar in both groups.   Conclusion:  Decreased TNF-a signaling in newborn mice undergoing MV-O2 results in increased TGF-b activation and apoptosis rather than decreased pulmonary inflammation, which needs to be considered when therapeutic strategies are discussed.
Percutaneous penetration of sodium lauryl sulphate is increased in uninvolved skin of patients with atopic dermatitis compared with control subjects
Authors: I. Jakasa, C.M. De Jongh, M.M. Verberk, J.D. Bos, S. Kežić
Journal: British Journal of Dermatology (2006)

Background Involved regions of the skin in patients with atopic dermatitis (AD) have been shown to have higher transepidermal water loss (TEWL), indicating a compromised skin barrier. Whether uninvolved skin also has diminished barrier characteristics is controversial. Objectives To study the penetration of sodium lauryl sulphate (SLS) into uninvolved skin of patients with AD compared with the skin of control subjects. Methods Percutaneous penetration was assessed using the tape stripping technique on the stratum corneum (SC). Twenty patients with AD and 20 healthy subjects were exposed to 1% SLS for 4 h on the mid‐volar forearm. After the end of exposure the SC was removed by adhesive tape. The amount of SLS was determined in each consecutive strip. Fick's second law of diffusion was used to deduce the diffusivity and the partition coefficient of SLS between water and the SC. Results The SC thickness was similar in both groups; however, the TEWL was higher in patients with AD compared with that of the control group (mean ± SD 8·4 ± 4·3 and 6·3 ± 2·0 g m−2 h−1, respectively). There was a correlation between SC thickness and TEWL in control subjects but no correlation was found in patients with AD. The diffusivity of SLS through uninvolved AD skin was higher compared with normal skin (mean ± SD 12·7 ± 5·8 × 10−9 and 6·2 ± 3·0 × 10−9 cm−2 h−1, respectively), while the partition coefficient between SC and water was lower (mean ± SD 137 ± 64 and 196 ± 107, respectively). Conclusions The results show a different penetration profile of SLS into the SC of patients with AD compared with control subjects. This indicates that even noninvolved skin in patients with AD has altered barrier characteristics, emphasizing the importance of skin protection and prevention of skin contact with chemicals.
Points from letters: Hopeless cases: referral to commission
Authors: H S Pasmore
Journal: BMJ (1975)

October, p 25) is not alone.At the inception of the NHS in 1948 I was an assistant in general practice and lived above the surgery in a traffic-congested area.At that time I managed my rounds quite easily on a bicycle.Unfortunately both your clientele and your colleagues come to regard you as an outsider, which adds to your emotional burden.The car becomes your
Mitral and Aortic Annular Calcification Are Highly Associated With Systemic Calcified Atherosclerosis
Authors: Matthew A. Allison, Philip Cheung, Michael H. Criqui, Robert D. Langer, C. Michael Wright
Journal: Circulation (2006)

Atherosclerosis has been implicated as a cause of valvular calcification. The aim of this study was to determine whether atherosclerotic calcification in multiple vascular areas is significantly associated with aortic or mitral annular calcification independent of traditional risk factors.A total of 1242 consecutive asymptomatic patients free of clinical coronary heart disease were studied by electron-beam computed tomography for the extent of calcium due to atherosclerosis in 5 distinct vascular beds and calcium in the aortic and mitral annuli. Nearly 24% had calcium in the aortic annulus, whereas 8% were found to have mitral annular calcification. Age and a history of hypertension were the only traditional cardiovascular risk factors that were independently associated with prevalent calcification in the aortic and mitral annuli. After adjustment for age, gender, and cardiovascular disease risk factors, subjects with calcium in the thoracic aorta had the highest odds for the presence of aortic annular calcium (OR=3.9, P<0.01), whereas those with calcium in the abdominal aorta had the highest odds for mitral annular calcification (OR=5.1, P=0.01). Standardized increases in calcium in the abdominal aorta (OR=2.0, P<0.01) and iliacs (OR=1.8, P=0.01) were significantly associated with calcium in the aortic annulus after adjustment for the extent of calcium in the other vascular beds, whereas the thoracic aorta was significantly associated (OR=1.4, P=0.02) with calcium in the mitral annulus.This study supports the hypothesis that calcification of the mitral and aortic annuli is related to atherosclerosis in other vascular beds.
SUSCEPTIBILITY OF RABBITS TO INFECTION BY THE INHALATION OF TYPE II PNEUMOCOCCI
Authors: Ernest G. Stillman
Journal: The Journal of Experimental Medicine (1930)

1. The susceptibility of rabbits to inhalations of pneumococci varies in direct proportion to the virulence of the organism for rabbits. 2. When rabbits are exposed to a pneumococcus spray, irrespective of the virulence of the organism, the bacteria readily penetrate into the lower respiratory tract. 3. When rabbits are exposed to a spray of avirulent degenerated "R" form of pneumococcus, septicemia does not occur and pneumococci are seldom recovered from the liver, kidney or spleen. 4. When rabbits are exposed to a spray of slightly virulent Pneumococcus Type II (SAv) a non-fatal septicemia may occur and pneumococci may be recovered from the liver, kidney and spleen. 5. When rabbits are exposed to a spray of virulent Type II (Sv) pneumococci, septicemia may occur which in certain instances terminates fatally. Pneumococci may also be recovered from the liver, kidney and spleen.
A longitudinal study of back pain and radiological changes in the lumbar spines of middle aged women. II. Radiographic findings.
Authors: D P Symmons, A M van Hemert, J P Vandenbroucke, H A Valkenburg
Journal: Annals of the Rheumatic Diseases (1991)

The natural history of radiological changes in the lumbar spine was evaluated in two groups of middle aged Dutch women selected from the general population. One group (n = 236) had recurrent back pain and the other (n = 241) had never experienced back pain. At the beginning of the study disc degeneration was more common in the group with back pain. Osteoporotic vertebral fractures were equally common in both groups. Nine years later both groups showed an increase in prevalence of disc degeneration and osteoporotic fractures. The strongest predictor for change in disc degeneration was the presence of degeneration at the beginning of the study. The development of disc degeneration for the first time was related to body mass index.