tbuckley/cabot-search huggingface dataset:
The meaning of lung dose
Authors: P. Le Souëf
Journal: Allergy (1999)

For a physician to understand how to prescribe appropriate doses of drugs via aerosol requires a basic understanding of the technical issues involved. Drugs are usually prescribed in terms of "nominal dose" (total dose of drug prescribed). This dose is device-specific, as recommended doses are different for different devices. The effective component of the nominal dose is the "lung dose", which is the mass of drug delivered to the lung. A given clinical effect should, in general, be produced by a given lung dose irrespective of the delivery device. However, the effect of a lung dose depends on several factors, including: 1) site of deposition 2) rate of clearance of the drug from airway 3) site of action of the drug. Confirmation that a particular lung dose will produce a desired clinical effect usually requires that a clinical trial be performed. The lung dose should be reflected by data on lung deposition, but interpreting such data requires that the following are considered: 1) Lung deposition figures can be stated in different ways: a) percentage of the nominal dose b) percentage of the mass of drug leaving the aerosol-generating device c) percentage of the mass of drug entering the mouth or nose. 2) The radiation from an inhaled aerosol is attenuated as it leaves the lung. Approaches vary as to how this correction is done, affecting the quoted data on percent deposition. 3) In children, lung deposition is age-dependent, but the effect of age on delivery is different for different devices. There are major differences in the efficiency of delivery for different devices with a range of 6-60%. When "adaptive aerosol delivery" nebulizers become available, they should provide an accurate dose of drug to the lung with very low variability. In summary, the concept of lung dose is useful in understanding the related technical aspects, and it has the potential to allow drugs to be prescribed more accurately.
Systemic mastocytosis: a rare cause of osteoporosis and its response to bisphosphonate treatment
Authors: A Y N Lim
Journal: Annals of the Rheumatic Diseases (2005)

Mastocytosis comprises a heterogeneous group of disorders of mast cell proliferation. Infiltration of multiple organs by mast cells may occur, including skin and bone, with cutaneous and systemic variants being well described. There are few reports of the treatment of osteoporosis, a secondary manifestation of systemic mastocytosis (SM).1–3 We undertook a retrospective analysis of six patients with osteoporosis associated with SM treated with bisphosphonates.

The mean age of the patients was 58 years (range 40–70) and the mean duration of SM was 8 years (range 3–13). All patients had a past history of urticaria pigmentosa and had presented to their general practitioner with back pain. Four patients had vertebral crush fractures on plain radiography. Isotope bone scans in the remaining two patients …
Reduction of leucocyte telomere length in radiographic hand osteoarthritis: a population-based study
Authors: G Zhai, A Aviv, D J Hunter, D J Hart, J P Gardner, M Kimura, X Lu, A M Valdes, T D Spector
Journal: Annals of the Rheumatic Diseases (2006)

Although age is the strongest predictor of osteoarthritis, the exact mechanism underlying this disorder remains elusive.To examine the association between leucocyte telomere length (LTL), a bio-indicator of ageing, and radiographic hand osteoarthritis.An unselected, predominantly female sample from the TwinsUK Adult Twin Registry (Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London, UK) was studied. Radiographs of both hands were obtained with a standard posteroanterior view and assessed for radiographic osteoarthritis according to the Kellgren/Lawrence (K/L) score. Individual radiographic features including osteophytes and joint space narrowing (JSN) were also assessed on a four-point scale using a standard atlas. Hand osteoarthritis was defined radiographically as having >or=3 osteoarthritis-affected joints of both hands (K/L score>or=2). Severity of hand osteoarthritis was indicated semiquantitatively by total K/L scores, osteophytes, JSN scores and proportion of joints affected. Mean LTL was measured by the terminal restriction fragment length using the Southern blot.A total of 1086 Caucasian subjects (mean (SD) age 55 (8.0) years) were studied. LTL was 6.95 (0.64) kb and was inversely correlated with age. After adjustment for age, sex, body mass index and smoking, LTL was significantly shorter by 178 bp in subjects with hand osteoarthritis (n = 160) than in those without (n = 926; p = 0.04). LTL was also significantly associated with semicontinuous measures of osteoarthritis (eg, total K/L score, JSN score, osteophyte score and proportion of joints affected) after adjustment (all p<or=0.02) in a dose-response fashion.Shorter LTL equivalent to around 11 years of annual loss in normal people is associated with radiographic hand osteoarthritis and disease severity, suggesting potential shared mechanisms between osteoarthritis and ageing, and implicating oxidative stress and low-level chronic inflammation in both conditions.
Abstract 57: Impaired Aldehyde Dehydrogenase 2 Activity Contributes To Inhibition Of Mitochondrial Respiration In Hyperglycemic Rats
Authors: Vishal Mali, Mandar Deshpande, Jiang Xu, Shailendra Giri, Xiao-Ping Yang, Suresh Palaniyandi
Journal: Circulation Research (2014)

Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial isozyme of the heart involved in the metabolism of toxic aldehydes produced from oxidative stress. A decrease in ALDH2 levels and activity was reported in the hearts of experimental hyperglycemia along with an increase in 4-hydroxy-2-nonenal (4HNE). 4HNE is produced in the mitochondria upon lipid peroxidation and known to form adduct with mitochondrial proteins. We hypothesize that reduced ALDH2 activity impairs mitochondrial respiration due to 4HNE adducts formation, ultimately resulting in cardiac damage in hyperglycemia. A single dose (65 mg/kg; i.p.) of streptozotocin in rats resulted in hyperglycemia with a blood glucose level of 443 ± 9 mg/dl versus 121 ± 7 mg/dl in control animals, p&lt;0.0001. N=7-11 in both groups. After 6 months of hyperglycemia, heart function was recorded and the rats were sacrificed. Increases in cardiomyocyte cross sectional area (446 ± 32 μm 2 Vs 221 ± 10 μm 2 ; p&lt;0.0001) indicated cardiac hypertrophy in diabetic rats. Both diastolic and systolic dysfunctions were recorded with diabetic rats compared to controls. For instance, % fractional shortening was lower in diabetic group versus control; (p&lt;0.0001). Most importantly, myocardial ALDH2 activity and levels were reduced and immunostaining for 4HNE protein adducts was increased in diabetic hearts compared to controls. The mitochondrial oxygen consumption rate (OCR), an index of mitochondrial respiration, was decreased in mitochondria isolated from diabetic hearts compared to controls (p&lt;0.0001). To check the direct effect of 4HNE and ALDH2 inhibition, we treated H9C2 cardiomyocytes with 4HNE and disufiram, an ALDH inhibitor, respectively, which reduced mitochondrial respiration (p&lt;0.0001) and cell viability (p&lt;0.0001) along with reduced ALDH2 activity and increased 4HNE adducts formation. We conclude that chronic hyperglycemia-induced 4HNE accumulation due to low ALDH2 activity in the heart leads to defective mitochondrial respiration and cardiac damage and dysfunction.
Preventive but Not Late Amiloride Therapy Reduces Morbidity and Mortality of Lung Disease in βENaC-overexpressing Mice
Authors: Zhe Zhou, Diana Treis, Susanne C. Schubert, Maria Harm, Jolanthe Schatterny, Stephanie Hirtz, Julia Duerr, Richard C. Boucher, Marcus A. Mall
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Increased airway Na(+) absorption mediated by epithelial Na(+) channels (ENaC) is a characteristic abnormality in the pathogenesis of cystic fibrosis (CF) lung disease. However, inhalation therapy with the ENaC blocker amiloride did not have therapeutic benefits in patients with CF with established lung disease.We hypothesized that preventive inhibition of increased Na(+) absorption in a structurally normal lung may be required for effective therapy of CF lung disease in vivo, and that therapeutic effects of late amiloride intervention may be impeded by the chronic disease process.To test this hypothesis in vivo, we used the betaENaC-overexpression mouse as a model of CF lung disease and determined therapeutic effects of preventive versus late amiloride therapy on survival, airway mucus plugging, chronic bronchitis, and airway remodeling.We show that early intervention, i.e., from the first day of life, with the intranasal administration of amiloride significantly reduced pulmonary mortality, airway mucus obstruction, epithelial necrosis, goblet cell metaplasia, and airway inflammation in betaENaC-overexpressing mice. In contrast, consistent with previous human trials in patients with CF, amiloride administration did not have benefits if treatment was started after the development of CF-like lung disease in betaENaC-overexpressing mice.We conclude that preventive inhibition of increased airway Na(+) absorption provides an effective therapy for CF-like lung disease in vivo. These results suggest that amiloride therapy may be an effective preventive therapy for patients with CF if initiated early in life before the onset of lung disease.
Value of FDG-PET in detecting residual or recurrent nonsmall cell lung cancer
Authors: T Bury, JL Corhay, B Duysinx, F Daenen, B Ghaye, N Barthelemy, P Rigo, P Bartsch
Journal: European Respiratory Journal (1999)

In order to evaluate the usefulness of 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the assessment of therapeutic effects, a study was performed before and after therapy in 126 patients with non-small cell lung cancer (NSCLC) codified stage I to stage IIIB. Treatment with an early curative result was given in 58 patients, whereas in 68 cases it was limited to palliation. During the treatment follow-up period (8-40 months), each patient was evaluated every 3 months by clinical examination and &lt; or =6 months by imaging techniques (PET and computed tomography (CT)). A diagnosis of persistent or recurrent tumour was established by means of pathological analysis in 31 patients and by clinical evolution and subsequent imaging progression in 29 other patients. PET showed increased FDG uptake in all cases (n = 60) of persistent or recurrent tumour, whereas CT was nonspecific in 17 cases. Conversely, there were five false positive cases via PET imaging and three via CT. In detecting residual or recurrent NSCLC, PET had a sensitivity of 100% and specificity of 92%, whereas CT had a sensitivity and specificity of 71% and 95% respectively. In conclusion, 18-fluorodeoxyglucose positron emission tomography correctly identified response to therapy in 96% (121 of 126) of patients. Positron emission tomography appears to be more accurate (p = 0.05) than conventional imaging in distinguishing persistent or recurrent tumour from fibrotic scar in patients undergoing treatment for non-small cell lung cancer.
The Pathobiology of Alzheimer's Disease
Authors: George G. Glenner
Journal: Annual Review of Medicine (1989)

The discovery of β protein, the major component of the amyloid fibrils of the plaques and cerebral vessels and of the paired helical filaments of the neurofibrillary tangles, has provided a means to decipher the pathogenesis of Alzheimer's disease. The same lesions in aged Down's syndrome individuals have also been shown to be composed of β protein. Gene probes localize the gene for β protein, as well as that for familial Alzheimer's disease, to chromosome 21, but these genes are not linked. A study of posttranslational modifications of the 695-amino-acid β-protein gene precursor, with specific reference to abnormal proteolysis, may provide insights into the cause of the amyloidotic lesions of Alzheimer's disease and the means of arresting them.
Genetic Sampling Error of Distance (δμ)2 and Variation in Mutation Rate Among Microsatellite Loci
Authors: Lev A. Zhivotovsky, David B. Goldstein, Marcus W. Feldman
Journal: Molecular Biology and Evolution (2001)

An expression is obtained for the time-dependent variance of the microsatellite genetic distance (δμ)2 when the mutation rate is allowed to vary randomly among loci. An estimator is presented for the coefficient of variation, Cw, in the mutation rate. Estimated values of Cw from genetic distances between African and non-African populations were less than 100%. Caveats to this conclusion are discussed.
Human Insulin Secretion: An Integrated Approach
Authors: D Porte, J D Bagdade
Journal: Annual Review of Medicine (1970)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Gender Gap in Aortic Cholesterol Accumulation in Cholesterol-Clamped Rabbits
Authors: Pernille Holm, Heidi L. Andersen, Gry Arrøe, Steen Stender
Journal: Circulation (1998)

Background —The purpose of the present study was to investigate plasma lipid–independent mechanisms for the sex difference in the development of atherosclerosis. Methods and Results —In the first experiment, 20 male and 20 female rabbits were balloon-injured in the middle thoracic aorta and maintained at the same plasma cholesterol level of ≈25 mmol/L by use of individualized cholesterol feeding for 13 weeks. In the undamaged aorta, female rabbits had accumulated less than half the amount of cholesterol found in male rabbits ( P &lt;0.05). In the balloon-injured aorta, cholesterol accumulation was 3- to 4-fold higher than in the undamaged aorta, with no difference between groups. When cholesterol accumulation data for the balloon-injured aorta were separately assessed for blue (deendothelialized) and white (reendothelialized) tissue, blue tissue surprisingly revealed a reverse gender gap, ie, a significantly higher accumulation of cholesterol in females than in males ( P &lt;0.05). White tissue, which constituted the majority of the balloon-injured area, showed no difference in aortic cholesterol accumulation between groups. In the second experiment, 6 male and 6 female rabbits were fed standard rabbit pellets and 6 male and 6 female rabbits were fed a 0.5% cholesterol-enriched chow for 2 weeks. Mononuclear cell binding was 5-fold higher in aortic segments from hypercholesterolemic than from normocholesterolemic rabbits ( P &lt;0.001). In hypercholesterolemic rabbits, cell binding was significantly lower in female than in male rabbits ( P &lt;0.05) and showed higher values in atherosclerosis-prone regions. These differences were not found in normocholesterolemic animals. Conclusions —The present results suggest that female atheroprotection is independent of sex differences in plasma cholesterol but vitally dependent on the state of the arterial endothelium and involves mononuclear-endothelial cell adhesion as an early step.
Good Enough: A Primer on the Analysis and Interpretation of Noninferiority Trials
Authors: Sanjay Kaul, George A. Diamond
Journal: Annals of Internal Medicine (2006)

Active-control noninferiority trials are being performed with increasing frequency when standard placebo-controlled trials are considered unethical. Three attributes are optimally required to establish noninferiority: 1) The treatment under consideration exhibits therapeutic noninferiority to the active control; 2) the treatment would exhibit therapeutic efficacy in a placebo-controlled trial if such a trial were to be performed; and 3) the treatment offers ancillary advantages in safety, tolerability, cost, or convenience. Trials designed to show noninferiority require an appropriate reference population, a proven active control and dose, a high level of adherence to treatment, and adequate statistical power. However, the formal analysis of such trials is founded on several assumptions that cannot be validated explicitly. These assumptions are evaluated in the context of 8 recently published noninferiority trials. The analyses in this paper confirm the establishment of noninferiority in only 4 of the 8 trials. The authors conclude that if noninferiority trials are to be applied to clinical and regulatory decisions about the marketing and use of new treatments, these assumptions must be made explicit and their influence on the resultant conclusions assessed rigorously.
Reduction of ACE Activity Is Insufficient to Decrease Microalbuminuria in Normotensive Patients With Type 1 Diabetes
Authors: Mats Bojestig, Bengt E. Karlberg, Torbjörn Lindström, Fredrik H. Nystrom
Journal: Diabetes Care (2001)

OBJECTIVE—To study whether administration of 1.25 and 5.0 mg ramipril daily, compared with placebo treatment, reduces the urinary albumin excretion rate (UAER) in normotensive patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—Ramipril was administered double blind at two different doses (1.25 [n = 19] and 5.0 mg [n = 18]), and compared with placebo (n = 18) after a single-blind placebo period of 1–4 weeks. The patients (total, n = 55; women, n = 14) were followed for 2 years. To document an effect on the renin-angiotensin system, ACE activity and plasma-renin activity (PRA) were measured. In addition, 24-h ambulatory blood pressure (BP) was recorded at baseline and repeated after 1 and 2 years using a Spacelab 90207 ambulatory BP recording device (Spacelab, Redmont, CA). RESULTS—Both doses of ramipril were sufficient to reduce ACE activity and to increase PRA significantly as compared with placebo (P &amp;lt; 0.05 for both). On the other hand, neither ambulatory nor clinic BP was affected by either dose of ramipril compared with the placebo group. There was no progression of UAER in the placebo group during the 2 years of the study. Analysis of covariance showed no differences in UAER between the three treatment groups at year 1 (P = 0.94) or year 2 (P = 0.97), after adjusting for baseline. Furthermore, there were no statistically significant changes from baseline UAER within any of the three treatment groups. CONCLUSIONS—Treatment with ramipril did not affect microalbuminuria or clinic or ambulatory BP in this study. On the basis of the present study, we question the clinical use of ACE inhibitors in stably normotensive patients with type 1 diabetes and microalbuminuria in whom a concomitant reduction in BP is not demonstrated.
Charities fear that standardised tobacco packaging may not be implemented before next election
Authors: A. O'Dowd
Journal: BMJ (2014)

Experts and charities have urged the government to move quickly on its plans to introduce standardised packaging of cigarette and tobacco products.

In a written ministerial statement published on 26 June, Jane Ellison, public health minister for England, said that the government was publishing proposals for introducing the regulations that will govern standardised packaging.

These regulations set out the minimum size of government health warnings, as well as the size and position of tobacco branding on packaging. They are published as a short …
Crucial Role for Ecto-5′-Nucleotidase (CD73) in Vascular Leakage during Hypoxia
Authors: Linda F. Thompson, Holger K. Eltzschig, Juan C. Ibla, C. Justin Van De Wiele, Regina Resta, Julio C. Morote-Garcia, Sean P. Colgan
Journal: The Journal of Experimental Medicine (2004)

Extracellular adenosine has been widely implicated in adaptive responses to hypoxia. The generation of extracellular adenosine involves phosphohydrolysis of adenine nucleotide intermediates, and is regulated by the terminal enzymatic step catalyzed by ecto-5′-nucleotidase (CD73). Guided by previous work indicating that hypoxia-induced vascular leakage is, at least in part, controlled by adenosine, we generated mice with a targeted disruption of the third coding exon of Cd73 to test the hypothesis that CD73-generated extracellular adenosine functions in an innate protective pathway for hypoxia-induced vascular leakage. Cd73−/− mice bred and gained weight normally, and appeared to have an intact immune system. However, vascular leakage was significantly increased in multiple organs, and after subjection to normobaric hypoxia (8% O2), Cd73−/− mice manifested fulminant vascular leakage, particularly prevalent in the lung. Histological examination of lungs from hypoxic Cd73−/− mice revealed perivascular interstitial edema associated with inflammatory infiltrates surrounding larger pulmonary vessels. Vascular leakage secondary to hypoxia was reversed in part by adenosine receptor agonists or reconstitution with soluble 5′-nucleotidase. Together, our studies identify CD73 as a critical mediator of vascular leakage in vivo.
Rosette formation between human lymphocytes and sheep erythrocytes. Inhibition of rosette formation by specific glycopeptides.
Authors: D H Boldt, J P Armstrong
Journal: Journal of Clinical Investigation (1976)

Rosette formation with unsensitized sheep erythrocytes is a characteristic of human thymus dependent lymphocytes. Release of glycopeptides from the sheep erythrocyte by trypsin reduces rosette formation. These tryptic glycopeptides inhibit rosette formation by untrypsinized sheep erythrocytes; this suggests that rosetting is mediated by erythrocyte surface glycopeptides. To investigate the molecular nature of this interaction, we examined the abilities of various model compounds to act as haptenic inhibitors of rosette formation. Inhibition is given by glycopeptides bearing oligosaccharide units rich in sialic acid, galactose, N-acetylglucosamine, and mannose linked to asparagine residues through glycosylamine bonds. Among compounds tested, fetuin glycopeptide is most effective, but human transferrin glycopeptide and human erythrocyte glycopeptide I also inhibit rosette formation. Other compounds including human erythrocyte glycopeptide II, human IgG glycopeptide, lacto-N-neotetraose, 3'- and 6'-sialyllactose show no significant inhibition. Neither sialic acid, galactose, manose, nor N-acetyl-glucosamine alone inhibits rosette formation. Stepwise degradation of fetuin glycopeptide established the galactose residues as important determinants of inhibitory activity. Fetuin glycopeptide blocks rosette formation when added to a suspension of human lymphocytes and sheep erythrocytes or when preincubated with human lymphocytes, but not when preincubated with sheep erythrocytes. Studies of the binding of [3H] fetuin glycopeptide to normal lymphocytes demonstrate 7.5 x 10(6) saturable binding sites per cell. No saturable binding of this compound to sheep erythrocyte membranes is observed. Compared to normals, lymphocytes from patients with chronic lymphatic leukemia demonstrate decreased fetuin glycopeptide binding with a mean of 0.9 x 10(6) sites per cell. This decreased binding correlates with the impaired ability of these cells to form rosettes. The data suggest that fetuin glycopeptide inhibits rosette formation by binding to the thymus-dependent cell where competition occurs with sheep erythrocytes for specific lymphocyte surface receptors.
Second Cancers Among 104760 Survivors of Cervical Cancer: Evaluation of Long-Term Risk
Authors: A. K. Chaturvedi, E. A. Engels, E. S. Gilbert, B. E. Chen, H. Storm, C. F. Lynch, P. Hall, F. Langmark, E. Pukkala, M. Kaijser, M. Andersson, S. D. Fossa, H. Joensuu, J. D. Boice, R. A. Kleinerman, L. B. Travis
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundGiven the extended survival of patients diagnosed with cervical cancer, the large number of these women treated with radiotherapy, and the presence in this population of established cancer risk factors such as human papillomavirus (HPV) infection and cigarette smoking, it is important to clarify long-term trends in second cancer risk.