tbuckley/cabot-search huggingface dataset:
Liposomes as sterile preparations and limitations of sterilisation techniques in liposomal manufacturing
Authors: Ming-Ren Toh, Gigi N.C. Chiu
Journal: Asian Journal of Pharmaceutical Sciences (2013)

Liposomes have been widely researched as a delivery system and there have been many manufacturing techniques used in the production of liposomal preparations, the most common being extrusion method which will be introduced in this paper. However because of the unique properties of liposomes and their susceptibility to chemical and physical degradation, sterilisation remains an unresolved issue in the manufacturing of liposome-based formulations. It is especially pertinent in the pharmaceutical industry where liposomes are commonly prepared for intravenous administration. Currently, filtration and aseptic manufacturing are recommended for the preparation of sterile liposomal products. Newer aseptic manufacturing techniques such as dense gas techniques have been devised to eliminate the need for terminal sterilisation. This paper will highlight the limitations of the conventional techniques that are specific to the liposome preparation under the respective sterilisation conditions specified by the 2011 British Pharmacopoeia to achieve 10−6 Sterility Assurance Level, as well as modifications incorporated in the newer sterilisation technologies to overcome these limitations. This paper will introduce these techniques in brief, including their advantages and limitations.
Retraction: Disruption of the NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Gene in Mice Causes Myelogenous Hyperplasia
Authors: Delwin J. Long, Amos Gaikwad, Asha Multani, Sen Pathak, Charles A. Montgomery, Frank J. Gonzalez, Anil K. Jaiswal
Journal: Cancer Research (2018)

NAD(P)H:quinone oxidoreductase1 (NQO1) is a cytosolic protein that reduces and detoxifies quinones and their derivatives, thus protecting cells against redox cycling and oxidative stress. Disruption of the NQO1 gene in mice caused myeloid hyperplasia of bone marrow and highly significant increases in blood neutrophils, eosinophils, and basophils. NQO1-null mice also showed a decrease in lymphocytes and WBCs as compared with wild-type mice. Various techniques also demonstrated an increase in megakaryocytes without an increase in blood platelets. Histological analysis of liver, kidney, spleen, and thymus did not demonstrate a difference between wild-type and NQO1-null mice or a sign of infection. Blood cultures and urine analysis also did not demonstrate any sign of infection in NQO1-null and wild-type mice. Additional analysis of the bone marrow from NQO1-null mice revealed that loss of NQO1 alters the intracellular redox status because of accumulation of NAD(P)H, cofactors for NQO1. This causes a reduction in the levels of pyridine nucleotides and tumor suppressor proteins p53 and p73, and a decrease in apoptosis. The decrease in apoptosis causes myelogenous hyperplasia in NQO1-null mice. These results demonstrate that NQO1 acts as an endogenous factor in the protection against myelogenous hyperplasia. This is significant because 2-4% of human individuals without known abnormalities, and >25% of individuals with benzene poisoning and acute myelogenic leukemia are homozygous for a mutant allele (P187S) of NQO1 and lack NQO1 protein/activity.
Continuous Positive Airway Pressure Treatment of Mild to Moderate Obstructive Sleep Apnea Reduces Cardiovascular Risk
Authors: Nikolaus J. Buchner, Bernd M. Sanner, Jan Borgel, Lars C. Rump
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Obstructive sleep apnea (OSA) is linked to increased cardiovascular risk, but the impact of mild forms of OSA and their treatment on cardiovascular outcomes remains controversial.To prospectively investigate cardiovascular outcomes in treated versus untreated patients with OSA.Consecutive sleep laboratory patients with all degrees of OSA were included. Endpoints were nonfatal (myocardial infarction, stroke, and acute coronary syndrome requiring revascularization procedures) and fatal (death from myocardial infarction or stroke) cardiovascular events.Comparison of event-free survival rates in treated versus untreated patients (Kaplan-Meier estimates, log-rank test). Of 449 patients enrolled (age, 56.0 +/- 10.5 years; body mass index, 30.8 +/- 5.4 kg/m(2)), 364 patients received OSA treatment, and 85 patients remained untreated. Median follow-up was 72.0 months (range, 1-156). Mean apnea-hypopnea index before treatment was 30.9 +/- 21.8/hour in treated and 15.3 +/- 13.0/hour in untreated patients, but there were no differences in cardiovascular comorbidities or risk factors. In patients with mild-moderate OSA (n = 288), events were more frequent in untreated patients (estimated event-free survival at 10 yr, 51.8 vs. 80.3% [P < 0.001]; absolute risk reduction, 28.5%; number needed to treat to prevent one event/10 yr, 3.5). After adjustment for age, gender, cardiovascular risk factors, and comorbidities at baseline, OSA treatment was an independent predictor for events (hazard ratio, 0.36; 95% confidence interval, 0.21-0.62; P < 0.001).OSA treatment was associated with a cardiovascular risk reduction of 64% independent from age and preexisting cardiovascular comorbidities. OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA.
Upper airway. 3: Sinonasal involvement in chronic obstructive pulmonary disease
Authors: J R Hurst
Journal: Thorax (2009)

This review presents the evidence that chronic obstructive pulmonary disease (COPD) is associated with significant sinonasal symptoms, inflammation and airway obstruction. Upper airway symptoms in COPD cause impairment to quality of life. The severity of upper airway involvement relates to that present in the lower airway, suggesting that the nose may be used to model the lung in COPD. More importantly, relationships between upper and lower airway bacteria and inflammation, and the association between sinusitis and treatment failure at exacerbation raise the possibility that nasal intervention in COPD may not only improve health status but may also affect important clinical outcomes such as exacerbation frequency.
Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study
Authors: Michael J Koren, Rob Scott, Jae B Kim, Beat Knusel, Thomas Liu, Lei Lei, Michael Bolognese, Scott M Wasserman
Journal: The Lancet (2012)
Clinical COPD phenotypes: a novel approach using principal component and cluster analyses
Authors: P-R. Burgel, J-L. Paillasseur, D. Caillaud, I. Tillie-Leblond, P. Chanez, R. Escamilla, I. Court-Fortune, T. Perez, P. Carré, N. Roche
Journal: European Respiratory Journal (2010)

Classification of chronic obstructive pulmonary disease (COPD) is usually based on the severity of airflow limitation, which may not reflect phenotypic heterogeneity. Here, we sought to identify COPD phenotypes using multiple clinical variables. COPD subjects recruited in a French multicentre cohort were characterised using a standardised process. Principal component analysis (PCA) was performed using eight variables selected for their relevance to COPD: age, cumulative smoking, forced expiratory volume in 1 s (FEV(1)) (% predicted), body mass index, exacerbations, dyspnoea (modified Medical Research Council scale), health status (St George's Respiratory Questionnaire) and depressive symptoms (hospital anxiety and depression scale). Patient classification was performed using cluster analysis based on PCA-transformed data. 322 COPD subjects were analysed: 77% were male; median (interquartile range) age was 65.0 (58.0-73.0) yrs; FEV(1) was 48.9 (34.1-66.3)% pred; and 21, 135, 107 and 59 subjects were classified in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1, 2, 3 and 4, respectively. PCA showed that three independent components accounted for 61% of variance. PCA-based cluster analysis resulted in the classification of subjects into four clinical phenotypes that could not be identified using GOLD classification. Importantly, subjects with comparable airflow limitation (FEV(1)) belonged to different phenotypes and had marked differences in age, symptoms, comorbidities and predicted mortality. These analyses underscore the need for novel multidimensional COPD classification for improving patient care and quality of clinical trials.
Relationship Between <i>MYCN</i> Copy Number and Expression in Rhabdomyosarcomas and Correlation With Adverse Prognosis in the Alveolar Subtype
Authors: Daniel Williamson, Yong-Jie Lu, Tony Gordon, Raf Sciot, Anna Kelsey, Cyril Fisher, Christopher Poremba, John Anderson, Kathy Pritchard-Jones, Janet Shipley
Journal: Journal of Clinical Oncology (2005)

Amplification of the transcription factor MYCN is an important molecular diagnostic tool in stratifying treatment for neuroblastoma. Increased copy number and overexpression of MYCN in the pediatric cancer rhabdomyosarcoma has been described in a number of small studies with conflicting conclusions about its association with clinicopathologic characteristics. We aimed to study the phenomenon in the largest series to date.Using quantitative polymerase chain reaction, we measured MYCN copy number and expression levels in rhabdomyosarcoma samples from 113 and 92 individuals with a confirmed diagnosis of rhabdomyosarcoma, respectively.Increased copy number of MYCN was found to be a feature of both the embryonal and alveolar subtypes. The copy number and expression levels were significantly greater in the alveolar subtype, although the range of expression in both subtypes spanned several orders of magnitude. MYCN copy number showed a significant correlation with expression in the alveolar subtype; this relationship between copy number and expression could be modeled as a logarithmic function. It is notable that relatively high expression frequently occurred in embryonal rhabdomyosarcoma without high copy number and that low expression was found in some cases with high copy number. In patients with alveolar rhabdomyosarcoma, overexpression (greater than median) or gain of genomic copies of MYCN were significantly associated with adverse outcome.MYCN deregulation is a feature of rhabdomyosarcoma tumorigenesis, defines groups of patients with a poor prognosis, and is a potential target for novel therapies.
Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study
Authors: J. Malcolm O. Arnold, Salim Yusuf, James Young, James Mathew, David Johnstone, Alvaro Avezum, Eva Lonn, Janice Pogue, Jackie Bosch
Journal: Circulation (2003)

Background— Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development of heart failure in high-risk patients without known low ejection fraction or heart failure. Methods and Results— We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and was associated with a 4.01-fold increase in the risk of death ( P &lt;0.0001). The rate of developing heart failure was significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy (1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5% to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87; P &lt;0.0001). Ramipril consistently reduced heart failure rate both in those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative risk, 0.67) compared with those below the median (relative risk, 0.91; P =0.024 for interaction of group by treatment). Conclusion— Ramipril significantly reduces the rate of development of heart failure in patients at high risk of cardiovascular events.
FEV<sub>1</sub> Decline in Patients with Chronic Obstructive Pulmonary Disease Associated with Biomass Exposure
Authors: Alejandra Ramírez-Venegas, Raul H. Sansores, Roger H. Quintana-Carrillo, Monica Velázquez-Uncal, Rafael J. Hernandez-Zenteno, Candelaria Sánchez-Romero, Alejandra Velazquez-Montero, Fernando Flores-Trujillo
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Biomass exposure is an important risk factor for chronic obstructive pulmonary disease (COPD). However, the time-course behavior of FEV1 in subjects exposed to biomass is unknown.We undertook this study to determine the FEV1 rate decline in subjects exposed to biomass.Pulmonary function was assessed every year in a Mexican cohort of patients with COPD associated with biomass or tobacco during a 15-year follow-up period.The mean rate of decline was significantly lower for the biomass exposure COPD group (BE-COPD) than for the tobacco smoke COPD group (TS-COPD) (23 vs. 42 ml, respectively; P < 0.01). Of the TS-COPD group, 11% were rapid decliners, whereas only one rapid decliner was found in the BE-COPD group; 69 and 21% of smokers versus 17 and 83% of the BE-COPD group were slow decliners and sustainers, respectively. A higher FEV1 both as % predicted and milliliters was a predictive factor for decline for BE-COPD and TS-COPD, whereas reversibility to bronchodilator was a predictive factor for both groups when adjusted by FEV1% predicted and only for the TS-COPD group when adjusted by milliliters.In the biomass exposure COPD group the rate of FEV1 decline is slower and shows a more homogeneous rate of decline over time in comparison with smokers. The rapid rate of FEV1 decline is a rare feature of biomass-induced airflow limitation.
Endoscopic release of fascia in CECS
Authors: H Lohrer, T Nauck
Journal: British Journal of Sports Medicine (2011)

Lecture 11 Introduction Endoscopic treatment of intractable chronic exertional compartment syndrome (CECS) of the lower leg in athletes is reported rarely and anecdotically. Methods We developed a minimally invasive, endoscopically assisted technique for release of CECS of the lower leg. Follow-up was performed by telephone interview 47 months (range 5 months to 7 years) after surgery. Results 38 compartments were released in 17 athletes (19 deep posterior, 16 anterior and 3 lateral compartments). All these patients were available for follow-up analyses. No complications were seen following anterior and lateral compartment decompression. Contrasting to this, two patients operated under tourniquet for deep posterior compartment syndrome suffered intraoperative haemorrhage and open revision surgery was required. No complications due to vascular injuries were seen in all further patients when the tourniquet was omitted. Ten patients returned to previous sport activity. At follow-up, results were good or excellent in 10 out of 17 patients. Visual analogue pain scale improved from 7.4 (range 5–9) before surgery to 2.4 (range 1–8) at follow-up (p = 0.0005). Discussion Our data indicate that endoscopic release for CECS of the lower leg is feasible und successful. The procedure is at risk for vascular complications during deep posterior compartment fasciotomy. Consequently, it is emphasised to perform the procedure without tourniquet.
Open label trial of anakinra in active ankylosing spondylitis over 24 weeks
Authors: H Haibel
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To examine the therapeutic effect of the interleukin 1 (IL1) receptor antagonist anakinra in ankylosing spondylitis in an open label trial. <b>Methods:</b> Anakinra (100 mg) was given subcutaneously daily over 24 weeks to 20 NSAID refractory patients with ankylosing spondylitis. Thirteen completed the study. Clinical outcome assessments included disease activity, function, metrology, patients' and physicians' global assessment, peripheral joint assessment, quality of life, and C reactive protein. Dynamic magnetic resonance imaging (MRI) of sacroiliac joints or spine, using gadolinium DTPA as contrast agent, was done before treatment in 15/20 patients, and in 10 patients at study end. The primary end point was the Bath ankylosing spondylitis disease activity index (BASDAI) and ASAS (assessments in ankylosing spondylitis) short term response after six months. <b>Results:</b> Using an intention to treat analysis, an ASAS 20% response (ASAS 20) was achieved in five patients, ASAS 40 in four, and ASAS 70 in two after 24 weeks. There was no change in mean C reactive protein (22.3 <i>v</i> 33.1 mg/l) or in MRI score. The drug was well tolerated. Injection site reaction was the commonest adverse event. <b>Conclusions:</b> In this open study, anakinra improved spinal symptoms in only a small subgroup of patients with active ankylosing spondylitis.
Alpha fetoprotein in metastatic gastric carcinoma
Authors: J. Kelleher, S. Colum, C. Doyle, T. Hennessy, M. J. Whelton
Journal: Gut (1974)

Two patients with primary gastric carcinoma and multiple liver secondaries who developed alpha fetoprotein in the serum are reported. Both had clinical features which were initially suggestive of primary liver cell carcinoma. Fetoprotein levels fell after ligation of the hepatic artery in one patient. Alpha fetoprotein may occur in the serum of adult patients with tumours of the foregut, other than primary liver cell carcinoma, when such tumours have metastasized to the liver.
Amygdaloid Nucleus Syndrome and Dehumanization Syndrome
Authors: Miller de Paiva
Journal: Psychotherapy and Psychosomatics (1979)

Through statistical tests 3 groups of impulsive-aggressive patients were studied: group 1, 100 individuals with temporal dysrhythmia; group 2, 18 individuals with temporal dysrhythmia submitted either to group analytical therapy or to psychoanalysis; group 3, 25 impulsive-aggressive individuals. Moreover the author differentiates between the amygdaloid nucleus and dehumanization syndromes, through psychoanalytical or psychiatric studies, and stresses the importance of the molding periods in relation to social factors (frustration-aggression-injustice). Amygdalotomy of the hippocampus was suggested in special cases.
Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study
Authors: R. de Heus, B. W. Mol, J.-J. H M Erwich, H. P van Geijn, W. J Gyselaers, M. Hanssens, L. Harmark, C. D van Holsbeke, J. J Duvekot, F. F A M Schobben, H. Wolf, G. H A Visser
Journal: BMJ (2009)

<b>Objective</b> To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations. <b>Design</b> Prospective cohort study. <b>Setting</b> 28 hospitals in the Netherlands and Belgium. <b>Participants</b> 1920 consecutive women treated with tocolytics for threatened preterm labour. <b>Main outcome measures</b> Maternal adverse events (those suspected of being causally related to treatment were considered adverse drug reactions) leading to cessation of treatment. <b>Results</b> An independent panel evaluated the recorded adverse events, without knowledge of the type of tocolytic used. Of the 1920 women treated with tocolytics, 1327 received a single course of treatment (69.1%), 282 sequential courses (14.7%), and 311 combined courses (16.2%). Adverse drug reactions were categorised as serious or mild in 14 cases each. The overall incidence of serious adverse drug reaction was 0.7%. Compared with atosiban, the relative risk of an adverse drug reaction for single treatment with a β adrenoceptor agonist was 22.0 (95% confidence interval 3.6 to 138.0) and for single treatment with a calcium antagonist was 12 (1.9 to 69). Multiple drug tocolysis led to five serious adverse drug reactions (1.6%). Multiple gestation, preterm rupture of membranes, and comorbidity were not independent risk factors for adverse drug reactions. <b>Conclusions</b> The use of β adrenoceptor agonists or multiple tocolytics for preventing preterm birth is associated with a high incidence of serious adverse drug reactions. Indometacin and atosiban were the only drugs not associated with serious adverse drug reactions. A direct comparison of the effectiveness of nifedipine and atosiban in postponing preterm delivery is needed.
Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells
Authors: Paul T. Brinkkoetter, Paul Olivier, Jimmy S. Wu, Scott Henderson, Ronald D. Krofft, Jeffrey W. Pippin, David Hockenbery, James M. Roberts, Stuart J. Shankland
Journal: Journal of Clinical Investigation (2009)

Cyclin I is an atypical cyclin because it is most abundant in postmitotic cells. We previously showed that cyclin I does not regulate proliferation, but rather controls survival of podocytes, terminally differentiated epithelial cells that are essential for the structural and functional integrity of kidney glomeruli. Here, we investigated the mechanism by which cyclin I safeguards against apoptosis and found that cyclin I bound and activated cyclin-dependent kinase 5 (Cdk5) in isolated mouse podocytes and neurons. Cdk5 activity was reduced in glomeruli and brain lysates from cyclin I-deficient mice, and inhibition of Cdk5 increased in vitro the susceptibility to apoptosis in response to cellular damage. In addition, levels of the prosurvival proteins Bcl-2 and Bcl-XL were reduced in podocytes and neurons from cyclin I-deficient mice, and restoration of Bcl-2 or Bcl-XL expression prevented injury-induced apoptosis. Furthermore, we found that levels of phosphorylated MEK1/2 and ERK1/2 were decreased in cyclin I-deficient podocytes and that inhibition of MEK1/2 restored Bcl2 and Bcl-XL protein levels. Of interest, this pathway was also defective in mice with experimental glomerulonephritis. Taken together, these data suggest that a cyclin I-Cdk5 complex forms a critical antiapoptotic factor in terminally differentiated cells that functions via MAPK signaling to modulate levels of the prosurvival proteins Bcl-2 and Bcl-XL.