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23259479 | Exercise and heart disease: from athletes and arrhythmias to hypertrophic cardiomyopathy and congenital heart disease. | The beneficial effects of regular physical activity on cardiovascular health are well established, with convincing evidence of improvements in blood pressure, lipid profile and overall mortality. Conversely, individuals with pre-existing congenital, inherited or acquired heart conditions may experience functional cardiac deterioration or sudden death during even moderate exertion. Exclusion from high-level sporting activity may be mandated in some cases, and pre-participation screening of competitive athletes plays an important role in the identification of such individuals. The issue of screening is complicated by the fact that physiological cardiovascular adaptation in healthy athletes, including modest left ventricular hypertrophy and biventricular cavity dilatation, may create a diagnostic overlap with pathological conditions such as hypertrophic cardiomyopathy. Furthermore, much interest has focused recently on the possibility of irreversible cardiac remodeling in a proportion of veteran endurance athletes, with the potential for arrhythmogenesis and adverse cardiac events. |
23259478 | Using cardiac biomarkers and treating cardiotoxicity in cancer. | Cardiotoxicity is a frequent and serious adverse effect of both conventional and novel anticancer treatments, affecting patient survival and quality of life. The current standard for cardiac monitoring during cancer therapy, mainly based on left ventricular ejection fraction assessment, detects myocardial damage only when a functional impairment has already occurred, not allowing for early preventive strategies. Measurement of cardiospecific biomarkers has proven to have higher prognostic value than imaging modalities. In particular, cardiac troponin elevation during chemotherapy allows the identification of patients who are more prone to develop myocardial dysfunction and cardiac events during follow-up. In these patients, the use of an angiotensin-converting enzyme inhibitor such as enalapril has shown to be effective in improving clinical outcome, giving the chance for a cardioprotective strategy in a selected population. Once left ventricular dysfunction occurs, heart failure therapies currently used for other forms of left ventricular dysfunction, particularly angiotensin-converting enzyme inhibitors and β-blockers, seem to be effective. However, their use in cancer patients is still undervalued. |
23259476 | New directions in antiarrhythmic drug therapy for atrial fibrillation. | Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and has a significant impact on morbidity and mortality. Current antiarrhythmic drugs for AF suffer from limited safety and efficacy, probably because they were not designed based on specific pathological mechanisms. Recent research has provided important insights into the mechanisms contributing to AF and highlighted several potential novel antiarrhythmic strategies. In this review, we highlight the main pathological mechanisms of AF, discuss traditional and novel aspects of atrial antiarrhythmic drugs in relation to these pathological mechanisms, and present potential novel therapeutic approaches including structure-based modulation of atrial-specific cardiac ion channels, restoring abnormal Ca(2+) handling in AF and targeting atrial remodeling. |
23259475 | Cardiovascular dysfunctions and sympathovagal imbalance in hypertension and prehypertension: physiological perspectives. | Hypertension (HTN) and prehypertension (pre-HTN) have been identified as independent risk factors for adverse cardiovascular events. Recently, increased psychosocial stress and work stress have contributed to the increased prevalence of HTN and pre-HTN, in addition to the contribution of obesity, diabetes, poor food habits and physical inactivity. Irrespective of the etiology, sympathetic overactivity has been recognized as the main pathophysiologic mechanism in the genesis of HTN and pre-HTN. Sympathovagal imbalance owing to sympathetic overactivity and vagal withdrawal is reported to be the basis of many clinical disorders. However, the role played by vagal withdrawal has been under-reported. In this review, we have analyzed the pathophysiologic involvement of sympathovagal imbalance in the development of HTN and pre-HTN, and the link of sympathovagal imbalance to cardiovascular dysfunctions. We have emphasized that adaptation to a healthier lifestyle will help improve sympathovagal homeostasis and prevent the occurrence of HTN and pre-HTN. |
23259474 | Examining the role of insulin in the regulation of cardiovascular health. | A substantial body of evidence has reported that insulin has direct actions on the cardiovascular system independent of its systemic effects on plasma glucose or lipids. In particular, insulin regulates endothelial synthesis of the vasoactive mediators nitric oxide and endothelin-1, yet the importance of this in the maintenance of cardiovascular health remains poorly understood. Recent studies using animals with targeted downregulation of insulin signaling in vascular tissues are improving our understanding of the role of insulin in vascular health. This article focuses on the direct actions of insulin in cardiovascular tissues, with particular emphasis on the molecular mechanisms of insulin action on endothelial function. The potential contribution of impaired vascular insulin action to the cardiovascular complications of diabetes will also be discussed. |
23259472 | NHLBI integrated pediatric guidelines: battle for a future free of cardiovascular disease. | The report of the National Heart, Lung and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents collects into one document atherosclerotic disease prevention in pediatric age groups. The guidelines summarize the evidence base and make recommendations that encourage universal adoption of healthier lifestyles, identification of children with cardiovascular disease risk factors, and treatment of those risk factors using targeted lifestyle modification and rarely pharmacotherapy. These recommendations highlight childhood as a frontier for cardiovascular disease prevention. The guideline recommendations are controversial and not universally embraced, but at the very least, they suggest directions for important research. This article explores key facets of the guidelines, controversies and future directions in preventive cardiology for children. |
23259473 | Regulation of cardiovascular remodeling by the counter-regulatory axis of the renin-angiotensin system. | The counter-regulatory axis of the renin-angiotensin system (RAS) is a novel therapeutic target in cardiovascular disease. Pathophysiological effects mediated via angiotensin II (Ang II) are well established in regulation of blood pressure, cardiac and vascular remodeling, and renal sodium handling, which lead to disorders such as hypertension and associated end-organ damage, atherosclerosis and heart failure. The counter-regulatory axis of the RAS is centered on the angiotensin-converting enzyme 2/angiotensin-1-7 (Ang-[1-7])/Mas receptor axis and has been shown to inhibit many detrimental phenotypes in cardiovascular disease. More recently, an alternative peptide, angiotensin-(1-9) (Ang-[1-9]), has been reported as a potential new member of this axis. This review will discuss the cardiovascular regulatory roles of Ang-(1-7) and Ang-(1-9) in the counter-regulatory axis of the RAS, and the potential for new therapeutic approaches in cardiovascular disease. |
23259471 | Prognostic value of cardiac magnetic resonance imaging in patients with aortic regurgitation. | Guidelines on valve replacement recommend aortic valve replacement for patients with severe aortic regurgitation (AR) with symptoms or left ventricular (LV) dysfunction. However, the optimal timing of surgery for asymptomatic AR patients without LV dilation or dysfunction is not known. There are data to suggest that excess volume load imposed by AR may not only produce subclinical LV dysfunction, but produce neurohormonal activation similar to the heart failure syndrome resulting in reduced survival. The study by Myerson et al. is the first to investigate the predictive ability of cardiac MRI (CMR) for the outcome of asymptomatic patients with AR. They studied 113 asymptomatic patients with moderate-to-severe AR on echocardiography in four centers. A total of 39 (35%) patients developed symptoms or an indication for surgery over a mean follow-up period of 2.6 years. AR volume, AR regurgitant fraction, LV end-diastolic and end-systolic volumes had high discriminatory powers (area under curve of 0.96, 0.93, 0.88 and 0.78, respectively) to predict these events. Higher association with the outcome was observed when LV end-diastolic volume and regurgitant fraction were combined. A significantly higher number of patients with regurgitant fraction >33% were likely to progress to surgery compared with patients with a regurgitant fraction of <33% (85 vs 8%; p < 0.001). These results demonstrate a potential role for CMR for risk stratification of patients with asymptomatic moderate or severe AR, given the ability of CMR to accurately quantify AR and LV volumes. Based on the data presented, it is possible that we may be waiting too long to offer surgery in patients with severe AR. |
23259468 | Fibrocytes and the pathogenesis of diffuse parenchymal lung disease. | Fibrosis is fundamental to the pathogenesis of many chronic lung diseases, including some lung infections, airway diseases such as bronchiectasis and asthma, and most of the diffuse parenchymal lung diseases. Idiopathic pulmonary fibrosis, the prototypical fibrotic lung disease, is amongst the most common diffuse parenchymal lung diseases and is characterized by progressive decline in lung function and premature death from respiratory failure. The clinical management of patients with this illness is hampered by our current inability to predict clinical deterioration and lack of an effective therapy. Fibrocytes are a population of bone marrow-derived circulating progenitor cells that home to injured tissues and differentiate into fibroblasts and myofibroblasts, thus contributing to scar formation. We summarize the evidence supporting the role of these cells in the pathogenesis of fibrotic lung diseases. |
23259467 | Assessing research impact in academic clinical medicine: a study using Research Excellence Framework pilot impact indicators. | Funders of medical research the world over are increasingly seeking, in research assessment, to complement traditional output measures of scientific publications with more outcome-based indicators of societal and economic impact. In the United Kingdom, the Higher Education Funding Council for England (HEFCE) developed proposals for the Research Excellence Framework (REF) to allocate public research funding to higher education institutions, inter alia, on the basis of the social and economic impact of their research. In 2010, it conducted a pilot exercise to test these proposals and refine impact indicators and criteria. The impact indicators proposed in the 2010 REF impact pilot exercise are critically reviewed and appraised using insights from the relevant literature and empirical data collected for the University of Oxford's REF pilot submission in clinical medicine. The empirical data were gathered from existing administrative sources and an online administrative survey carried out by the university's Medical Sciences Division among 289 clinical medicine faculty members (48.1% response rate). The feasibility and scope of measuring research impact in clinical medicine in a given university are assessed. Twenty impact indicators from seven categories proposed by HEFCE are presented; their strengths and limitations are discussed using insights from the relevant biomedical and research policy literature. While the 2010 pilot exercise has confirmed that the majority of the proposed indicators have some validity, there are significant challenges in operationalising and measuring these indicators reliably, as well as in comparing evidence of research impact across different cases in a standardised manner. It is suggested that the public funding agencies, medical research charities, universities, and the wider medical research community work together to develop more robust methodologies for capturing and describing impact, including more valid and reliable impact indicators. |
23259466 | Ghrelin and adipokines as circulating markers of disease activity in patients with Takayasu arteritis. | The current markers of disease activity in Takayasu arteritis (TA) are insufficient for proper assessment. We investigated circulating levels of unacylated and acylated ghrelin, leptin and adiponectin and their relationships with disease activity in patients with TA. This study included 31 patients with TA and 32 sex-, age- and body mass index-matched healthy controls. Disease activity was assessed in TA patients using various tools, including Kerr's criteria, disease extent index-Takayasu, physician's global assessment, radiological parameters, and laboratory markers. Plasma unacylated and acylated ghrelin, and serum leptin and adiponectin levels were measured using an enzyme-linked immunosorbent assay. Unacylated and acylated ghrelin levels were found to be significantly lower in TA patients than that in healthy controls. Patients with active disease had lower unacylated ghrelin levels than those with inactive disease and had lower acylated ghrelin levels than healthy controls. Ghrelin levels were negatively correlated with various parameters of disease activity. The leptin/ghrelin ratio was significantly higher in TA patients than controls. It was positively correlated with disease activity. There was a positive correlation between unacylated and acylated ghrelin and a negative correlation between leptin and ghrelin. There was no statistical difference in adiponectin levels between TA patients and controls. The radiological activity markers were positively correlated with other parameters of disease activity. This study suggests that plasma unacylated and acylated ghrelin levels may be useful in monitoring disease activity and planning treatment strategies for patients with TA. The serum leptin level and leptin/ghrelin ratio may also be used to help assess the disease activity. |
23259465 | Soil transmitted helminths and scabies in Zanzibar, Tanzania following mass drug administration for lymphatic filariasis--a rapid assessment methodology to assess impact. | Ivermectin and albendazole are used in annual mass drug administration (MDA) for the lymphatic filariasis elimination programmes in African countries co-endemic for onchocerciasis, but have additional impact on soil transmitted helminths and the ectoparasitic mite which causes scabies. Assessing these collateral impacts at scale is difficult due to the insensitivity of available parasite detection techniques. The numbers of cases diagnosed with intestinal helminths and scabies and who received prescriptions for treatment were evaluated in 50 health centres in Zanzibar. Records were examined from 2000, prior to the initiation of MDA to 2005, after six rounds of MDA for lymphatic filariasis had taken place. Health centre records showed a consistent decline in the number of cases of intestinal helminths and scabies diagnosed by community health workers in Zanzibar and the number of prescriptions issued across five age groups. A 90-98% decline in soil transmitted helminths and 68-98% decline in scabies infections were recorded. Poisson regression models aggregated to both the island-level and district-level indicated that the decline was statistically significant. The described method of examining health centre records has the potential for use on a large scale, despite limitations, as a rapid method to evaluate the impacts resulting from both lymphatic filariasis and onchocerciasis MDA. This would result in a reduction in the need for parasitological evaluations to determine prevalence and intensity. |
23259464 | Discrete distribution of implanted and annealed arsenic atoms in silicon nanowires and its effect on device performance. | We have theoretically investigated the effects of random discrete distribution of implanted and annealed arsenic (As) atoms on device characteristics of silicon nanowire (Si NW) transistors. Kinetic Monte Carlo simulation is used for generating realistic random distribution of active As atoms in Si NWs. The active As distributions obtained through the kinetic Monte Carlo simulation are introduced into the source and drain extensions of n-type gate-all-around NW transistors. The current-voltage characteristics are calculated using the non-equilibrium Green's function method. The calculated results show significant fluctuation of the drain current. We examine the correlation between the drain current fluctuation and the factors related to random As distributions. We found that the fluctuation of the number of dopants in the source and drain extensions has little effect on the on-current fluctuation. We also found that the on-current fluctuation mainly originated from the randomness of interatomic distances of As atoms and hence is inherent in ultra-small NW transistors. |
23259463 | Use of the NeuroBalloon catheter for endoscopic third ventriculostomy. | Endoscopic third ventriculostomy (ETV) has become the procedure of choice for treatment of obstructive hydrocephalus. While patient selection is the most critical factor in determining the success of an ETV procedure, the technical challenge lies in the proper site of fenestration and the successful creation of a patent stoma. Positioning of a single balloon catheter at the level or below the floor of the third ventricle to achieve an optimal ventriculostomy can at times be challenging. Here, the authors describe the use of a double-barrel balloon catheter (NeuroBalloon catheter), which facilitates positioning across, as well as dilation of, the floor of the third ventricle. The surgical technique and nuances of using the NeuroBalloon catheter and the experience in more than 1000 cases are described. The occurrence of vascular injury was less than 0.1%, and the risk of balloon rupture was less than 2%. The authors found that the placement and deployment of this balloon catheter facilitate the creation of an adequate ventriculostomy in a few simple steps. |
23259462 | Thoracic wall reconstruction with Collamend® in trauma: report of a case and review of the literature. | Despite progress in reconstructive techniques, rebuilding portions of the thorax remains challenging, in particular when large resections, contamination or infection are involved. No other cases of thoracic reconstruction in trauma patients with biological prosthesis have been described since now. We report a case of thoracic reconstruction in highly infected field in a trauma patient. We also performed a literature review about the topic. Collamend® demonstrated its usefulness in thoracic wall reconstruction even in trauma patients and infected fields. |
23259460 | Next generation sequencing analysis reveals a relationship between rDNA unit diversity and locus number in Nicotiana diploids. | Tandemly arranged nuclear ribosomal DNA (rDNA), encoding 18S, 5.8S and 26S ribosomal RNA (rRNA), exhibit concerted evolution, a pattern thought to result from the homogenisation of rDNA arrays. However rDNA homogeneity at the single nucleotide polymorphism (SNP) level has not been detailed in organisms with more than a few hundred copies of the rDNA unit. Here we study rDNA complexity in species with arrays consisting of thousands of units. We examined homogeneity of genic (18S) and non-coding internally transcribed spacer (ITS1) regions of rDNA using Roche 454 and/or Illumina platforms in four angiosperm species, Nicotiana sylvestris, N. tomentosiformis, N. otophora and N. kawakamii. We compared the data with Southern blot hybridisation revealing the structure of intergenic spacer (IGS) sequences and with the number and distribution of rDNA loci. In all four species the intragenomic homogeneity of the 18S gene was high; a single ribotype makes up over 90% of the genes. However greater variation was observed in the ITS1 region, particularly in species with two or more rDNA loci, where >55% of rDNA units were a single ribotype, with the second most abundant variant accounted for >18% of units. IGS heterogeneity was high in all species. The increased number of ribotypes in ITS1 compared with 18S sequences may reflect rounds of incomplete homogenisation with strong selection for functional genic regions and relaxed selection on ITS1 variants. The relationship between the number of ITS1 ribotypes and the number of rDNA loci leads us to propose that rDNA evolution and complexity is influenced by locus number and/or amplification of orphaned rDNA units at new chromosomal locations. |
23259461 | Polymer nanoparticle-protein interface. Evaluation of the contribution of positively charged functional groups to protein affinity. | Cationic-functionalized polymer nanoparticles (NPs) show strikingly distinct affinities to proteins depending on the nature of the cationic functional group. N-Isopropylacrylamide (NIPAm) polymer NPs incorporating three types of positively charged functional groups (guanidinium, primary amino, and quaternary ammonium groups) were prepared by precipitation polymerization. The affinities to fibrinogen, a protein with an isoelectric point (pI) of 5.5, were compared using UV-vis spectrometry and a quartz crystal microbalance (QCM). Guanidinium-containing NPs showed the highest affinity to fibrinogen. The observation is attributed to strong, specific interactions with carboxylate groups on the protein surface. The affinity of the positively charged NPs to proteins with a range of pIs revealed that protein-NP affinity is due to a combination of ionic, hydrogen bonding, and hydrophobic interactions. Protein affinity can be modulated by varying the composition of these functional monomers in the acrylamide NPs. Engineered NPs containing the guanidinium group with hydrophobic and hydrogen bonding functional groups were used in an affinity precipitation for the selective separation of fibrinogen from a plasma protein mixture. Circular dichroism (CD) revealed that the protein was not denatured in the process of binding or release. |
23259458 | Membranoproliferative glomerulonephritis complicating Waldenström's macroglobulinemia. | Lymphoproliferative disorders causing paraproteinemia can be associated with various kidney injuries including the deposition of monoclonal immunoglobulins (Ig). A known glomerular manifestation of Waldenström's macroglobulinemia is characterized by prominent intracapillary hyaline thrombi and lack of conspicuous glomerular proliferation. The present case was special in 2 aspects: 1. the diagnosis of glomerulonephritis was unexpected before renal biopsy, 2. the prominent glomerular proliferation paired with large intracapillary hyaline thrombi is uncommon in Waldenström's macroglobulinemia-associated glomerulonephritis. A 73-year-old Caucasian woman with a long-standing history of rheumatoid arthritis and Waldenström's macroglobulinemia was admitted for acute renal failure (ARF), which initially was presumed to be the consequence of extrarenal causes. Proteinuria and hematuria were only mild. In renal core biopsy, a membranoproliferative glomerulonephritis (MPGN) and prominent intracapillary hyaline monoclonal IgM thrombi were found in addition to acute tubular necrosis. Of note, the patient's history was positive for purpuric skin changes, suspicious for cryoglobulinemia. However, serological tests for cryoglobulins were repeatedly negative. The ARF resolved before the start of immunomodulatory therapy for Waldenström's macroglobulinemia. The presence of MPGN with prominent hyaline thrombi in the context of Waldenström's macroglobulinemia is uncommon and can be oligosymptomatic. We discuss this case in the context of previous literature and classifications suggested for monoclonal Ig-related renal pathologies. |
23259459 | Skin benefits with a novel emollient-treated menstrual pad. | Manufacturers of consumer products consistently seek to improve marketed products in terms of both safety and efficacy. The desire for continued improvement is seen even in well-established products such as catamenial products which have existed in some form for thousands of years. A recent innovation in the design of menstrual pads is the addition of a surface finish of emollient for the purpose of increasing comfort during wear. The present paper presents different evaluations of such an emollient-treated menstrual pad with a novel absorbent core. These investigations demonstrated product tolerability, defined the optimal formulation and concentration of the emollient-containing finish, and demonstrated successful transfer of the emollient to the relevant skin surface. In addition, enhancement of skin moisturization, associated with exposure to the emollient-treated pad, was demonstrated by several technologies: assessment of skin moisturization by Corneometer®, skin friction testing, and skin capacitance. |
23259457 | Metal-metal interactions in C3-symmetric diiron imido complexes linked by phosphinoamide ligands. | The tris(phosphinoamide)-bridged Fe(II)Fe(II) diiron complex Fe(μ-(i)PrNPPh2)3Fe(η(2)-(i)PrNPPh2) (1) can be reduced in the absence or presence of PMe3 to generate the mixed-valence Fe(II)Fe(I) complexes Fe(μ-(i)PrNPPh2)3Fe(PPh2NH(i)Pr) (2) or Fe(μ-(i)PrNPPh2)3Fe(PMe3) (3), respectively. Following a typical oxidative group transfer procedure, treatment of 2 or 3 with organic azides generates the mixed-valent Fe(II)Fe(III) imido complexes Fe((i)PrNPPh2)3Fe≡NR (R = (t)Bu (4), Ad (5), 2,4,6-trimethylphenyl (6)). These complexes represent the first examples of first-row bimetallic complexes featuring both metal-ligand multiple bonds and metal-metal bonds. The reduced complexes 2 and 3 and imido complexes 4-6 have been characterized via X-ray crystallography, Mössbauer spectroscopy, cyclic voltammetry, and SQUID magnetometry, and a theoretical description of the bonding within these diiron complexes has been obtained using computational methods. The effect of the metal-metal interaction on the electronic structure and bonding in diiron imido complexes 4-6 is discussed in the context of similar monometallic iron imido complexes. |
23259456 | Anomalous isosteric enthalpy of adsorption of methane on zeolite-templated carbon. | A thermodynamic study of the enthalpy of adsorption of methane on high surface area carbonaceous materials was carried out from 238 to 526 K. The absolute quantity of adsorbed methane as a function of equilibrium pressure was determined by fitting isotherms to a generalized Langmuir-type equation. Adsorption of methane on zeolite-templated carbon, an extremely high surface area material with a periodic arrangement of narrow micropores, shows an increase in isosteric enthalpy with methane occupancy; i.e., binding energies are greater as adsorption quantity increases. The heat of adsorption rises from 14 to 15 kJ/mol at near-ambient temperature and then falls to lower values at very high loading (above a relative site occupancy of 0.7), indicating that methane/methane interactions within the adsorption layer become significant. The effect seems to be enhanced by a narrow pore-size distribution centered at 1.2 nm, approximately the width of two monolayers of methane, and reversible methane delivery increases by up to 20% over MSC-30 at temperatures and pressures near ambient. |
23259455 | Higher levels of psychological distress are associated with a higher risk of incident diabetes during 18 year follow-up: results from the British household panel survey. | Reviews have shown that depression is a risk factor for the development of type 2 diabetes. However, there is limited evidence for general psychological distress to be associated with incident diabetes. The aim of the present study was to test whether persons who report higher levels of psychological distress are at increased risk to develop type 2 diabetes during 18 years follow up, adjusted for confounders. A prospective analysis using data from 9,514 participants (41 years, SD=14; 44% men) of the British Household Panel Survey. The General Health Questionnaire 12 item version was used to assess general psychological distress, diabetes was measured by means of self-report. Cox proportional hazards regression models were used to calculate the multivariate-adjusted hazard ratio (HR) of incident diabetes during 18 years follow up, comparing participants with low versus high psychological distress at baseline (1991). A total of 472 participants developed diabetes 18 year follow up. Those with a high level of psychological distress had a 33% higher hazard of developing diabetes (HR=1.33, 95% CI 1.10-1.61), relative to those with a low level of psychological distress, adjusted for age, sex, education level and household income. After further adjustment for differences in level of energy, health status, health problems and activity level, higher psychological distress was no longer associated with incident diabetes (HR=1.10, 95% CI 0.91-1.34). Higher levels of psychological distress are a risk factor for the development of diabetes during an 18 year follow up period. This association may be potentially mediated by low energy level and impaired health status. |
23259454 | NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell. | Expression of NKX2-1 is required to specify definitive endoderm to respiratory endoderm. However, the transcriptional regulation of NKX2-1 is not fully understood. Here we demonstrate that aside from specifying undifferentiated human embryonic stem cell (hESC) to definitive endoderm, high concentrations of Activin-A are also necessary and sufficient to induce hESC-derived definitive endodermal progeny to a FOXA2/NKX2-1/GATA6/PAX9 positive respiratory epithelial fate. Activin-A directly mediates the induction of NKX2-1 by interacting with ALK4, leading to phosphorylation of SMAD2, which binds directly to the NKX2-1 promoter and activates its expression. Activin-A can be replaced by GDF11 but not transforming growth factor β1. Addition of Wnt3a, SHH, FGF2, or BMP4 failed to induce NKX2-1. These results suggest that direct binding of Activin-A-responsive SMAD2 to the NKX2-1 promoter plays essential role during respiratory endoderm specification. |
23259453 | Augmentation of hepatitis B virus-specific cellular immunity with programmed death receptor-1/programmed death receptor-L1 blockade in hepatitis B virus and HIV/hepatitis B virus coinfected patients treated with adefovir. | The immunological parameters leading to viral persistence in chronic hepatitis B (CHB) are not clearly established. We analyzed HBV-specific immunoregulatory mechanisms in HIV-infected and HIV-uninfected HBeAg(+) CHB patients to determine (1) the roles of immunoregulatory pathways, (2) the effect of anti-HBV therapy on immunoregulatory pathways, and (3) the role of immunomodulatory therapy to overcome the effect of T regulatory cells (Tregs, CD4(+)CD25(+)FoxP3(+)) in HBV-infected individuals. A prospective, double blind, randomized, placebo-controlled trial treated HBV (HIV(+/-))-infected patients with adefovir 10 mg daily or placebo for 48 weeks. HBV viral load (VL), immunophenotying, and functional studies were performed at multiple time points. Suppression of HBV VL with adefovir leads to decreased peripheral expansion of Tregs. While declining, Tregs significantly inhibit cytokine-secreting HBV-specific CD8(+) T cell responses over 48 weeks of anti-HBV adefovir therapy (p<0.05). A large proportion of these Tregs express programmed death receptor-1 (PD-1), blockade of which in vitro leads to improved cytokine-secreting HBV-specific CD8(+) T cell responses, particularly in HIV/HBV-coinfected patients (p<0.05). Peripheral expansion of Treg levels correlated with HBV viral load and decreased HBV-specific CD8(+) T cells. PD-1 blockade increased survival of HBV-specific CD8(+) T cells, removing the inhibitory effect of PD-1(+) peripheral Tregs. Hence therapies involving PD-1 blockade in combination with directly acting antivirals should be investigated to reduce the need for life-long directly acting antiviral therapy. |
23259452 | Stable isotope probing and Raman spectroscopy for monitoring carbon flow in a food chain and revealing metabolic pathway. | Accurately measuring carbon flows is a challenge for understanding processes such as diverse intracellular metabolic pathways and predator-prey interactions. Combined with stable isotope probing (SIP), single-cell Raman spectroscopy was demonstrated for the first time to link the food chain from carbon substrate to bacterial prey up to predators at the single-cell level in a quantitative and nondestructive manner. Escherichia coli OP50 with different (13)C content, which were grown in a mixture of (12)C- and fully carbon-labeled (13)C-glucose (99%) as a sole carbon source, were fed to the nematode. The (13)C signal in Caenorhabditis elegans was proportional to the (13)C content in E. coli. Two Raman spectral biomarkers (Raman bands for phenylalanine at 1001 cm(-1) and thymine at 747 cm(-1) Raman bands), were used to quantify the (13)C content in E. coli and C. elegans over a range of 1.1-99%. The phenylalanine Raman band was a suitable biomarker for prokaryotic cells and thymine Raman band for eukaryotic cells. A biochemical mechanism accounting for the Raman red shifts of phenylalanine and thymine in response to (13)C-labeling is proposed in this study and is supported by quantum chemical calculation. This study offers new insights of carbon flow via the food chain and provides a research tool for microbial ecology and investigation of biochemical pathways. |
23259450 | Aortic valvular heart disease: Is there a place for angiotensin-converting-enzyme inhibitors? | Aortic valve disease (AVD) is the most common form of valvular heart disease in the western world. The only proven therapy for severe AVD is open aortic valve replacement, with trans-catheter aortic valve implantation emerging as a promising modality to treat severe aortic stenosis in a selected group of patients. AVD has a long asymptomatic phase with symptoms occurring late in the disease and once symptoms develop, prognosis is poor. There is a growing appreciation that aortic valvular heart disease incorporates a disease process that extends beyond the valve itself leading to an aortic valvular 'heart' disease. The renin-angiotensin system is known to modulate adverse left ventricular remodeling and myocardial fibrosis, which could be caused by increased load caused by the AVD. In this review, the authors explore evidence that suggest that drugs that target the renin-angiotensin system may have a potential therapeutic role in AVD. |
23259449 | Role of dihydropyridinic calcium channel blockers in the management of hypertension. | Dihydropyridinic calcium channel blockers are a subclass of antihypertensive drugs with growing significance in the therapeutic armamentarium. Early studies in the 1990s had aroused certain fears with regard to the safety of the first drugs from this class, since they had a fast onset of action and a short half-life, and thus they were associated with reflex adrenergic activation. New molecules with long half-lives and high lipophilia have shown safety and efficacy in the control of blood pressure, as well as in the reduction of several end points related to hypertension. Moreover, these new molecules, which block special subtypes of calcium channel receptors, provide drugs not only with an action profile that goes beyond the antihypertensive effect, but also with a lower rate of side effects. Therefore, in the light of new studies that include calcium channel blockers alone or in combination, these agents will probably be used even more extensively for the management of hypertension in the following years. |
23259448 | Stroke risk stratification scores in atrial fibrillation: current recommendations for clinical practice and future perspectives. | Atrial fibrillation (AF) increases the risk of stroke. This additional risk varies depending on the presence of various clinical risk factors. The contribution of some risk factors, for example vascular disease and female gender, has been disputed. Stroke risk stratification scores (RSS) incorporate these risk factors to identify patients at different levels of stroke risk. These RSS enable the targeting of oral anticoagulants (OAC) at high-risk patients, who stand to gain the most in terms of stroke risk reduction, and avoidance of their use in low-risk patients, in whom the harms of OAC (increased risk of bleeding) may outweigh their stroke prevention capabilities. Guidelines on the management of AF have used and adapted various RSS for this purpose, and have tailored their therapeutic recommendations around the different risk categories. Current guidelines advocate the use of the CHA₂DS₂-VASc RSS to assess stroke risk in AF patients, to identify truly low-risk patients (men and women aged <65 years with no risk factors) who may not require antithrombotic therapy, with consideration of OAC for all other patients. The recent development of novel OACs is changing the risk threshold at which it is acceptable to treat AF patients. However, consideration of OAC therapy for stroke prevention also requires assessment of the associated bleeding risk and incorporation of patients' preferences when making treatment decisions. |
23259447 | Masquerading bundle branch block: a variety of right bundle branch block with left anterior fascicular block. | The so-called 'masquerading' type of right bundle branch block is caused by the simultaneous presence of a high-degree left anterior fascicular block often accompanied with severe left ventricular enlargement and/or fibrotic block in the anterolateral wall of the left ventricle. These conditions tend to reorient the terminal electrical forces of the QRS complex towards the left and upwards, in such a way that the characteristic slurred S wave in lead I becomes smaller or even disappears. In many cases of standard masquerading right bundle branch block, a small Q wave in lead I is present due to the initial forces of the left anterior fascicular block, which are oriented rightwards and inferiorly. However, in some cases, the Q wave in lead I also vanishes, and the mimicking of a left bundle branch block becomes perfect in standard leads. This is commonly associated with an inferior myocardial infarction or severe inferior fibrosis in cardiomyopathies. The typical QRS changes of right bundle branch block may eventually be concealed even in the right precordial leads; under such circumstances, the ECG diagnosis may be mistaken and the right bundle branch block totally missed. The masquerading right bundle branch block carries a poor prognosis, since it always implies the presence of a severe underlying heart disease. |
23259446 | Metabolomic profiling as a useful tool for diagnosis and treatment of chronic disease: focus on obesity, diabetes and cardiovascular diseases. | There have been considerable improvements in therapeutics for chronic diseases. However, the maximum benefit of these or other options are hard to achieve in practice, due in part to the difficulties associated with determining optimal targets for such interventions. Recent developments have suggested that understanding changes in metabolite profiles will confer a high degree of predictive accuracy in terms of understanding the fundamental mechanisms resulting in perturbations of the metabolic state. Metabolomics involves the establishment of relationships between phenotype and a metabolic signature, which are key aspects of biological function. These approaches have been applied to the identification of serum/plasma metabolic markers involved in obesity, diabetes and vascular disease using animal models or in humans. Different kinds of metabolite profiling techniques using nuclear magnetic resonance spectroscopy, mass spectrometry, ultraperformance liquid chromatography and so on are currently employed to generate global metabolic profiles. Scientific information derived from these techniques can be applied to provide accurate and clinically useful prognostic/diagnostic capability for the management of major chronic diseases. One current consideration limiting the widespread use of metabolomic profiling is the analysis of its cost-effectiveness. In summary, it is hoped that the information derived from metabolite profiling will make it possible to suggest individualized therapies that more effectively treat disease. |
23259445 | Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. | The role of inflammatory markers in cardiovascular diseases has been studied extensively and a consistent relationship between various inflammatory markers and cardiovascular diseases has been established in the past. Neutrophil to lymphocyte ratio (NLR) is a new addition to the long list of these inflammatory markers. NLR, which is calculated from complete blood count with differential, is an inexpensive, easy to obtain, widely available marker of inflammation, which can aid in the risk stratification of patients with various cardiovascular diseases in addition to the traditionally used markers. It has been associated with arterial stiffness and high coronary calcium score, which are themselves significant markers of cardiovascular disease. NLR is reported as an independent predictor of outcome in stable coronary artery disease, as well as a predictor of short- and long-term mortality in patients with acute coronary syndromes. It is linked with increased risk of ventricular arrhythmias during percutaneous coronary intervention (PCI) and higher long-term mortality in patients undergoing PCI irrespective of indications of PCI. In patients admitted with advanced heart failure, high NLR was reported with higher inpatient mortality. Recently, NLR has been reported as a prognostic marker for outcome from coronary artery bypass grafting and postcoronary artery bypass grafting atrial fibrillation. |
23259444 | Feasibility and clinical implementation of hand-held echocardiography. | Echocardiography is essential in the evaluation of patients with suspected or known cardiovascular disease. The development of pocket-size hand-held echocardiographic devices, suitable for a quick assessment of cardiac structures and function, has been shown to improve diagnostics and patient workflow. In the hands of experts, pocket-size machines capable of gray tone and color flow imaging offer high accuracy for the assessment of ventricular function, the detection of pericardial and pleural effusions and are suitable for semiquantitative evaluation of valvular function. The machines are also suitable for noncardiac imaging. Point-of-care echocardiography with pocket-size hand-held echocardiographic devices should be an integrated part of the physical examination of patients in many situations and will probably be performed by an increasing number of both experts and nonexperts as well. However, the benefit relies on the level of competence of the users and tailored training is needed to answer specific questions. |
23259443 | Recent advances in pediatric echocardiography. | Echocardiography is the fundamental tool in the management of children with congenital heart disease (CHD), and cross-sectional echocardiography is still the main technique used for diagnosis and therapeutic planning. Recent advances in pediatric echocardiography include 3D echocardiography and functional imaging. The recent development of specific pediatric probes allows imaging of pediatric hearts with high temporal and spatial resolution. Lesions are often anatomically complex, and 3D echocardiography allows increased appreciation of complex spatial relationships and can thereby be valuable in understanding functional anatomy and planning interventions. Assessment of pediatric myocardial function can be difficult, with highly variable ventricular morphology. Assessment of right ventricular function and function of the single ventricle are current challenges in CHD. The introduction of myocardial tissue Doppler velocities and deformation imaging (strain and strain-rate quantification) facilitates the quantification of myocardial function independent of underlying morphology. These techniques offer new insights into the mechanics of CHD. |
23259442 | Clinical safety and efficacy of a next-generation stent-graft device for thoracic endovascular aortic repair. | Thoracic endovascular aortic repair has significantly improved the treatment of patients with acute and chronic diseases of the descending thoracic aorta. Retrograde transarterial implantation of a membrane-covered stent graft aims at excluding the aortic pathology at risk for complications (e.g., aneurysm, dissection) from the circulation to prevent expansion and ultimately rupture. Today, several stent grafts from different manufacturers are approved by the respective authorities and thus commercially available. The Medtronic Talent® stent graft used to be one of the initially available devices and has been broadly used to become the world-wide market leader at its time. In 2005, it has been replaced by the second-generation Medtronic Valiant® device, which features several technical improvements. In this article, we evaluate a recent publication investigating the clinical performance of this second-generation stent graft device, and discuss the results in the view of the current literature and developments. |
23259441 | Treprostinil for the treatment of pulmonary arterial hypertension. | Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by increasing pulmonary vascular resistance leading to right ventricular failure and death. Treprostinil is a stable prostacyclin analog approved for the treatment of PAH to improve exercise capacity. In the setting of PAH, the major pharmacological actions of treprostinil include vasodilatation of the pulmonary and systemic vascular beds, inhibition of platelet aggregation and inhibition of smooth muscle cell proliferation. Treprostinil therapy may be delivered via parenteral (subcutaneous and intravenous) or inhaled routes of administration, with oral tablets in the later stages of clinical development. In clinical trials, treprostinil has been shown to improve clinical status, functional class, exercise capacity and quality of life. Common side effects of treprostinil therapy include headache, flushing, jaw pain, diarrhea, and for subcutaneous administration, infusion site pain or reaction. This article provides an overview of treprostinil therapy for the treatment of PAH with a focus on the available efficacy and safety data for parenteral, inhaled and oral administration. |
23259435 | Dynamics of Schistosoma haematobium egg output and associated infection parameters following treatment with praziquantel in school-aged children. | Praziquantel is the drug of choice in preventive chemotherapy targeting schistosomiasis. Increasing large-scale administration of praziquantel requires monitoring of drug efficacy to detect early signs of development of resistance. Standard protocols for drug efficacy monitoring are necessary. Here, we determined the optimal time point for praziquantel efficacy assessment against Schistosoma haematobium and studied the dynamics of infection parameters following treatment. Ninety school-aged children from south Côte d'Ivoire with a parasitologically confirmed S. haematobium infection were treated with a single oral dose of praziquantel (40 mg/kg) and followed up for 62 days post-treatment. Urine samples were collected on 23 schooldays during this period and were subjected to visual examination (macrohaematuria), urine filtration and microscopy (S. haematobium eggs) and reagent strip testing (microhaematuria, proteinuria and leukocyturia). Observed cure and egg reduction rates were highly dependent on the time point post-treatment. Egg reduction rates were high (>97%) in weeks 3-9 post-treatment. Cure rates were highest in weeks 6 (92.9%) and 9 (95.0%) post-treatment. The prevalence of infection-associated parameters decreased after treatment, reaching a minimum of 2.4% in weeks 5 (proteinuria) and 7 (leukocyturia) post-treatment, and 16.3% at the end of week 8 (microhaematuria). Macrohaematuria disappeared between weeks 3 and 6 post-treatment. For monitoring praziquantel efficacy against S. haematobium, we recommend that the cure rate is assessed at week 6 post-treatment. The egg reduction rate can be evaluated earlier, from day 14 post-treatment onwards. Reagent strips are a useful additional tool for evaluating treatment outcomes in areas with high endemicity, preferably at weeks 5 and 6 post-treatment. The delayed decrease of microhaematuria confirms that lesions in the urinary tract persist longer than egg excretion post-treatment. |
23259436 | Myelofibrosis: molecular and cell biological aspects. | A subset of myeloproliferative disorders (MPN) and myelodyplastic syndromes (MDS) evolves to fibrosis of the bone marrow associated with haematopoietic insufficiency. We have been interested in chemokines involved in fibrogenesis within the bone marrow. Besides TGFβ we could identify a number of additional mediators including osteoprotegerin and bone morphogenic proteins. In MPN JAK2 or MPL mutation are not linked to the propensity for bone marrow fibrosis. The hypothesis that an increased intramedullary decay of megakaryocytes undergoing appotosis takes place within the marrow, thus liberating fibrogenic cytokines, could not be confirmed. On the contrary, megakaryocytes in primary fibrosis revealed low expression of proapoptotic genes such as BNIP3. Interestingly, BNIP 3 expression was down regulated in megakaryocytic cell lines kept in hypoxic conditions. Furthermore, expression arrays revealed hypoxia inducible genes to be up-regulated in primary myelofibrosis. Fibrotic MPN are characterized by aberrant proplatelet formation which represent cytoplasmic pseudopodia and normally extend into the sinus. In fibrotic MPN orientation of proplatelet growth appears to be disturbed, which could lead to an aberrant deposition of platelets in the marrow with consecutive liberation of fibrogenic cytokines. |
23259434 | Shaping healthcare-seeking processes during fatal illness in resource-poor settings. A study in Lao PDR. | There are profound social meanings attached to bearing children that affect the experience of losing a child, which is akin to the loss of a mother in the household. The objective of this study is to comprehend the broader processes that shape household healthcare-seeking during fatal illness episodes or reproductive health emergencies in resource-poor communities. The study was conducted in six purposively selected poor, rural communities in Lao PDR, located in two districts that represent communities with different access to health facilities and contain diverse ethnic groups. Households having experienced fatal cases were first identified in focus group discussions with community members, which lead to the identification of 26 deaths in eleven households through caregiver and spouse interviews. The interviews used an open-ended anthropological approach and followed a three-delay framework. Interpretive description was used in the data analysis. The healthcare-seeking behavior reported by caregivers revealed a broad range of providers, reflecting the mix of public, private, informal and traditional health services in Lao PDR. Most caregivers had experienced multiple constraints in healthcare-seeking prior to death. Decisions regarding care-seeking were characterized as social rather than individual actions. They were constrained by medical costs, low expectations of recovery and worries about normative expectations from healthcare workers on how patients and caregivers should behave at health facilities to qualify for treatment. Caregivers raised the difficulties in determining the severity of the state of the child/mother. Delays in reaching care related to lack of physical access and to risks associated with taking a sick family member out of the local community. Delays in receiving care were affected by the perceived low quality of care provided at the health facilities. Care-seeking is influenced by family- and community-based relations, which are integrated parts of people's everyday life. The medical and normative responses from health providers affect the behavior of care-seekers. An anthropological approach to capture the experience of caregivers in relation to deciding, seeking and reaching care reveals the complexity and socio-cultural context surrounding maternal and child mortality and has implications for how future mortality data should be developed and interpreted. |
23259431 | Screening for prostate cancer: an updated review. | Prostate cancer is the most frequently diagnosed malignancy in men and its incidence has been increasing in the last decades. Diagnosis and treatment of prostate cancer were radically improved after the discovery of prostatic-specific antigen. Early detection rates increased, especially in asymptomatic individuals, confirmed by recent published randomized trials. The impact of screening in overdiagnosis and overtreatments is discussed, since benefits in overall mortality rates were not clearly demonstrated. Perhaps younger patients with a longer life expectancy would be the ones with the most benefits from screening. This study presents an update of the most important screening methods for prostate cancer as well as the recent recommendations for screening. |
23259430 | Maximizing survival in metastatic castrate-resistant prostate cancer: a clinical viewpoint. | Recently, licensed and emerging treatments for metastatic castrate-resistant prostate cancer are transforming the prognosis for men whose disease has already progressed during or after docetaxel-based chemotherapy. Two agents (cabazitaxel and abiraterone) are already accessible to prescribers, having shown survival benefits versus their comparators in randomized controlled trials, and other agents are showing promising results. A future in which metastatic castrate-resistant prostate cancer can be managed as a 'chronic disease' looks tantalizingly close. The challenge for clinicians will be to use these treatments rationally, in a way that optimizes each individual patient's chances of prolonged survival. |
23259429 | Current standards and future directions for prostate cancer radiation therapy. | Definitive radiation therapy is a well-recognized curative treatment option for localized prostate cancer. A suitable technique, dose, target volume and the option of a combination with androgen deprivation therapy need to be considered. An optimal standard external beam radiotherapy currently includes intensity-modulated and image-guided radiotherapy techniques with total doses of ≥76-78 Gy in conventional fractionation. Protons or carbon ions are alternatives available only in specific centers. Data from several randomized studies increasingly support the rationale for hypofractionated radiotherapy. A simultaneous integrated boost with dose escalation focused on a computed tomography/PET- or MRI/magnetic resonance spectroscopy-detected malignant lesion is one option to increase tumor control, with potentially no additional toxicity. The application of a spacer is a promising concept for optimal protection of the rectal wall. |
23259428 | Class III b-tubulin overexpression in gynecologic tumors: implications for the choice of microtubule targeted agents? | The tubulins are significant players in maintaining microtubule dynamics and have important signaling and apoptotic functions. Alterations in microtubules as a result of changes in tubulin isotype content or polymerization affect the sensitivity of cell lines to tubulin-binding agents (e.g., taxol) in vitro. Epothilones, such as patupilone and ixabepilone, contain a 16-membered macrolide ring and act as competitive inhibitors of taxol. Class III β-tubulin overexpression has been linked to resistance to paclitaxel and correlated with poor survival in ovarian, breast, gastric, non-small-cell lung cancer and unknown primary tumors. Recent data suggest that class III β-tubulin may not only serve as a marker for sensitivity to epothilones, but also as a mediator of a bioaggressive tumor phenotype through activation of multiple cell survival pathways active under stress conditions. |
23259426 | Dendritic cell immunotherapy in ovarian cancer. | Ovarian cancer is one of the most frequent gynecological malignancies. However, as there is no effective screening method to detect early disease, it is usually only diagnosed when already widespread in the abdomen. The majority of patients diagnosed with advanced-stage disease will relapse and require additional therapy. In the search for additional effective treatments for the management of recurrent disease, researchers have focused on the potential usefulness of immunotherapeutic modulation by administering autologous immune cells, such as dendritic cells (DCs), to stimulate antitumor host responses. With the ultimate goal of improved survival, this review addresses mechanisms in ovarian cancer that may limit the expansion of antitumor immunity, discusses the parameters to be considered for optimal DC immunotherapy, outlines evaluation methodology used to monitor the success of treatment regimens and reviews reported DC immunotherapy trials in ovarian cancer. |
23259427 | Current status of sentinel lymph node mapping in the management of endometrial cancer. | The prognosis of endometrial cancer (EC) is generally favorable, while lymph node status remains the most important prognostic factor. Sentinel lymph node mapping (SLNM) could help to find women in whom adjuvant therapy could be omitted. This review analyzes different techniques of injection and histopathologic elaboration of SLNM in EC. Results of studies on SLNM in ECs seem to be promising, but only a small series have been published so far. The studies are subdivided into three groups by the technique of injection (hysteroscopic, subserosal and cervical). Range of detection rate for SLNM varies from 45 to 100%. Hysteroscopic injection is not easy to learn; moreover, exact peritumoral injection in large tumors is often impossible. Subserosal administration of tracer is difficult during laparoscopic or robotic surgery. Cervical injection is quite a controversial technique because distribution of SLNs in ECs is different from cervical cancer; moreover, there is no large study using cervical injection with systematic pelvic and para-aortic lymphadenectomy. |
23259425 | Immunosuppression and risk of cervical cancer. | A markedly increased risk of cervical cancer is known in women immunosuppressed due to AIDS or therapy following organ transplantation. The aim of this review is to determine the association between other conditions affecting the immune system and the risk of cervical cancer. Patients with end-stage renal disease seem to be at an increased risk of cervical cancer. A higher risk of cervical precancerous lesions was found in patients with some autoimmune diseases; particularly if treated with immunosuppressants. Among behavioral factors weakening the immune system, smoking appeared to strongly increase the risk of cervical cancer, while poor diet only moderately increased the risk. It is difficult to determine whether sexually transmitted infections other than human papillomavirus infection are independent risk factors. Identifying those groups of women likely to fail in clearing persistent human papillomavirus infections would help individualize screening guidelines and target immune-associated factors in the cervical cancer etiology. |
23259424 | Altered expression of the miRNA processing endoribonuclease Dicer has prognostic significance in human cancers. | Several studies have implicated miRNAs in the initiation and progression of human cancers. Examining the biogenesis pathways that generate these important regulatory molecules has revealed new mechanisms for tumor development. Altered expression of the endoribonuclease Dicer in many tumors has given new hope to unraveling the complex relationship between miRNA processing and cancer. This may provide further insight into mechanisms for targeting multiple genes that are critical for the malignant phenotype of several cancers. The evaluated article demonstrates that Dicer is transcriptionally regulated by Sox4 and reduced levels of this transcription factor consequently leads to a reduction in expression, and therefore deregulation of cancer-related miRNAs in melanoma. Reduced Dicer expression in malignant melanoma is an independent predictor of poor survival. In this review, we assess the prognostic significance of Dicer expression in different tumor types. |
23259423 | Exploring new frontiers: sirolimus as a pharmacokinetic modulator in advanced cancer patients. | The mTOR pathway mediates many biologic functions such as transcriptional and translational control, and is a target for anticancer drug development. mTOR inhibitors, such as sirolimus (SRL), display immunosuppressive and antiproliferative properties, and the use of SRL in kidney transplant recipients reduces the risk of post-transplant cancer. However, its use in advanced cancer patients has not been fully evaluated. The authors review the study by Cohen et al., evaluating the dose for oral, weekly SRL alone or in combination with grapefruit juice or ketoconazole to achieve the desired whole-blood concentration with antitumoral activity. This study demonstrates that SRL can be feasibly administered orally once weekly and displays a similar pharmacokinetic profile compared with other mTOR inhibitors. This study encouraged the use of SRL in advanced cancer patients and can stimulate clinical trials with a larger number of patients, evaluating the role of SRL as a new targeted therapy in cancer patients. |
23259422 | A shared fight against cancer: the complementary roles of oncology physicians and oncology pharmacists. | Over the last decades, antineoplastic treatment has made significant progress and has clearly contributed to the benefit of patients with cancer. As it can be seen in all aspects of life, however, there is a second side of the coin showing us that these achievements have not been without unwanted effects on the patient, the public and those working on the oncology ward. Whereas oncology physicians try to reduce the harm from neoplastic disease, oncology pharmacists try to reduce the harm from antineoplastic therapy. The first European Conference of Oncology Pharmacy in Budapest, Hungary, from 27 to 29 September with nearly 500 participants demonstrated that pharmacists can make significant contributions in many different ways. |
23259418 | The treatment of iatrogenic male incontinence: latest results and future perspectives. | Male Stress Urinary Incontinence (SUI) is an increasingly recognized problem particularly after the treatment of prostate cancer. Postprostatectomy incontinence is a major problem that needs to be solved, since it has great impact on quality of life affecting the patient's physical activity and social well-being. The initial treatment for SUI that persists after 12 months consists of conservative measures such as pelvic floor muscle exercises and behavioral therapy. Properly selected and informed patients can also be treated efficiently with minimally invasive procedures such as the implantation of a male suburethral sling, although the experience with such devices is not extensive. However, the implantation of artificial urinary sphincter is the gold standard therapy. |
23259417 | Fentanyl for breakthrough cancer pain: where are we? | Despite relative stable and adequately controlled background pain, Breakthrough Cancer Pain (BTcP) is a transient exarcebation of pain that occurs either spontaneously or in relation to a specific predictable trigger. It is characterized by a typical temporal pattern which includes a short onset (generally a few minutes) and a short duration (30-90 minutes). It has a strong influence on quality of life (QoL), including detrimental effects on activities of daily living, sleep, social relationships and enjoyment of life. Therefore, BTcP represents an important clinical challenge in the care of patients with cancer. Transmucosal fentanyl, a rapid onset opioid (ROO), is indicated for the treatment of BTcP in patients who are already receiving and are tolerant to opioid therapy for underlying, persistent pain. In order to identify published studies on BTcP and ROOs a Medline search was carried out. The characteristics of the various formulations of transmucosal fentanyl used for BTcP and clinical data published in literature will be described in this review. |
23259416 | The PARAMOUNT trial: a phase III randomized study of maintenance pemetrexed versus placebo immediately following induction first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. | The search for new agents and for innovative strategies is warranted in the treatment of advanced non small cell lung cancer (NSCLC) because the outcomes remain unsatisfactory for most patients. Maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first-line chemotherapy is a very interesting strategy that has been largely investigated in the last years. Maintenance treatment can consist of drugs included in the induction regimen (continuation maintenance) or other non-cross-resistant agents not included in the induction regimen (switch maintenance). The switch maintenance strategy with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor erlotinib (in all the histologies) or with pemetrexed (in non-squamous histologies) have been demonstrated to be two possible effective options versus the classic break from cytotoxic chemotherapy after a fixed course in the treatment of advanced NSCLC. However some biases may have influenced the outcomes of switch maintenance trials as the low rate of patients treated with erlotinib and pemetrexed in the placebo arms. Very recently, a randomized phase III trial named PARAMOUNT has demonstrated a clinically significant benefit in overall survival with a good safety profile versus placebo in favour of continuation maintenance with pemetrexed after four cycles of induction with cisplatin plus pemetrexed. Continuation maintenance can be considered the true maintenance strategy because switch maintenance is an early second-line treatment. Continuation maintenance with pemetrexed after cisplatin plus pemetrexed induction for patients selected for a maintenance strategy is recommended as first-line treatment of advanced non-squamous NSCLC. |
23259415 | ERCC1 mRNA levels can predict the response to cisplatin-based concurrent chemoradiotherapy of locally advanced cervical squamous cell carcinoma. | The purpose of this study was to investigate whether the excision repair cross-complementation group 1 (ERCC1) mRNA expression could predict treatment response of patients with locally advanced cervical squamous cell carcinoma (LACSCC) who underwent cisplatin-based concurrent chemoradiotherapy (CCCRT). A total of sixty LACSCC patients, treated with radical CCCRT from a single institution were evaluated. ERCC1 mRNA expression was determined by quantitative real-time RT-PCR in pre-treatment tumor tissues. The association of ERCC1 status with clinicopathological characteristics (age, histological grade, tumor size, parametrial invasion, lymph node metastasis and FIGO stage) and treatment response were analyzed. No significant association between ERCC1 mRNA expression and clinicopathological characteristics were observed. Patients with low ERCC1 mRNA level had a significantly higher rate of complete response (86.21%) than patients with high level of ERCC1 expression (19.36%; p < 0.001). In the logistic regression analysis, low ERCC1 mRNA level retained an independent role in predicting complete response to CCCRT (P < 0.001). An ERCC1 expression level of 0.0901 was determined as an optimal cutoff value to identify complete response patients to CCCRT treatment. The sensitivity for detection of a complete response was 81.48% with a specificity of 96.97% (area under the curve, 0.893; 95% confidence interval, 0.804-0.983). This is the first analysis of the association between ERCC1 mRNA levels and treatment response in patients with LACSCC. Low ERCC1 mRNA level appears to be a highly specific predictor of response to CCCRT in LACSCC. |
23259413 | Plasma 25-hydroxyvitamin D concentrations and periodontal disease in postmenopausal women. | Vitamin D has anti-inflammatory and antimicrobial properties that, together with its influence on bone health, may confer periodontal benefit. Cross-sectional associations (years 1997-2000) between plasma 25-hydroxyvitamin D concentration [25(OH)D] and periodontal measure were investigated among 920 postmenopausal women. Measures of chronic disease were defined based on: 1) alveolar crestal height (ACH) measures from intraoral radiographs and tooth loss and 2) Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) criteria using measures of clinical attachment level and probing depth (PD). Acute oral inflammation was assessed by the percentage of gingival sites that bled upon assessment with a probe. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for periodontal disease among participants with adequate [25(OH)D ≥50 nmol/L] compared with deficient/inadequate [25(OH)D <50 nmol/L] vitamin D status adjusted for age, dental visit frequency, and body mass index. No association was observed between vitamin D status and periodontal disease defined by ACH and tooth loss (adjusted OR = 0.96, 95% CI = 0.68 to 1.35). In contrast, women with adequate compared with deficient/inadequate vitamin D status had 33% lower odds (95% CI = 5% to 53%) of periodontal disease according to the CDC/AAP definition and 42% lower odds (95% CI = 21% to 58%) of having ≥50% of gingival sites that bled. Vitamin D status was inversely associated with gingival bleeding, an acute measure of oral health and inflammation, and inversely associated with clinical categories of chronic periodontal disease that incorporated PD, an indicator of oral inflammation. However, vitamin D was not associated with chronic periodontal disease based on measures of ACH in combination with tooth loss. |
23259414 | Efficacy of collagen membrane seeded with autologous gingival fibroblasts in gingival recession treatment: a randomized, controlled pilot study. | Gingival recession (GR) is one of the most common esthetic concerns associated with periodontal tissues. Recently, tissue engineering technology has been developed and applied in periodontology for the treatment of GR. The aim of this study is to compare the clinical efficacy of collagen membrane with or without autologous gingival fibroblasts under a coronally advanced flap for root coverage. In this split-mouth, controlled clinical study, 22 sites are selected from 11 patients with Miller Class I recessions affecting canines or premolars in the maxillary arch. One tooth in each patient was randomized to receive either a collagen membrane (CM) (control group) or a collagen membrane seeded with autologous gingival fibroblasts (CM+GF) (test group) under a coronally advanced flap. Thickness of the gingiva, GR, and percentage of root coverage (PRC) were recorded by a calibrated examiner at baseline and 3, 6, and 12 months postoperatively. Furthermore, GR and PRC were evaluated using photogrammetric analysis at baseline and 3, 6, and 12 months. Both treatments resulted in a significant gain in root coverage compared with baseline. A statistically significant increase was detected in PRC in the test group compared with the control group. No significant difference was noted between the test and control sites regarding the thickness of the gingiva. The results indicated that CM+GF prepared by tissue engineering technology can be considered an alternative method for the treatment of Miller Class I recession defects. |
23259412 | Virulence mechanism of bacteria in mixed infection: attenuation of cytokine levels and evasion of polymorphonuclear leukocyte phagocytosis. | The objective of the present study is to evaluate the effect of bacterial viability on the virulence of mixed infection. Expression of pro- and anti-inflammatory cytokines (interleukin [IL]-1β and IL-10, respectively) was tested in vivo, following live versus heat-killed infection (mono or mixed), using the mouse chamber model of infection. Ex vivo, phagocytosis of fluorescently labeled bacteria was tested in primary mouse polymorphonuclear leukocytes by flow cytometry. In monoinfection, heat-killed Porphyromonas gingivalis led to augmented levels of IL-1β 2 hours postinfection, whereas IL-10 levels remained unaffected. Phagocytosis of heat-killed P. gingivalis was reduced compared with that of the live P. gingivalis, whereas phagocytosis of heat-killed Fusobacterium nucleatum was augmented compared with that of live F. nucleatum. In mixed infection, both IL-1β and IL-10 levels were augmented 24 hours postinfection when the bacteria were heat-killed. Although the phagocytosis pattern of F. nucleatum in the mixed infection remained similar to that upon monoinfection, phagocytosis of P. gingivalis was reduced following mixed infection. The inflammatory response to live mixed infection is attenuated with reduced phagocytosis, compared with that of heat-killed mixed infection. The lower response to live mixed infection could stem from a mechanism enabling the bacteria to evade the host response, thereby increasing bacterial survival. |
23259411 | Sn-doped In2O3 nanowires: enhancement of electrical field emission by a selective area growth. | Selective area growth of single crystalline Sn-doped In2O3 (ITO) nanowires synthesized via vapor-liquid-solid (VLS) method at 600°C was applied to improve the field emission behavior owing to the reduction of screen effect. The enhanced field emission performance reveals the reduction of turn-on fields from 9.3 to 6.6 V μm-1 with increase of field enhancement factors (β) from 1,621 to 1,857 after the selective area growth at 3 h. Moreover, we find that the screen effect also highly depends on the length of nanowires on the field emission performance. Consequently, the turn-on fields increase from 6.6 to 13.6 V μm-1 with decreasing β values from 1,857 to 699 after the 10-h growth. The detailed screen effect in terms of electrical potential and NW density are investigated in details. The findings provide an effective way of improving the field emission properties for nanodevice application. |
23259410 | Experiences from consumer reports on psychiatric adverse drug reactions with antidepressant medication: a qualitative study of reports to a consumer association. | The new European pharmacovigilance legislation has been suggested as marking the beginning of a new chapter in drug safety, making patients an important part of pharmacovigilance. In Sweden since 2008 it has been possible for consumers to report adverse drug reactions (ADRs) to the Medical Products Agency (MPA), and these reports are now understood as an increasingly valuable contribution in the monitoring of safety aspects in medicines. Already in 2002 it was possible to report experiences with medicines to the non-profit and independent organization Consumer Association for Medicines and Health (KILEN) through a web-based report form with an opportunity to describe ADR experiences in free text comments. The aim of this study was to qualitatively analyze the free text comments appended to consumer reports on antidepressant medication. All reports of suspected adverse reactions regarding antidepressant medications submitted from January 2002 to April 2009 to KILEN's Internet-based reporting system in Sweden were analyzed according to reported narrative experience(s). Content analysis was used to interpret the content of 181 reports with free text comments. Three main categories emerged from the analyzed data material: (1) Experiences of drug treatment with subcategories (a) Severe psychiatric adverse reactions, and (b) Discontinuation symptoms; (2) Lack of communication and (3) Trust and distrust. A majority of the reports to KILEN were from patients experiencing symptoms of mental disturbances (sometimes severe) affecting them in many different ways, especially during discontinuation. Several report included narratives of patients not receiving information of potential ADRs from their doctor, but also that there were no follow-ups of the treatment. Trust was highlighted as especially important and some patients reported losing confidence in their doctor when they were not believed about the suspected ADRs they experienced, making them attempt to discontinue their antidepressant treatment on their own. The present study indicates that free text comments as often contained in case reports directly submitted by patients can be of value in pharmacovigilance and provide important information on how a drug may affect the person using it and influence his or her personal life. |
23259409 | Integrated view of the human chromosome X-centric proteome project. | This article introduces how the human chromosome X-centric proteome project is carried out by the Japan Chromosome X Project Consortium. The inactivation of one of two chromosomes in female mammals and accumulation of genes related to neural/immune systems/tumor/testis are characteristic of chromosome X. In this Chromosome X Project, information on proteins translated from genes on chromosome X is collected by both mass spectrometry- and antibody-based proteomics. Information on the following resources is also provided: antibodies to proteins translated and full-length cDNAs transcripted from the chromosome X genes for recombinant proteins. The consortium aims to provide the following tools to search useful antibodies in the literature (Antibody Ranker), to find gene expression sites in microarray databases (Transcript Localizer) and to do advanced MRM analysis (information-based MRM). |
23259408 | Novel iron(II) microporous spin-crossover coordination polymers with enhanced pore size. | In this Communication, we report the synthesis and characterization of novel Hofmann-like spin-crossover porous coordination polymers of composition {Fe(L)[M(CN)(4)]}·G [L = 1,4-bis(4-pyridylethynyl)benzene and M(II) = Ni, Pd, and Pt]. The spin-crossover properties of the framework are closely related to the number and nature of the guest molecules included in the pores. |
23259407 | Contraception matters: indicators of poor usage of contraception in sexually active women attending family planning clinics in Victoria, Australia. | Unintended pregnancy (mistimed or unwanted) remains an important health issue for women. The purpose of this study was to determine the prevalence of and factors associated with risk of unintended pregnancy in a sample of Victorian women attending family planning clinics. This cross-sectional survey of three Family Planning Victoria Clinics from April to July 2011 recruited women aged 16-50 years with a male sexual partner in the last 3 months, and not intending to conceive. The questionnaire asked about contraceptive behaviours and important factors that influence contraception use (identified from a systematic literature review). Univariate analysis was calculated for the variables of interest for associations with contraceptive use. An overall multivariate model for being at risk for unintended pregnancy (due to inconsistent or ineffective contraceptive use or non-use) was calculated through backward elimination with statistical significance set at <0.05. 1006 surveys were analyzed with 96% of women reporting contraception use in the last 3 months. 37% of women were at risk for unintended pregnancy due to imperfect use (61% inconsistent users; 31% ineffective methods) or never using contraception (8%). On multivariate analysis, women at risk for unintended pregnancy compared with women not at risk were <25 years old (OR 1.8, 95% CI 1.2-2.7); had no university/postgraduate degree (OR 1.7, 95% CI 1.2-2.4); and had >1 partner in the last 3 months (OR 3.2, 95% CI 2.3-4.6). These women were dissatisfied with current contraception (OR 2.5, 95% 1.8-3.5); felt "vulnerable" to pregnancy (OR 2.1, 95% CI 1.6-3.0); were not confident in contraceptive knowledge (OR 2.6, 95% CI 1.5-4.8); were unable to stop to use contraception when aroused (OR 2.1, 95% CI 1.5-2.9) but were comfortable in speaking to a doctor about contraception (OR 2.3, 95% CI 1.1-4.1). Despite reported high contraceptive usage, nearly 40% of women were at risk for unintended pregnancy primarily due to inconsistent contraceptive use and use of ineffective contraception. Strategies for improving consistency of effective contraception use or greater emphasis on long-acting contraception may be needed for certain subpopulations at higher risk for unintended pregnancy. |
23259403 | Reconstruction of an in vitro niche for the transition from intervertebral disc development to nucleus pulposus regeneration. | The nucleus pulposus (NP) plays a prominent role in both the onset and progression of intervertebral disc degeneration. While autologous repair strategies have demonstrated some success, their in vitro culture system is outdated and insufficient for maintaining optimally functioning cells through the required extensive passaging. Consequently, the final population of cells may be unsuitable for the overwhelming task of repairing tissue in vivo and could result in subpar clinical outcomes. Recent work has identified synovium-derived stem cells (SDSCs) as a potentially important new candidate. This population of precursors can promote matrix regeneration and additionally restore the balance of catabolic and anabolic metabolism of surrounding cells. Another promising application is their ability to produce an extracellular matrix in vitro that can be modified via decellularization to produce a tissue-specific substrate for efficient cell expansion, while retaining chondrogenic potential. When combined with hypoxia, soluble factors, and other environmental regulators, the resultant complex microenvironment will more closely resemble the in vivo niche, which further improves the cell capacity, even after extensive passaging. In this review, the adaptive mechanisms NP cells utilize in vivo are considered for insight into what factors are important for constructing a tissue-specific in vitro niche. Evidence for the use of SDSCs for NP regeneration is also discussed. Many aspects of NP behavior are still unknown, which could lead to future work yielding key information on producing sufficient numbers of a high-quality NP-specific population that is able to regenerate deteriorated NP in vivo. |
23259406 | Blood parasites in nestlings of wood stork populations from three regions of the American continent. | This study documents the prevalences and lineages of hemoparasites in wood stork nestlings from 3 regions of the American continent: southeastern United States (n = 90), northern Brazil (n = 74), and central-western Brazil (n = 125). Identification was based on PCR amplification of a mitochondrial small subunit ribosomal RNA gene. A fragment of the hemoparasite cytochrome B gene in infected individuals was utilized for Bayesian phylogenetic analysis. Four wood stork nestlings were infected by Haemoproteus, 1 from northern Brazil and 3 from the United States, and all shared the same haplotype. Morphological analysis confirmed the infection of the U.S. birds by Haemoproteus. Infection by Plasmodium was found in wood stork nestlings from northern (6) and central-western Brazil (14). Five Plasmodium lineages (MYCAMP1-2, and MYCAMP4-6) were found in the Brazilian central-western region and 3 Plasmodium lineages (MYCAMP2-3, and MYCAMP7) were found in the northern region. The most prevalent haplotype (MYCAMP2) differs from the others by 1 mutation, and the less prevalent haplotypes are derived from MYCAMP2. We did not find Plasmodium or Haemoproteus in nestlings younger than 15 and 30 days old, respectively. This is the first documentation of Plasmodium and Haemoproteus infection in wood storks in Brazilian breeding populations. Potential connectivity among wood stork populations was indirectly supported by the presence of identical Haemoproteus lineages in U.S. and northern Brazilian populations, and by the presence of identical Plasmodium haplotypes in the northern and central-western Brazilian populations. |
23259405 | Strand-specific RNA-seq reveals widespread occurrence of novel cis-natural antisense transcripts in rice. | Cis-natural antisense transcripts (cis-NATs) are RNAs transcribed from the antisense strand of a gene locus, and are complementary to the RNA transcribed from the sense strand. Common techniques including microarray approach and analysis of transcriptome databases are the major ways to globally identify cis-NATs in various eukaryotic organisms. Genome-wide in silico analysis has identified a large number of cis-NATs that may generate endogenous short interfering RNAs (nat-siRNAs), which participate in important biogenesis mechanisms for transcriptional and post-transcriptional regulation in rice. However, the transcriptomes are yet to be deeply sequenced to comprehensively investigate cis-NATs. We applied high-throughput strand-specific complementary DNA sequencing technology (ssRNA-seq) to deeply sequence mRNA for assessing sense and antisense transcripts that were derived under salt, drought and cold stresses, and normal conditions, in the model plant rice (Oryza sativa). Combined with RAP-DB genome annotation (the Rice Annotation Project Database build-5 data set), 76,013 transcripts corresponding to 45,844 unique gene loci were assembled, in which 4873 gene loci were newly identified. Of 3819 putative rice cis-NATs, 2292 were detected as expressed and giving rise to small RNAs from their overlapping regions through integrated analysis of ssRNA-seq data and small RNA data. Among them, 503 cis-NATs seemed to be associated with specific conditions. The deep sequence data from isolated epidermal cells of rice seedlings further showed that 54.0% of cis-NATs were expressed simultaneously in a population of homogenous cells. Nearly 9.7% of rice transcripts were involved in one-to-one or many-to-many cis-NATs formation. Furthermore, only 17.4-34.7% of 223 many-to-many cis-NAT groups were all expressed and generated nat-siRNAs, indicating that only some cis-NAT groups may be involved in complex regulatory networks. Our study profiles an abundance of cis-NATs and nat-siRNAs in rice. These data are valuable for gaining insight into the complex function of the rice transcriptome. |
23259404 | Mechanistic studies on the metal-free activation of dihydrogen by antiaromatic pentarylboroles. | The perfluoro- and perprotiopentaphenylboroles 1 and 2 react with dihydrogen to effect H-H bond cleavage and formation of boracyclopentene products. The mechanism of this reaction has been studied experimentally through evaluation of the kinetic properties of the slower reaction between 2 and H(2). The reaction is first-order in both [borole] and [H(2)] with activation parameters of ΔH(‡) = 34(8) kJ/mol and ΔS(‡) = -146(25) J mol(-1) K(-1). A minimal kinetic isotope effect of 1.10(5) was observed, suggesting an asynchronous geometry for H-H cleavage in the rate-limiting transition state. To explain the stereochemistry of the observed products, a ring-opening/ring-closing mechanism is proposed and supported by the separate synthesis of a proposed intermediate and its observed conversion to product. Furthermore, extensive DFT mapping of the reaction mechanism supports the plausibility of this proposal. The study illustrates a new mechanism for the activation of H(2) by a strong main group Lewis acid in the absence of an external base, a process driven in part by the antiaromaticity of the borole rings in 1 and 2. |
23259402 | An automated method for analysis of microcirculation videos for accurate assessment of tissue perfusion. | Imaging of the human microcirculation in real-time has the potential to detect injuries and illnesses that disturb the microcirculation at earlier stages and may improve the efficacy of resuscitation. Despite advanced imaging techniques to monitor the microcirculation, there are currently no tools for the near real-time analysis of the videos produced by these imaging systems. An automated system tool that can extract microvasculature information and monitor changes in tissue perfusion quantitatively might be invaluable as a diagnostic and therapeutic endpoint for resuscitation. The experimental algorithm automatically extracts microvascular network and quantitatively measures changes in the microcirculation. There are two main parts in the algorithm: video processing and vessel segmentation. Microcirculatory videos are first stabilized in a video processing step to remove motion artifacts. In the vessel segmentation process, the microvascular network is extracted using multiple level thresholding and pixel verification techniques. Threshold levels are selected using histogram information of a set of training video recordings. Pixel-by-pixel differences are calculated throughout the frames to identify active blood vessels and capillaries with flow. Sublingual microcirculatory videos are recorded from anesthetized swine at baseline and during hemorrhage using a hand-held Side-stream Dark Field (SDF) imaging device to track changes in the microvasculature during hemorrhage. Automatically segmented vessels in the recordings are analyzed visually and the functional capillary density (FCD) values calculated by the algorithm are compared for both health baseline and hemorrhagic conditions. These results were compared to independently made FCD measurements using a well-known semi-automated method. Results of the fully automated algorithm demonstrated a significant decrease of FCD values. Similar, but more variable FCD values were calculated using a commercially available software program requiring manual editing. An entirely automated system for analyzing microcirculation videos to reduce human interaction and computation time is developed. The algorithm successfully stabilizes video recordings, segments blood vessels, identifies vessels without flow and calculates FCD in a fully automated process. The automated process provides an equal or better separation between healthy and hemorrhagic FCD values compared to currently available semi-automatic techniques. The proposed method shows promise for the quantitative measurement of changes occurring in microcirculation during injury. |
23259401 | Flow-through comb electroporation device for delivery of macromolecules. | We present a microfluidic electroporation device with a comb electrode layout fabricated in polydimethylsiloxane (PMDS) and glass. Characterization experiments with HeLa cells and fluorescent dextran show efficient delivery (∼95%) with low toxicity (cell viability ∼85%) as well as rapid pore closure after electroporation. The activity of delivered molecules is also verified by silencing RNA (siRNA) studies that demonstrate gene knockdown in GFP expressing cells. This simple, scalable approach to microfluidic, flow-through electroporation could facilitate the integration of electroporation modules within cell analysis devices that perform multiple operations. |
23259400 | Increased activity of extrinsic and intrinsic apoptosis pathways in different mononuclear cell types in HIV type 1-infected patients regardless of whether they are depleted in disease. | Myeloid dendritic cells (mDCs) are essential for initiation of adaptive immune responses but are depleted in HIV infection. Evidence suggests that apoptosis mediates loss, and to further understand the pathways involved, expression of caspases mediating apoptosis via the extrinsic and intrinsic pathways was analyzed. Blood samples were obtained from 14 HIV-infected patients (nine HAART and five antiretroviral naive) and 10 healthy controls. The expression of intracellular active caspases 8 and 9, associated with extrinsic and intrinsic pathways of apoptosis, and the expression of cell membrane death receptors and their ligands were assessed by flow cytometry in mDC. Additionally, expression of active caspases 8 and 9 in purified mDCs cultured for 5 days with HIV-Bal was analyzed. Frequencies of mDCs in the blood of HIV-infected patients were decreased while expression of CCR7 was up-regulated. Up to 94.4% and 91.8% of mDCs from HIV-infected patients expressed active caspases 8 and 9, respectively, compared to 24.5% and 19.9% from healthy controls (both p<0.0001). However, monocytes and B and T cells from HIV-infected patients also showed increased levels of these caspases. Percentages of FASL expression in mDCs were also elevated in HIV-infected individuals while mDCs expressing cell membrane death receptors remained unchanged. No differences between HAART and naive patients were observed for any of the molecules measured. Caspases 8 and 9 were up-regulated in mDCs cocultured with HIV despite lack of productive infection in vitro. Extrinsic and intrinsic pathways of apoptosis are up-regulated in HIV infection but do not correlate with cell depletion. |
23259398 | [Pharmacotherapy of parasitic and tropical diseases in Japan]. | Parasitic and tropical diseases are relatively rare in Japan. However, physicians have to realize that a patient may visit your hospital today, who is infected with a potentially fatal parasite. This review focuses on the treatment of the domestic and imported parasitic infections in Japan. Many of the drugs against parasitic diseases, especially imported protozoan diseases, have not been approved, nor have been covered by the National Health Insurance Policy. Therefore, patients who need pharmacotherapy with an unapproved drug have to be treated in one of the hospitals of the Research Group on Chemotherapy of Tropical Diseases, which imports effective drugs against major tropical diseases. |
23259397 | [Specific adverse events caused by monoclonal antibodies, focusing on the prophylaxis and management]. | Monoclonal antibodies play important roles in medical oncology. The antibodies were designed as specific molecular targeting drugs and supposed to have less toxicity to normal cells compared to classical cytotoxic agents. Indeed, they do not have severe bone marrow suppression, nausea, or vomiting unlike cytotoxic drugs. On the other hand, clinicians often undergo characteristic adverse events we have never experienced before the appearance of the molecular targeting drugs. To fully utilize these powerful yet particular medicines, we have to be well aware of their severe or fatal adverse events and comprehend how to manage those toxic events. In this manuscript, important adverse events including infusion reaction, gastrointestinal perforation, cardiotoxicity, venous thromboembolism, and interstitial lung disease are subjects for discussion. |
23259396 | [Mechanisms of resistance to target therapy]. | Cancer therapies are changing from general chemotherapeutic agents to drugs that target specific proteins and signaling pathways. Target therapies, which attack specific cancer cells without harming normal cells, have the potential to treat cancers with fewer side effects than conventional therapies. This article reviews mechanisms of resistance to targeted agents, including genetic resistance, bypass track resistance, and defect growth arrest/apoptosis. Secondary mutations reduce the biologic effects of inhibiting the driver oncoprotein. Interaction and cross signaling from targeting receptor to other growth factor receptors may potentially contribute to therapeutic resistance. They explain why solid tumors develop resistance to target therapies in a highly reproducible fashion. |
23259395 | [Epitope peptide vaccine with oncoantigen for cancer and its biomarker]. | For the breakthrough of the tumor escape mechanisms, immuno-chemo-combined therapy has been conducted. Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to up regulate tumor-associated antigen expression, and down regulate tumor cell resistance to the cytotoxic T lymphocytes. We conducted a phase II trials, administration of epitope peptides with FOLFOX to evaluate immunologic and clinical responses. Research into biomarkers that correlate with the clinical outcome of immunotherapy has behind vaccine development. Very few immunological or other markers exist that can be used in clinical trials for immunotherapy. We discuss with biomarkers specifically for the efficacy and monitoring of cancer vaccines. |
23259394 | [Immune monitoring and cancer vaccine]. | NY-ESO-1 antigen is a prototype of a class of cancer/testis antigens. We carried out three serial clinical trials using NY-ESO-1 whole protein, NY-ESO-1f long peptide and overlapping peptides as a cancer vaccine for advanced cancer patients. Although vaccines elicited NY-ESO-1 humoral and cellular immune responses in most patients, results of immune monitoring using peripheral blood was not consistent with clinical responses. Analysis of immunohistochemistry revealed possible involvement of regulatory mechanisms in local antitumor immunity. Immune checkpoint molecules, e.g., CTLA-4 and PD-1, on immune effector cells, and regulatory T cells are known to regulate the induced immune responses and minimize local tissue damage. We should take these factors into consideration for further strategy of cancer vaccine and its monitoring. |
23259393 | [Antibody therapy for malignant mesothelioma: humanized anti-cD26 mAb therapy]. | Malignant mesothelioma (MM) is an aggressive malignancy arising from the mesothelial cells. It is generally associated with a history of asbestos exposure and has a very poor prognosis. Due to lack of efficacy of conventional treatments, novel therapeutic strategies are urgently needed to improve outcomes. Recently we showed that CD26 is preferentially expressed on epithelial type of MM cells but not on normal mesothelial cells. We have developed a highly biological active humanized anti-CD26 mAb and this antibody inhibited growth and invasion of MM cells and induced long-term survival of tumor transplanted SCID mice. It is conceivable that CD26 is a new therapeutic target for MM. Phase I/II clinical trial for MM has been already starting in France and we plan to start the clinical trial for MM as soon as possible in Japan. |
23259392 | [Antibody therapies for melanoma]. | Melanoma is one of the most immunogenic tumors. However, objective response of immunotherapies has remained less than 5%. Since suppressive immunoreactions in tumor microenvironment have been illustrated in the past decade, immunosuppressive molecules are supposed to be useful targets of antibody therapies. One of the promising antibody therapies for melanoma is ipilimumab, anti-cytotoxic T-lymphocyte antigen (CTLA)4 antibody, which was approved by Food and Drug Administration in the U.S. in 2011. Although 10 mg/kg of ipilimumab showed 10-15% of objective response, phase 3 study of ipilimumab with gp100 vaccination or with dacarbazine showed prolonged survival. PD-1 blockade also showed more safe and great durable antitumor reactivity. Anti-CD137 agonist antibody and anti-CD40 agonist antibody are also good candidates for melanoma therapy. These immunomodulating therapies are the most promising treatment to overcome immunosuppression of melanoma. |
23259391 | [Treatment of bone metastasis by denosumab, the human monoclonal neutralizing antibody to RANKL]. | Solid cancers such as breast, prostate and lung cancer have a predilection for spreading to bone. Accumulating data suggest that the crosstalk between metastatic cancer cells and bone-resorbing osteoclasts plays a central role in the development and progression of bone metastases. Recent studies have revealed that osteoblasts mediate this crosstalk by expressing the receptor activator of NF-kappaB ligand (RANKL) in response to cancer-produced osteotropic factors. The RANKL promotes osteoclast formation and bone resorption via the binding to RANK expressed in hematopoietic osteoclast precursor cells and mature osteoclasts. Denosumab is the humanized anti-RANKL neutralizing monoclonal antibody and thus would be a specific and effective therapeutic agent for the treatment of bone metastases. In fact, clinical studies clearly demonstrated that denosumab significantly inhibited the development of skeletal-related events associated with bone metastases and indicate its usefulness for bone metastases. |
23259390 | [Anti-VEGF therapy for lung cancer]. | Bevacizumab is a humanized monoclonal antibody that specifically targets vascular endothelial growth factor (VEGF), and thereby prevents its interaction with the VEGF receptor. First line treatment with bevacizumab plus platinum-doublet and maintenance monotherapy with bevacizumab until disease progression has been shown to be effective in patients with non-squamous non-small-cell lung cancer. Two phase III trials have shown that the addition of bevacizumab to chemotherapy significantly increased progression-free survival and response rate. However, results in overall survival remain controversial. Bevacizumab's safety profile is well established. The risk of severe toxicity may be increased in elderly patients. The risks and benefits should be discussed with patients before decision making. Studies of combined therapy with pemetrexed, and bevacizumab beyond progression, are ongoing. |
23259389 | [Anti-EGFR antibody therapy for colorectal cancer]. | The epidermal growth factor receptor (EGFR) triggers a downstream signaling cascade such as the RAS-RAF-MAPK and PI3K-AKT pathways, which are involved in cell proliferation, differentiation, survival and invasion. Two monoclonal antibodies (moABS) targeting EGFR, cetuximab and panitumumab, are established to be a new treatment for metastatic colorectal cancers. Among activating mutations in the downstream of EGFR, the KRAS gene mutation has shown to be predictive biomarker for resistance to anti-EGFR antibody therapy. This review focuses on the current status of chemotherapy with anti-EGFR antibody for colorectal cancers. The identification of patients who are likely to benefit from EGFR-targeted moABS is increasingly crucial for improving therapeutic strategies. |
23259388 | [GammadeltaT cell therapy]. | Human gammadeltaT cells recognize pyrophosphomonoesters such as isopentenyl diphosphate and (E)-4-hydroxy-3-methylbut-2 enyl diphosphate derived from microbial pathogens. In addition, they display cytotoxic activity against various tumor cells in an NK receptor-dependent manner. When tumor cells are treated with nitrogen-containing bisphosphonates, gammadeltaT cells exhibit potent anti-tumor activity in a gammadeltaTCR-dependent manner. Based on these findings, gammadeltaT cells have attracted considerable attention in tumor immunotherapy. When gammadeltaT cell frequencies are relatively low, however, it is practically difficult to expand gammadeltaT cells. IL-18 has been recently shown to facilitate the development and proliferation of helper NK cells, which in turn promoted the expansion of gammadeltaT cells. The finding may contribute to the development of novel immunotherapeutic strategies for various cancers. |
23259386 | [The cancer specific antigen, glypican-3 (GPC3)-targeted immunotherapy]. | The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of tumor antigen-specific immunotherapy against hepatocellular carcinoma (HCC), because it is overexpressed specifically in HCC. We have reported that a GPC3-derived peptide vaccination was well-tolerated, and immune responses and antitumor efficacy were noted in a phase I trial for HCC patients. We have begun a phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for HCC patients, and a pilot study of liver biopsies performed before and after GPC3 peptide vaccination for advanced HCC to determine whether tumor-infiltrating lymphocytes are indeed GPC3 peptide-specific CTLs. Furthermore, we are initiating clinical trials of a GPC3-derived peptide vaccine for patients with hepatoblastoma or ovarian clear cell carcinoma. |
23259387 | [Immunotherapy targeting cancer stem cells]. | Cancer stem cells are relatively resistant to chemotherapy, and cause relapse of cancer. Thus, various strategies to eliminate cancer stem cells have recently been exploited. One of them is immunotherapy. To develop the immunotherapy targeting cancer stem cells, tumor antigens expressed in cancer stem cells have been identified, and their use in the immunotherapy is expected. However, cancer stem cells may have an immunosuppressive ability. Therefore, blockade of the immunosuppressive mechanisms of cancer stem cells may also be required for development of effective immunotherapies against cancer stem cells. |
23259385 | [Dendritic cells for cancer immunotherapy]. | Dendritic cells (DC) are the antigen presenting cells that initiate and regulate immunity. There are distinct DC subsets with specialized functions spread throughout the body. The type of immune response is determined by the DC subsets involved. Therefore, it is important to understand distinct phenotype and functions of these DC subsets in terms of antigen uptake and processing for MHC class I- and II-restricted presentation and receptors for foreign and endogenous signals. These insights facilitate the direct targeting of antigens to DC surface receptors in vivo rather than ex vivo culturing DC and antigen loading. In addition, novel DC immunotherapies will be in combination with drugs targeting immunological check points. |
23259384 | [Targeting cancer antigen (MAGE-A4, NY-ESO -1) for immunotherapy]. | Cancer/testis (CT) antigen is a group of antigens that are expressed in a wide variety of malignant tumors but not in normal adult tissues except for testis. Since CT antigens are immunogenic and highly restricted to tumors, they are considered as ideal targets for cancer immunotherapy. Many clinical studies targeting CT antigens have been tested. Here we review the history and the recent progress of clinical studies targeting MAGE family and NY-ESO-1 including our trials. |
23259383 | [Personalized peptide vaccination]. | We conducted personalized peptide vaccination (PPV) for various types of advanced cancers in the past 10 years. A maximum of four HLA-matched peptides, which were selected based on the pre-existing host immunity before vaccination, were subcutaneously administered at PPV trials. Randomized phase II trial for patients with castration resistant prostate cancer showed the favorite clinical responses in the PPV group. PPV was also conducted for recurrent or progressive glioblastoma multiforme patients with median overall survival of 10.6 months, resulting in the initiation of randomized phase III clinical trial. A randomized phase III trial is essential to prove clinical benefits of PPV. |
23259382 | [Cancer peptide vaccine therapy based on human genomics approach]. | We established a strategy as follows to identify oncoantigens and HLA-restricted epitope peptides, which can be applied as cancer vaccine therapy; i) To identify genes overexpressed in solid tumors using the cDNA microarray, ii) To validate the clinicopathological significance of their protein expression by tissue microarray covering thousands of human cancers, iii) To verify whether they are essential for the cell growth by siRNAs, iv) To screen for the epitope peptides recognized by human HLA-A* 0201/A* 2402-restricted cytotoxic T lymphocyte by ELISPOT assay. We identified dozens of epitopes derived from oncoantigens. In clinical trials, the cancer vaccine therapy against lung cancer using a combination of peptides demonstrated safety and good immunogenicity, and warrants further studies. |
23259381 | [WT1-targeting cancer vaccine]. | Wilms' tumor gene WT1 encodes a transcription factor and functions as an oncogene. WT1 gene product WT1 protein is a promising par-tumor-associated antigen. WT1 peptide-based immunotherapy has been performing for more than six hundred patients with leukemias and various types of solid tumors. This immunotherapy is safe and has clinical benefit especially for leukemia, glioblastoma multiforme, advanced pancreatic cancer, and ovarian cancer. As a new strategy for cancer treatment, it should be recommended to initiate immunotherapy that had a potential of eradication of cancer stem cells before surgery, chemo- and radio-therapy. |
23259380 | [Development trends for therapeutic antibody]. | Recent developments for therapeutic antibody have provided new options for cancer treatments. Modification of antibody molecules pursuing improvement of binding efficacy for Fcgamma receptors and enabling efficient recycling of antibody have been performed. Novel constructs of antibody possessing multivalent specificity and conjugated agents have also been developed. Based on exploration of new class of target molecules for therapeutic antibody, antibodies enhancing anti-tumor immunity such as anti-CTLA-4 antibody have appeared. These advancements would achieve more effective and safer therapy for various kinds of cancers. |
23259379 | [Mechanisms of antibody-based therapy against solid tumors]. | Advances in technology of antibody modification, such as chimeric antibody or humanized antibody against cancer specific proteins, allows us to apply them into the clinic efficiently. Most therapeutic antibodies inhibit proliferation of cancer cells by blockade of their receptors or ligands as well as related signal transductions. In addition to cancer cells, therapeutic antibodies are able to target vascular endothelial cells and immune cells, exerting their anti-tumor effects by inhibition of angiogenesis and enhancement of immune system. Recently, new therapeutic antibodies have been developed, which are able to induce cell death by binding to a cytotoxin or a radioisotope. In this review, we summarize the mechanisms of therapeutic antibodies by classifying their actions in regard to blocking, targeting, and signaling. |
23259378 | [An overview of antibody therapy against cancer]. | Monoclonal antibodies have become the most effective therapeutic modality for treating human cancer. Anti-cancer monoclonal antibodies can be targeted against cancer cells by several mechanisms. Even unconjugated antibodies show significant efficacy in the treatment of solid tumors and hematological malignancies. Immunoconjugates composed of antibodies conjugated to chemo-drugs, radioactive or toxins are powerful therapy for lymphomas and solid tumors. Moreover, immunomodulatory antibodies can promote the induction of anti-tumor immune responses by directly activating or inhibiting molecules of the immune system. Antibody structures now can be readily manipulated to facilitate selective interaction between the immune system and cancer cells, so that these reagents will become important components of the anti-neoplastic protocols of the future. |
23259377 | [New directions in immunotherapy for malignant solid tumors]. | Despite advances in treatment modalities, malignant solid tumors remain devastating maladies. Conventional treatment with chemotherapy and radiation is still only partially effective and highly toxic. In the era of increasing knowledge of the molecular biology of tumors and the interaction between the tumor and immune system, the development of targeted agents, including cancer vaccines, has emerged as a promising modality. This article will summarize the recent progress in developing cancer vaccines and immunotherapeutic approaches including adoptive cell transfer and will further review currently ongoing phase II/III studies for malignant solid tumors in the world. |
23259376 | [Mechanism of action for immunotherapy drugs]. | Cancer therapy utilizing cellular immunity has been developed using various reagents including stimulus for innate immunity, cytokines, vaccines, autologous cells and gene-vectors. Recently, mono-clonal antibodies have been added to the list as well. These reagents of modalities have been developed base on the findings in the basic research in cellular immunology which has been proven to have potent activities to suppress the tumor growth in either in vitro or in vivo. This review describes the characteristics of the reagents of modalities focusing on their mechanisms of action. |
23259375 | [Basic background for adjuvant immunotherapy]. | Pattern recognition receptors (PRRs) are evolved for sensing microbial infections by recognizing microbe--specific patterns to activate the innate immune system. In PRRs, Toll-like receptors(TLRs) are best characterized as a maturation inducer for dendritic cells and shown to participate in host defense and cellular immune responses against infection and cancer. Cancers usually harbor antigens but lack PRR agonists, namely adjuvant, that essentially differs from infections provided with antigen and adjuvant. Here we briefly review the role of TLRs in the aspect of adjuvant receptors which evoke innate and cognate immunity, and discuss the progress of clinical studies in the context of antitumor immunotherapy. |
23259374 | [Present status and future prospects of antibody therapy against solid tumor]. | Anti-tumor antibodies show significant anti-tumor activity against various tumor types especially by the combination with other cytotoxic drugs. Antibodies have been targeted against (1) Cell surface differentiation antigen, (2) Growth factor, (3) Growth factor receptor, (4) Signal transduction factors. By these antibodies significant increase in response rate, and prolongation of PFS/OS have been reported. Some antibodies have contributed to the establishment of new standard treatment. Patient selection has extensively been tried except for the treatment with bevacizumab. New problem appeared for the proof of principle study for immunotherapeutic antibody, ipilimumab because the mode of action of it seems to be non specific. |
23259373 | [Immunotherapy of solid tumor: perspectives on vaccine and cell therapy]. | Molecular identification of tumor antigens has made possible to develop tumor-specific immunotherapy. Provenge was approved by FDA as a first therapeutic drug for cancer in 2010. A line of drug candidates is in late phase clinical trials as therapeutic vaccine for patients with solid tumors. Adoptive immunotherapy with tumor-specific T cells demonstrated clinical effectiveness in patients with advanced malignancy such as metastatic melanoma and synovial cell sarcoma. Genetically engineered T cells were administrated to cancer patients with promising results and may extend the application of adoptive immunotherapy of tumor. Although recent findings in tumor biology and immunity suggest the integrated immune response against tumor with special emphasis on inhibitory mechanism, we are unmistakably witnessing the moment that immunotherapy of cancer becomes a medical option. |
23259370 | Rice bran oil: preparation and evaluation of novel liquisolid and semisolid formulations. | Rice bran oil and its bioactive constituents have been reported to possess different health benefit effects. Rice bran oil-containing pharmaceutical and cosmeceutical formulae are dispensed and characterized to elucidate the impact of their properties on clinical applications. Liquisolid and semisolid formulations employing rice bran oil were dispensed and characterized. Semisolid formulae were characterized for organoleptic properties, rheological behavior, and physical stability, at zero time and after three months storage, at 30 degrees C and 40 degrees C. Patch test of transdermal emollient creams and sunscreen was conducted in addition to evaluation of sensory attributes of emollient cream and sunscreen. Liquisolid formulations revealed flow and bulk density figures close to those reported as optimum acceptable values for powders. Semisolid formulations revealed adequate properties after three months of storage compared with zero time. Patch test showed safety of transdermal and emollient creams and sunscreen. Sensory evaluation of cosmetics showed satisfactory results. Results indicate the high potential of the formulated rice bran oil products regarding physical properties, stability, and acceptance by consumers. The formulae are simple to dispense, cost effective, and highly accepted by consumers. These facts pave the way for future clinical trials involving these products. |
23259369 | Stability of propranolol hydrochloride in SyrSpend SF. | Propranolol hydrochloride is a beta blocker used to treat high blood pressure, abnormal heart rhythms, heart disease, pheochromocytoma, and certain types of tremors. Propranolol is marketed by Wyeth (now a part of Pfizer) and AstraZeneca under the brand names Inderal, Inderal LA, Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilium, Bedranol SR (Sandoz). It is also available generically from several manufacturers. Propranolol hydrochloride is available as tablet, capsule, and oral liquid dosage forms in several strengths. Some patients are unable to tolerate oral tablets and capsules, challenging compounding pharmacies to seek alternative dosing options; namely oral solutions and suspensions. The objective of this study was to determine the stability of propranolol hydrochloride in SyrSpend SF. The drug was compounded into a 1-mg/mL suspension using SyrSpend SF and subsequently stored in a low-actinic plastic prescription bottle at room temperature conditions. Six samples were assayed at each specific time point extending to 90 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specificity through forced-degradation studies. Based on the data collected, when protected from light at room temperature, the beyond-use date of propranolol hydrochloride in SyrSpend SF was shown to be at least 90 days. |
23259368 | Stability of ursodiol in SyrSpend SF Cherry flavored. | Ursodiol is used in the treatment and prevention of certain types of gallstones and for patients with primary biliary cirrhosis. Ursodiol is marketed for this purpose by Watson Pharma, Inc. as ACTIGALL, by Axcan Scandipharm Inc. as URSO 250 and URSO Forte, and by a number of generic manufacturers. Ursodiol is available as capsules of varying strengths. The need for other dose-form options for those patients who cannot take capsules has led compounding pharmacies to seek other alternatives, namely oral solutions and suspensions. Additionally, some patients are unable to tolerate suspending agents containing alcohol or sorbitol. The objective of this study was to determine the stability of ursodiol in SyrSpend SF Cherry Flavored which does not contain sorbitol or alcohol. The studied sample was compounded into a 3-mg/mL [corrected] suspension and stored in a low-actinic plastic bottle at temperatures between 2 degrees C and 8 degrees C. Six samples were assayed at each time point out to 66 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specificity through forced degradation studies. The sample remained within 90% to 110% of the initial concentration throughout the course of the study. The beyond-use-date of this product is at least 66 days, based on data collected when refrigerated and protected from light. |
23259367 | Implementing United States Pharmacopeia Chapter <1163> quality assurance in pharmaceutical compounding, Part 5: Outsourcing and responsible personnel. | This final installment of a five-part series relating to United States Pharmacopeia Chapter <1163> provides the pros and cons of outsourcing, an extremely important topic because of the many drug shortages and discontinued drugs being experienced, and provides a brief discussion of the importance of having a responsible employee in charge of the quality-assurance program. |
23259366 | Quality control analytical methods: Certificates of Analysis, Part 1. | When comparing a CofA for an official ingredient, product, or preparation, it is required that all the specifications are within the allowable tolerances. For APIs for which there is not an official monograph, one can usually select a monograph of an API in a similar class for a guideline for individual specifications. |
23259364 | Colds & cough. | The common cold leads to approximately 75 to 100 million physician visits annually. An estimated 22 to 189 million school days are missed annually due to a cold, which affects working parents with approximately 126 million workdays staying home to care for their children. Add this to the approximately 150 million workdays missed by employees suffering from a cold, which accounts for approximately 40% of time lost from work in the U.S., and you can see why the "common" cold is referred to as the most "common" human disease. Common colds are not a trivial health problem, as these statistics indicate, and that can be attributed to the fact that there simply is no cure for the common cold and the fact that it is highly contagious. However, the symptoms can be treated, and compounding pharmacists can work with the patient and the physician in this endeavor. |
23259362 | Beyond-use date: establishment and maintenance. | With the introduction of United States Pharmacopeia Chapters <795> and <797>, the long-standing concept of drug stability (beyond-use dates and expiration dates) came to the forefront of pharmacy compounding practice. Beyond-use date extension can only be done if end-point sterility testing is done on compounded sterile preparations. It is not for everyone and can only be accomplished by using an analytical approach. This article discusses the unique skill set required by pharmacists to accomplish and maintain these processes. |