bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Global Diversion of Pharmaceutical Drugs Non‐medical use and diversion of psychotropic prescription drugs in North America: a review of sourcing routes and control measures
Authors: Fischer Benedikt , Bibby Meagan , Bouchard Martin 
Published: September 2010

ABSTRACTAims  North America features some of the world's highest consumption levels for controlled psychoactive prescription drugs (PPDs; e.g. prescription opioids, benzodiazepines, stimulants), with non‐medical use and related harms (e.g. morbidity, mortality) rising in key populations in recent years. While the determinants, characteristics and impacts of these ‘use’ problems are increasingly well documented, little is known about the ‘supply’ side of non‐medical PPD use, much of which is facilitated by ‘diversion’ as a key sourcing route. This paper provides a select review of the phenomenon of PPD diversion in North America, also considering interventions and policy implications.Methods  A conceptual and empirical review of select‐peer‐ and non‐peer‐reviewed research literature from 1991 to 2010 focusing upon PPD diversion in North America was conducted.Results  The phenomenon of PPD diversion is heterogeneous. Especially among general populations, a large proportion of PPDs for non‐medical use are obtained from friends or family members. Other PPD diversion routes involve ‘double doctoring’ or ‘prescription shopping’; street drug markets; drug thefts, prescription forgeries or fraud; as well as PPD purchases from the internet.Conclusions  The distinct nature and heterogeneity make PPD diversion a complex and difficult target for interventions. Prescription monitoring programs (PMPs) appear to reduce overall PPD use, yet their impact on reducing diversion or non‐medical use is not clear. Law enforcement is unlikely to reach PPD diversion effectively. Effective reduction will probably require reductions in overall PPD consumption volumes, although such will need to be accomplished without compromising standards of good medical (e.g. pain) care.
Why target early adolescents and parents in alcohol prevention? The mediating effects of self‐control, rules and attitudes about alcohol use
Authors: Koning Ina M. , van den Eijnden Regina J. J. M. , Engels Rutger C. M. E. , Verdurmen Jacqueline E. E. , Vollebergh Wilma A. M. 
Published: September 2010

ABSTRACTAims  To examine the effects of a parent and student intervention offered separately and simultaneously (PAS) on onset of weekly drinking via its putative mediators.Design  A randomized trial with four conditions; (1) parent intervention, (2) student intervention, (3) combined parent–student intervention and (4) control group.Setting  High schools selected randomly, located in different areas.Participants  A total of 2937 early adolescents (mean age = 12.6, standard deviation = 0.49) and their parents.Measurements  Mediation effects were analysed using pretest data and two follow‐up measurements (10 and 22 months after baseline). A path model was estimated (Mplus) to examine the effect of the interventions on adolescent‐reported mediators (self‐control, perceived parental rules and attitudes about alcohol) and parent‐reported mediators (parental rules and attitudes about alcohol). Outcome was onset of weekly drinking.Findings  The parent intervention modified rules and attitudes about alcohol as reported by parents. An indirect effect of the parent intervention via parental rules was found. The combined intervention affected both adolescent‐reported and parent‐reported rules and attitudes about alcohol and adolescents' perceived self‐control, yet only perceived rules and self‐efficacy, as reported by adolescents, and parental attitudes mediated the association between the combined intervention and onset of weekly drinking. No significant effects were found of the separate student intervention on the mediating factors.Conclusions  The PAS programme proved to be effective as predicted by the theoretical assumptions underlying the interventions. Interventions with parents and adolescents to prevent adolescent alcohol consumption may usefully target parental rules about alcohol and adolescents' self‐confidence.
The calpain inhibitor calpeptin prevents bleomycin-induced pulmonary fibrosis in mice
Authors: Tabata C , Tabata R , Nakano T 
Published: September 2010

SummaryPulmonary fibrosis is characterized by progressive worsening of pulmonary function leading to a high incidence of death. Currently, however, there has been little progress in therapeutic strategies for pulmonary fibrosis. There have been several reports on cytokines being associated with lung fibrosis, including interleukin (IL)-6 and transforming growth factor (TGF)-β1. We reported recently that two substances (ATRA and thalidomide) have preventive effects on pulmonary fibrosis by inhibiting IL-6-dependent proliferation and TGF-β1-dependent transdifferentiation of lung fibroblasts. Rheumatoid arthritis is a chronic autoimmune disorder, and its pathogenesis is also characterized by an association with several cytokines. It has been reported that calpain, a calcium-dependent intracellular cysteine protease, plays an important role in the progression of rheumatoid arthritis. In this study, we examined the preventive effect of Calpeptin, a calpain inhibitor, on bleomycin-induced pulmonary fibrosis. We performed histological examinations and quantitative measurements of IL-6, TGF-β1, collagen type Iα1 and angiopoietin-1 in bleomycin-treated mouse lung tissues with or without the administration of Calpeptin. Calpeptin histologically ameliorated bleomycin-induced pulmonary fibrosis in mice. Calpeptin decreased the expression of IL-6, TGF-β1, angiopoietin-1 and collagen type Iα1 mRNA in mouse lung tissues. In vitro studies disclosed that Calpeptin reduced (i) production of IL-6, TGF-β1, angiopoietin-1 and collagen synthesis from lung fibroblasts; and (ii) both IL-6-dependent proliferation and angiopoietin-1-dependent migration of the cells, which could be the mechanism underlying the preventive effect of Calpeptin on pulmonary fibrosis. These data suggest the clinical use of Calpeptin for the prevention of pulmonary fibrosis.
A shift towards a T cell cytokine deficiency along with an anti-inflammatory/regulatory microenvironment may enable the synthesis of anti-FVIII inhibitors in haemophilia A patients
Authors: Chaves D G , Velloso-Rodrigues C , Oliveira C A , Teixeira-Carvalho A , Santoro M M , Martins-Filho O A 
Published: September 2010

Summary
Despite the clinical relevance of anti-factor VIII (FVIII) antibodies (anti-FVIII inhibitors) impairing haemostatic activity of haemophilia A (HA) patients, the immunological mechanisms underlying their production are unknown. Aiming to understand more clearly the immune response in patients with [HAα-FVIII(+)] and without [HAα-FVIII(−)] anti-FVIII inhibitors, we have characterized the cytokine pattern of peripheral blood leucocytes, using an in vitro stimulation of whole blood samples with plasma-derived (pFVIII) or recombinant FVIII (rFVIII). The results highlighted decreased levels of tumour necrosis factor (TNF)-α+ neutrophils with higher interleukin (IL)-5/TNF-α ratio in HAα-FVIII(+). All HA samples displayed decreased levels of IL-10+ monocytes when compared to the blood donor (BD) samples. HAα-FVIII(+) showed lower levels of TNF-α+ monocytes and increased IL-10/TNF-α ratio. Analysis of adaptive immunity revealed increased levels of interferon (IFN)-γ+, TNF-α+ and IL-4+ T-cells, from both CD4+ and CD8+ T cells, in HAα-FVIII(−) when compared to BD. Moreover, increased frequency of IL-10+ B cells and higher levels of α-FVIII IgG1 were observed in HAα-FVIII(−). Basal levels of cytokine+ B-cells, similar to BD, and higher levels of α-FVIII IgG4 are major features in HAα-FVIII(+). The global cytokine profile demonstrated a major anti-inflammatory/regulatory pattern in HAα-FVIII(+), confirmed by the in vitro stimuli with pFVIII or rFVIII. The polarized anti-inflammatory/regulatory immune response in HAα-FVIII(+) and the mixed pattern with a bias towards an inflammatory cytokine profile, modulated by IL-4 in HAα-FVIII(−), may be the key element to drive the development of distinct subclasses of anti-FVIII antibodies. These finding have implications for the design of safe and effective therapeutic protocols to control inhibitors synthesis in HA patients.
Investigation of nuclear factor-κB inhibitors and interleukin-10 as regulators of inflammatory signalling in human adipocytes
Authors: Turner J J O , Foxwell K M , Kanji R , Brenner C , Wood S , Foxwell B M J , Feldmann M 
Published: September 2010

SummaryThe poor prognosis of obesity is now known to involve a proinflammatory state associated with elevated circulating levels of cytokines and with macrophage infiltration of adipose tissue. In particular, Toll-like receptor (TLR)-4-driven adipose inflammation has been implicated recently in obesity and the development of diabetes. Adipocytes are now recognized as an important source of cytokine and chemokine production, including interleukin (IL)-6 and monocyte chemotractant protein (MCP)-1, and this appears to be a key step in the development of the obesity-associated inflammatory state. Interventions targeted at adipocyte inflammation may therefore form novel therapies to treat or prevent medical complications of obesity. We set out to explore whether anti-inflammatory interventions which are effective in conventional immune cells would operate on primary human cultures of in-vitro differentiated adipocytes. IL-10 was ineffective against TLR-4-induced cytokine secretion due to lack of IL-10 receptor on human adipocytes, in contrast to the widely used murine 3T3-L1 adipocyte model, which is known to respond to IL-10. Adenoviral delivery of an IL-10 receptor construct to the cells restored IL-10 responsiveness as assessed by signal transducer and activator of transcription-3 (STAT-3) phosphorylation. However, the small molecule nuclear factor (NF)-κB inhibitors 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA)-1 and carbobenzoxyl-Ile-Glu(O-t-butyl)-Ala-leucinal (PSI) as well as adenovirally delivered dominant negative inhibitor of IkappaB kinase 2 (IKK2) and wild-type IκBα were effective inhibitors of TLR-4-driven IL-6 and MCP-1 induction. These data identify a central role for canonical NF-κB signalling in adipocyte cytokine induction and indicate that small molecule inhibitors of NF-κB may form the basis of future treatments for obesity-related conditions where adipocyte inflammatory signalling is implicated.
Pressor and vascular effects of cardiac glycosides
Authors: Kirch W. 
Published: September 2010

Background:For the past two decades, it has generally been accepted ('Blaustein hypothesis') that cardiac glycosides such as ouabain and digoxin increase the sodium and calcium content of smooth muscle cells, so inducing arterial vasoconstriction and a rise in blood pressure. Recent data from an experimental study we carried out led us to question this assumption.Design:A retrospective literature survey covering 20 years and including animal and human studies was performed. Representative results are presented.Results:Contradictory effects of cardiac glycosides on blood pressure and vasculature have been described. Increased, decreased or unaltered blood‐pressure values have been observed following administration of the glycosides ouabain, digoxin and digitoxin. Moreover, vasoconstricting as well as vasodilating effects of cardiac glycosides have been demonstrated. Several recent studies show that cardiac glycosides such as digoxin and digitoxin can lead to a reduction of at least diastolic blood pressure.Conclusion:A slight vasodilation of resistance vessels followed by a fall in diastolic blood pressure could be a contributing factor for the beneficial effects of cardiac glycosides in patients with congestive heart failure. This vasodilation may be caused by central (neurohumoral) effects of digitalis glycosides.
Aquaporins in the hepatobiliary tract. Which, where and what they do in health and disease
Authors: Portincasa P. , Palasciano G. , Svelto M. , Calamita G. 
Published: September 2010

ABSTRACTThe biological importance of the aquaporin family of water channels was recently acknowledged by the 2003 Nobel Prize for Chemistry awarded to the discovering scientist Peter Agre. Among the pleiotropic roles exerted by aquaporins in nature in both health and disease, the review addresses the latest acquisitions about the expression and regulation, as well as physiology and pathophysiology of aquaporins in the hepatobiliary tract.Of note, at least seven out of the thirteen mammalian aquaporins are expressed in the liver, bile ducts and gallbladder. Aquaporins are essential for bile water secretion and reabsorption, as well as for plasma glycerol uptake by the hepatocyte and its conversion to glucose during starvation. Novel data are emerging regarding the physio‐pathological involvement of aquaporins in multiple diseases such as cholestases, liver cirrhosis, obesity and insulin resistance, fatty liver, gallstone formation and even microparasite invasion of intrahepatic bile ducts. This body of knowledge represents the mainstay of present and future research in a rapidly expanding field.
Swelling activated chloride currents in the electrical activity of pulmonary vein cardiomyocytes
Authors: Lee S. H. , Chen Y. C. , Chen S. Y. , Lin C. I. , Chen Y. J. , Chen S. A. 
Published: September 2010

ABSTRACTBackground  Pulmonary veins (PVs) contain cardiomyocytes with a high arrhythmogenicity for inducing atrial fibrillation. The swelling‐activated outwardly rectifying Cl− currents (ICl,swell) are important in the electrical activity of cardiomyocytes. This study was to investigate whether ICl,swell play a role in the PV electrophysiological characteristics.Materials and methods  A whole‐cell patch clamp was used to investigate the action potentials and ICl,swell in isolated rabbit single PV and atrial cardiomyocytes during immersion in isotonic (290–300 mosm L−1) and hypotonic (220–230 mosm L−1) solutions. The cell length and cell width were measured using confocal microscopy.Results  Hypotonic solution induced larger ICl,swell in the PV cardiomyocytes with pacemaker activity than those in the PV cardiomyocytes without pacemaker activity or atrial cardiomyocytes. Hypotonic solution shortened the action potential duration and increased the cell width to a greater extent in the PV cardiomyocytes than in the atrial cardiomyocytes. Moreover, hypotonic solution decreased the PV firing with a decrease in the transient inward currents and delayed after depolarizations.Conclusions  These findings suggest that the ICl,swell plays an important role in the electrical activity of the PV cardiomyocytes.
Platelets interact with tissue factor immobilized on surfaces: effects of shear rate
Authors: Tonda R. , Lopez‐Vilchez I. , Navalon F. , Pino M. , Hernandez M. R. , Escolar G. , Galan A. M. 
Published: September 2010

ABSTRACTBackground  While procoagulant activities of Tissue Factor (TF) have been widely investigated, its possible pro‐adhesive properties towards platelets have not been studied in detail.Material and methods  We explored the interaction of platelets with human Tissue Factor (hTF) firmly adsorbed on a synthetic surface of polyvinilidene difluoride (PVDF) using different shear rates. For studies at 250 and 600 s−1, TF firmly adsorbed was exposed to flowing anticoagulated blood in flat perfusion devices. Deposition of platelets and fibrin were evaluated by morphometric, immunocytochemical and ultrastructural methods. Prothrombin fragment 1 + 2 (F1 + 2) levels were also measured. Experiments at 5000 s−1, were performed on the Platelet Function Analyzer (PFA‐100™) with experimental cartridges with collagen (COL) or collagen‐hTF (COL + TF). Haemostatic effect of recombinant activated FVIIa (rFVIIa) was assessed in the same experimental settings.Results  Platelet deposition on hTF reached 19·8 ± 1·3% and 26·1 ± 3·4% of the total surface, at 250 and 600 s−1, respectively. Fibrin formation was significantly higher at 250 s−1 than at 600 s−1 (P < 0·05). The addition of rFVIIa did not influence platelet deposition but raised fibrin formation and thrombin generation at both shear rates (P < 0·05). At 5000 s−1, closure times (CT) in the PFA‐100 were significantly shortened in the presence of hTF (154·09 ± 14·69 s vs. 191·45 ± 16·09 s COL alone; P < 0·05). Addition of rFVIIa did not cause a further reduction of CT.Conclusions  Our studies demonstrate that hTF is an adhesive substrate for platelets and suggest that the von Willebrand factor could mediate these interactions. At low and intermediate shear rates, rFVIIa enhanced the procoagulant action of hTF, but this effect was not observed at very high shear rates.
MMP‐9 haplotypes and carotid artery atherosclerosis: An association study introducing a novel multicolour multiplex RealTime PCR protocol
Authors: Rauch I. , Iglseder B. , Paulweber B. , Ladurner G. , Strasser P. 
Published: September 2010

ABSTRACTBackground  Among other matrix metalloproteinases (MMPs), gelatinase B (MMP‐9) is discussed to be associated with the pathogenesis of vascular diseases. Two single nucleotide polymorphisms (SNPs) of the MMP‐9 gene, C‐1562T in the promoter region and a G/A transition in exon 6 (R + 279Q), have been addressed in previous association studies which, however, produced conflicting results.Material and methods  A novel multiplex RealTime PCR protocol for the fast and simultaneous detection of both polymorphisms is presented, which was used for genotyping 1737 participants of a prospective study investigating genetic factors influencing the progression of atherosclerosis.Results  Haplotype analysis revealed –1562C/+279Q as the major haplotype in this population. Allelic distribution of the C‐1562T polymorphism was consistent with data published for similar cohorts; however, we found that R + 279Q allelic distribution appears to vary significantly among Caucasian populations. Considering clinical data available from 1487 participants, we found significant associations between the presence of atherosclerotic plaque and the CA‐haplotype in men (P = 0·028, phi = 0·08), and between the AG variant of exon 6 and common carotid artery intima‐media thickness (CIMT) in women (P = 0·004, Eta2 = 0·019).Conclusions  In summary, our results demonstrate associations of MMP‐9 genotypes with different stages of carotid atherosclerosis.
The expression of TNF‐α converting enzyme at the site of ruptured plaques in patients with acute myocardial infarction
Authors: Satoh M. , Ishikawa Y. , Itoh T. , Minami Y. , Takahashi Y. , Nakamura M. 
Published: September 2010

AbstractBackground  Tumour necrosis factor‐α (TNF‐α) converting enzyme (TACE) plays an essential role in the TNF‐α shedding process, which could affect the outcome of acute myocardial infarction (AMI). However, it remains unclear whether it originates from the ruptured plaque or represents a systemic process. This study analysed TACE‐mediated TNF‐α shedding at the site of ruptured plaques in AMI patients and compared them with a systemic mechanism.Materials and methods  The study included 60 patients with AMI who underwent percutaneous coronary intervention (PCI) and 21 patients with stable angina pectoris (SA). Local samples from the site of plaque were taken from AMI using aspiration catheter treatment. Systemic samples were also taken from the aorta in all patients with AMI and SA.Results  Systemic levels of TACE and TNF‐α were higher in AMI patients than in SA patients. In AMI patients, these levels were higher in local samples than in systemic samples. A positive correlation was seen between local TACE and TNF‐α levels in AMI patients. Thrombus material removed from the ruptured plaque showed immunostainings of TACE and TNF‐α in infiltrating macrophages. By six months follow‐up study, local TACE levels remained the only significant independent predictors of adverse cardiac events in AMI patients.Conclusions  This study demonstrates that local expression of TACE is related to TNF‐α shedding at the site of ruptured plaques in AMI patients. In addition, local TACE expression at the site of ruptured plaques may play an important role in poor outcomes in patients with AMI.
Intravenous clusterin administration reduces myocardial infarct size in rats
Authors: Van Dijk Annemieke , Vermond Rob A. , Krijnen Paul A. J. , Juffermans Lynda J. M. , Hahn Nynke E. , Makker Sudesh P. , Aarden Lucien A. , Hack Erik , Spreeuwenberg Marieke , Rossum Bert C. van , Meischl Cristof , Paulus Walter J. , Van Milligen Florine J. , Niessen Hans W. M. 
Published: September 2010

Eur J Clin Invest 2010; 40 (10): 893–902AbstractBackground  Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement‐inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage.Methods  Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n = 15) or vehicle (n = 13) intravenously, for 3 days post‐MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied.Results  Administration of human clusterin significantly reduced both infarct size (with 75 ± 5%) and death of animals (23% vehicle group vs. 0% clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co‐localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin.Conclusions  Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI.
Association of vitamin D receptor genotypes with early onset rheumatoid arthritis
Authors: Garcia‐Lozano J. R. , Gonzalez‐Escribano M. F. , Valenzuela A. , Garcia A. , Núñez‐Roldán A. 
Published: September 2010

AbstractThe presence of certain vitamin D receptor (VDR) genotypes has been associated with low bone mineral density (BMD) in elderly populations as well as with accelerated bone loss in patients with rheumatoid arthritis (RA). In the present study, VDR genotypes from 120 Spanish patients with RA were investigated. Three VDR gene polymorphisms (BsmI, ApaI and TaqI) were investigated using polymerase chain reaction followed by enzymatic digestion. The distributions of VDR allelic frequencies were similar in patients and controls and therefore no influence of VDR polymorphisms on rheumatoid arthritis susceptibility could be demonstrated. However, in an analysis of the clinical features of the different VDR‐related genetic subgroups, the BB/tt genotype, defined by the BsmI and TaqI restriction site polymorphisms, was identified to be weakly associated with an early onset RA in female patients. This VDR genotype has been associated with a low BMD level in various studies. When patients were stratified according to the presence of the shared HLA epitope SE, it was found that SE + female patients bearing the BB/tt genotype showed the earliest disease onset. The mechanisms by which the VDR polymorphism is associated with RA is unknown, but they could be related to the immunoregulatory properties of vitamin D.