A steady-state kinetic interface-sensitive tracer (KIS-SST) method to measure capillary associated interfacial area in a simultaneous co-flow condition.

We propose a novel method to measure the specific capillary-associated interfacial area (awn) between non-wetting and wetting fluids by applying kinetic interface-sensitive (KIS) tracers under steady-state two-phase co-flow conditions. Seven column experiments were conducted with a column filled with glass beads (diameter d50 = 170 µm), serving as the solid grain network of a porous granular material. The experiments were performed for two flow scenarios, i.e., five experiments were performed for drainage conditions (increasing non-wetting saturation) and two experiments for imbibition conditions (increasing wetting saturation). To obtain different saturation levels in the column and, consequently, different capillarity-induced interfacial areas between the fluids, the experiments were performed for different fractional flow ratios (i.e., the ratio between injection rate of the wetting phase and total injection rate). The concentrations of the KIS tracer reaction by-product were recorded at each saturation level and the corresponding interfacial area was calculated. As a result of the fractional flow condition a wide range of wetting phase saturation is created (0.3 < Sw < 0.8). The measured awn increases with decreasing wetting phase saturation for the range 0.55 < Sw < 0.8, and then is followed by a drop in wetting phase saturation of 0.3 < Sw < 0.55. A good fit for our calculated awn is obtained (RMSE <0.16) using a polynomial model. Additionally, the results of the proposed method are compared to published experimental data and the method's main advantages and limitations are discussed.

Targeting Cell-Specific Molecular Mechanisms of Innate Immunity in Atherosclerosis.

Mechanisms of innate immunity contribute to inflammation, one of the major underlying causes of atherogenesis and progression of atherosclerotic vessel disease. How immune cells exactly contribute to atherosclerosis and interact with molecules of cholesterol homeostasis is still a matter of intense research. Recent evidence has proposed a potential role of previously underappreciated cell types in this chronic disease including platelets and dendritic cells (DCs). The pathophysiology of atherosclerosis is studied in models with dysfunctional lipid homeostasis and several druggable molecular targets are derived from these models. Specific therapeutic approaches focussing on these immune mechanisms, however, have not been successfully introduced into everyday clinical practice, yet. This review highlights molecular insights into immune processes related to atherosclerosis and potential future translational approaches targeting these molecular mechanisms.

[Emergency room activation due to trauma mechanism]. / Schockraumindikation nach Unfallhergang.

BACKGROUND: The quality of trauma care in Germany has been significantly increased due to the establishment of standards in the white paper on severe injury care and the S3 guidelines. A key issue of multiple trauma treatment is the trauma resuscitation unit (TRU)/emergency room management, which is associated with extensive material and human resources. From the very beginning of the introduction of structured care for the severely injured, the choice of the target hospital and the indications for TRU have been the focus of scientific research. Furthermore, a reduction of the TRU team for presumably less seriously injured patients is discussed. MATERIAL AND METHODS: The emergency room assignments of a level I trauma center (n = 686) were analyzed in more detail. Of the patients 235 were assigned with the TRU indications according to the cause of the accident (GoR B criteria) and compared with the collective of TRU patients admitted according to the severity of injuries or life-threatening signs, the so-called GoR A criteria (n = 104) during the corresponding period. In addition to basic data (age, sex), the injured region and severity (injury severity score, ISS), the length of stay in the intensive care unit (ICU) and hospital as well as the necessity for surgery and transfusion were compared. RESULT: Of the emergency room allocations at the trauma center 34% were due to the cause of the accident and the severity of the injuries in this patient group was almost half as high as that of the control group with an ISS of 11. Of the patients 74% were admitted to the IMC/ICU and stayed there for an average of almost 3 days. There were between 4% and 18% severe injuries (abbreviated injury scale, AIS 3) and 17.9% were characterized as polytrauma with an ISS ≥ 16 points. CONCLUSION: A significant number of patients admitted to a TCU due to the cause of accident (the so-called B criteria of the white book), have severe and potentially life-threatening injuries, which necessitate a prioritized and immediate treatment by a TCU team. Whether a reduced TCU team is sufficient in this situation needs to be critically examined.

Coating of PLA-nanoparticles with cyclic, arginine-rich cell penetrating peptides enables oral delivery of liraglutide.

Until today, the oral delivery of peptide drugs is hampered due to their instability in the gastrointestinal tract and low mucosal penetration. To overcome these hurdles, PLA (polylactide acid)-nanoparticles were coated with a cyclic, polyarginine-rich, cell penetrating peptide (cyclic R9-CPP). These surface-modified nanoparticles showed a size and polydispersity index comparable to standard PLA-nanoparticles. The zeta potential showed a significant increase indicating successful CPP-coupling to the surface of the nanoparticles. Cryo-EM micrographs confirmed the appropriate size and morphology of the modified nanoparticles. A high encapsulation efficiency of liraglutide could be achieved. In vitro tests using Caco-2 cells showed high viability indicating the tolerability of this novel formulation. A strongly enhanced mucosal binding and penetration was demonstrated by a Caco-2 binding and uptake assay. In Wistar rats, the novel nanoparticles showed a substantial, 4.5-fold increase in the oral bioavailability of liraglutide revealing great potential for the oral delivery of peptide drugs.

Hypoxia and the group VII ethylene response transcription factor HRE2 promote adventitious root elongation in Arabidopsis.

Soil water-logging and flooding are common environmental stress conditions that can impair plant fitness. Roots are the first organs to be confronted with reduced oxygen tension as a result of flooding. While anatomical and morphological adaptations of roots are extensively studied, the root system architecture is only now becoming a focus of flooding research. Adventitious root (AR) formation shifts the root system higher up the plant, thereby facilitating supply with oxygen, and thus improving root and plant survival. We used Arabidopsis knockout mutants and overexpressors of ERFVII transcription factors to study their role in AR formation under hypoxic conditions and in response to ethylene. Results show that ethylene inhibits AR formation. Hypoxia mainly promotes AR elongation rather than formation mediated by ERFVII transcription factors, as indicated by reduced AR elongation in erfVII seedlings. Overexpression of HRE2 induces AR elongation to the same degree as hypoxia, while ethylene overrides HRE2-induced AR elongation. The ERFVII transcription factors promote establishment of an AR system that is under negative control by ethylene. Inhibition of growth of the main root system and promotion of AR elongation under hypoxia strengthens the root system in upper soil layers where oxygen shortage may last for shorter time periods.

New Experimental Equipment Recreating Geo-Reservoir Conditions in Large, Fractured, Porous Samples to Investigate Coupled Thermal, Hydraulic and Polyaxial Stress Processes.

Use of the subsurface for energy resources (enhanced geothermal systems, conventional and unconventional hydrocarbons), or for storage of waste (CO2, radioactive), requires the prediction of how fluids and the fractured porous rock mass interact. The GREAT cell (Geo-Reservoir Experimental Analogue Technology) is designed to recreate subsurface conditions in the laboratory to a depth of 3.5 km on 200 mm diameter rock samples containing fracture networks, thereby enabling these predictions to be validated. The cell represents an important new development in experimental technology, uniquely creating a truly polyaxial rotatable stress field, facilitating fluid flow through samples, and employing state of the art fibre optic strain sensing, capable of thousands of detailed measurements per hour. The cell's mechanical and hydraulic operation is demonstrated by applying multiple continuous orientations of principal stress to a homogeneous benchmark sample, and to a fractured sample with a dipole borehole fluid fracture flow experiment, with backpressure. Sample strain for multiple stress orientations is compared to numerical simulations validating the operation of the cell. Fracture permeability as a function of the direction and magnitude of the stress field is presented. Such experiments were not possible to date using current state of the art geotechnical equipment.

Valor nutritivo da Coastcross-1 inoculada com Azospirillum brasilense / Nutritive value of Coastcross-1 inoculated with Azospirillum brasilense

Objetivou-se com este trabalho avaliar a taxa de produção de forragem e o valor nutritivo da Coastcross-1, inoculada com Azospirillum brasilense, fertilizada com diferentes doses de N e submetida ao regime de corte. O delineamento experimental foi o de blocos ao acaso, com três repetições, em esquema fatorial. Os fatores foram o uso da inoculação (não inoculada, inoculada somente no plantio e reinoculada no segundo ano), níveis de N (0, 100 e 200kg/ha/ano de N) e os períodos do ano. Avaliaram-se a taxa de produção e a composição botânica da forragem, a composição morfológica, o teor de proteína bruta, a digestibilidade in situ da matéria orgânica e os nutrientes digestíveis totais da Coastcross-1. A inoculação, quando não associada ao adubo nitrogenado, ocasionou aumento na taxa de produção de forragem, na participação da Coastcross-1 e na produção de nutrientes digestíveis totais. Houve redução nos teores de proteína bruta da Coastcross-1, quando a gramínea adubada com 200kg/ha/ano de N foi inoculada. A inoculação tem efeito positivo na Coastcross-1 não submetida à adubação nitrogenada.(AU)

The objective of this study was to evaluate the forage yield rate and nutritive value of Coastcross-1 inoculated with Azospirillum brasilense and fertilized with different levels of nitrogen subjected to cut. The experimental design was randomized blocks with three replications, in a factorial scheme. The factors were the inoculation (without inoculation, inoculated just in the implantation and reinoculated in the second year), levels of nitrogen (0, 100 and 200kg/ha/year of N) and periods of the year. Forage yield rate and botanical composition; morphological composition, crude protein content, in situ digestibility of organic matter and the total digestible nutrients of Coastcross-1 were evaluated. Inoculation increased the forage yield rate, Coastcross-1 contribution and production of total digestible nutrients, when the pasture was not fertilized with N. There was reduction in Coastcross-1 crude protein content when fertilized with 200kg/ha/yr of N. The inoculation has a positive effect on Coastcross-1 not submitted to nitrogen fertilization.(AU)

Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice.

UNLABELLED: During the 2009 H1N1 influenza pandemic, infection attack rates were particularly high among young individuals who suffered from pneumonia with occasional death. Moreover, previously reported determinants of mammalian adaptation and pathogenicity were not present in 2009 pandemic H1N1 influenza A viruses. Thus, it was proposed that unknown viral factors might have contributed to disease severity in humans. In this study, we performed a comparative analysis of two clinical 2009 pandemic H1N1 strains that belong to the very early and later phases of the pandemic. We identified mutations in the viral hemagglutinin (HA) and the nucleoprotein (NP) that occurred during pandemic progression and mediate increased virulence in mice. Lethal disease outcome correlated with elevated viral replication in the alveolar epithelium, increased proinflammatory cytokine and chemokine responses, pneumonia, and lymphopenia in mice. These findings show that viral mutations that have occurred during pandemic circulation among humans are associated with severe disease in mice. IMPORTANCE: In this study, novel determinants of 2009 pandemic H1N1 influenza pathogenicity were identified in the viral hemagglutinin (HA) and the nucleoprotein (NP) genes. In contrast to highly pathogenic avian influenza viruses, increased virulence in mice did not correlate with enhanced polymerase activity but with reduced activity. Lethal 2009 pandemic H1N1 infection in mice correlated with lymphopenia and severe pneumonia. These studies suggest that molecular mechanisms that mediate 2009 pandemic H1N1 influenza pathogenicity are distinct from those that mediate avian influenza virus pathogenicity in mice.

Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

[Nephrotic syndrome in a woman with tuberous sclerosis]. / Nephrotisches Syndrom bei einer Patientin mit tuberöser Sklerose.

HISTORY AND CLINICAL FINDINGS: A 50-year-old woman with known tuberous sclerosis complex (TSC) was referred for further work-up of nephrotic syndrome. A left-side nephrectomy due to an anamnestically reported "shrunken kidney" had been performed at the age of 15 years. The patient presented with massive edematous swelling of all extremities and typical cutaneous lesions of TSC. DIAGNOSTIC FINDINGS, TREATMENT AND CLINICAL COURSE: Laboratory analysis revealed nephrotic proteinuria, hypalbuminemia and advanced impairment of kidney function. Computed tomography revealed a massively enlarged remaining kidney with confluent angiomyolipomata. As kidney biopsy was deemed to be too hazardous, a thorough work-up for potentially underlying diseases finally revealed endometrial carcinoma. Hysterectomy resulted in a prompt and sustained decrease of proteinuria and disappearance of edema. CONCLUSION: Although a renal involvement is typical in TSC the occurrence of nephrotic syndrome is not and should give reason for further evaluation.

Toward more accurate measurements of anorectal motor and sensory function in routine clinical practice: validation of high-resolution anorectal manometry and Rapid Barostat Bag measurements of rectal function.

BACKGROUND: Measurements of anorectal function using high-resolution anorectal manometry (HR-ARM) and rectal barostat technology provide more reliable results than standard ARM with an elastic balloon; however, HR-ARM results have not been compared to ARM and standard barostat protocols are impractical in routine clinical practice. The aim of this study was to validate HR-ARM against standard ARM and standard barostat against a novel Rapid Barostat Bag (RBB) measurement and elastic balloon measurements of rectal function. METHODS: Twenty-six healthy volunteers (15 female, 11 male, 19-52 years) were studied. Measurements of anal function and simulated defecation were compared for 12-sensor HR-ARM and 6-sensor standard ARM using line plots from the same recording. Rectal capacity, compliance, and sensation (volume threshold) were measured by elastic balloon, standard barostat, and RBB methods using stepwise inflation of a 700-mL polyethylene bag to 40 mmHg distension by electronic barostat and handheld syringe monitored by sphygmo-manometer, respectively. Results are reported as mean ± SD. Bland-Altman plots and correlation coefficients (r) for measurements were calculated. KEY RESULTS: There was excellent agreement between HR- and standard ARM measurements (r > 0.86, <25 mmHg difference) and between standard barostat and RBB measurements of rectal capacity (r = 0.97, <25 mL difference). Correlation coefficients of threshold volumes for initial perception, urgency and discomfort were 0.37, 0.71, and 0.95, respectively. No significant correlation was present with elastic balloon measurements. Time to complete studies was shorter for HR-ARM than standard ARM and for RBB than standard barostat in historical controls. CONCLUSIONS & INFERENCES: HR-ARM with RBB measurements of anorectal function provides quick and reasonably accurate measurements of continence function suitable for use in routine clinical practice (ClinicalTrial.gov NCT01456442).

[Therapy refractory stromal Herpes keratitis under aciclovir]. / Therapierefraktäre stromale Herpeskeratitis unter Aciclovir.

We report the case of a patient with suspected ulcerating necrotizing herpetic stromal keratitis who showed no improvement despite intensive (amongst others antiherpetic) topical and systemic therapy. The ulcer healed following amniotic membrane transplantation and penetrating excimer laser keratoplasty was performed to improve visual acuity. The excision showed deep stromal proof of herpes simplex virus (HSV) type 1 antigens.

The effect of standard compared to enhanced instruction and verbal feedback on anorectal manometry measurements.

BACKGROUND: Guidelines recommend instruction and motivation during anorectal manometry; however, its impact on findings has not been reported. This study assessed the effects of standard versus enhanced instruction and verbal feedback on the results of anorectal manometry. METHODS: High-resolution manometry was performed by a solid-state catheter with 10 circumferential sensors at 6 mm separation across the anal canal and two rectal sensors. Measurements were acquired first with standard instruction and then with enhanced instruction and verbal feedback. On both occasions, squeeze pressure and duration during three voluntary contractions and intra-rectal pressure and recto-anal pressure gradient (RAPG) during three attempts at simulated defecation were assessed. KEY RESULTS: A total of 70 consecutive patients (54 female; age 25-82 years) referred for investigation of fecal incontinence (n = 31), constipation, and related disorders of defecation (n = 39) were studied. Enhanced instruction and verbal feedback increased maximum squeeze pressure (Δ10 ± 28.5 mmHg; P < 0.0038) and duration of contraction (Δ3 ± 4 s; P < 0.0001). During simulated defecation, it increased intra-rectal pressure (Δ12 ± 14 mmHg; P < 0.003) and RAPG (Δ11 ± 20 mmHg; P < 0.0001). Using standard diagnostic criteria, the intervention changed manometric findings from locally validated 'pathologic' to 'normal' values in 14/31 patients with incontinence and 12/39 with disorders of defecation. CONCLUSIONS & INFERENCES: Enhanced instruction and verbal feedback significantly improved voluntary anorectal functions and resulted in a clinically relevant change of manometric diagnosis in some patients. Effective explanation of procedures and motivation during manometry is required to ensure consistent results and to provide an accurate representation of patient ability to retain continence and evacuate stool.

[Ping-pong transmission of herpes simplex virus 1 following corneal transplantation]. / Ping-Pong-Transmission von Herpes-simplex-Virus 1 nach Hornhauttransplantation.

BACKGROUND: Primary corneal graft failure (PCGF) after penetrating keratoplasty (PKP) despite good endothelial cell count of the transplant in organ culture rarely occurs in young patients. A herpes simplex virus type I (HSV-1) infection (transmission through the donor or reactivation by the patient) can lead to PCGF. METHODS: We report on a 43-year-old man with pellucid marginal corneal degeneration and neurodermitis, who was underwent penetrating keratoplasty (PKP) on the left eye after acute corneal hydrops in both eyes. A repeat keratoplasty (re-PKP) had to be performed 15 days after the first PKP due to a primary graft failure. A re-re-PKP with simultaneous amniotic membrane transplantation (as a patch) and partial lateral tarsorrhaphy became necessary 4 months after the re-PKP due to melting on the edge of the graft with persistent epithelial defects. RESULTS: After intensive cooperation between ophthalmologists and pathologists the histopathological findings showed keratocytes which reacted immunohistochemically positive for HSV-1 antigens in the deep corneal stroma of both corneal grafts. The excised own cornea of the patient was histopathologically negative but the DNA-PCR for HSV-1 was weakly positive. After adequate topical and systemic antiviral therapy the third graft has remained clear for 12 months. CONCLUSION: In cases of PCGF after normal risk corneal transplantation the possibility of HSV infection should always be considered. After confirmation of the diagnosis with the help of the immunohistochemical tests and/or PCR, an adequate treatment with antiviral medication (acyclovir tablets 2 × 400 mg for more than 1 year) should be administered to the patient after repeat PKP.

Measuring the interaction of meal and gastric secretion: a combined quantitative magnetic resonance imaging and pharmacokinetic modeling approach.

BACKGROUND: The stimulation and intragastric accumulation of gastric secretion has been recognized as an important factor in gastroesophageal reflux disease. However, the interaction of gastric secretion and meal emptying has not been fully understood. Current methods to assess gastric secretion are either invasive or unable to provide information on its volume, distribution and dynamics. The aim of this study was to quantify the interaction between meal emptying and meal induced gastric secretion by using quantitative magnetic resonance imaging (MRI) and pharmacokinetic analysis. METHODS: A chocolate test meal was developed which is secretion stimulating and MRI compatible. Meal emptying and gastric secretion were assessed in fourteen healthy volunteers using a validated quantitative MRI technique. A population based pharmacokinetic model was developed and applied to the extracted volume data, assessing the meal emptying rate, rate of secretion and their interaction. KEY RESULTS: The test meal continuously induced gastric secretion in all subjects, which partly accumulated at the meal-air interface, forming a 'secretion layer' in the proximal stomach. Traditional fitting detected a significant correlation between meal emptying rate and rate of secretion. The pharmacokinetic model quantified this interaction and estimated a 2.3 ± 1 fold higher effect of meal on secretion than vice versa. The efficacy of the emptied meal to produce gastric secretion was 61%. CONCLUSIONS & INFERENCES: The combined quantitative MRI and pharmacokinetic model approach allows for the quantification of gastric secretion volume and its interaction on meal emptying. The observed secretion layer might explain previous findings postulating the presence of an intragastric 'acid pocket'.

Exploring the influence of operational parameters on the reactivity of elemental iron materials.

In an attempt to characterize material intrinsic reactivity, iron dissolution from elemental iron materials (Fe(0)) was investigated under various experimental conditions in batch tests. Dissolution experiments were performed in a dilute solution of ethylenediaminetetraacetate (Na(2)-EDTA - 2mM). The dissolution kinetics of 18 Fe(0) materials were investigated. The effects of individual operational parameters were assessed using selected materials. The effects of available reactive sites [Fe(0) particle size (

Evaluation of the effects of shaking intensity on the process of methylene blue discoloration by metallic iron.

The term mixing (shaking, stirring, agitating) is confusing because it is used to describe mass transfer in systems involving species dissolution, species dispersion and particle suspension. Each of these mechanisms requires different flow characteristics in order to take place with maximum efficiency. This work was performed to characterize the effects of shaking intensity on the process of aqueous discoloration of methylene blue (MB) by metallic iron (Fe(0)). The extent of MB discoloration by three different materials in five different systems and under shaking intensities varying from 0 to 300 min(-1) was directly compared. Investigated materials were scrap iron (Fe(0)), granular activated carbon (GAC), and deep sea manganese nodules (MnO(2)). The experiments were performed in essay tubes containing 22 mL of the MB solution (12 mg/L or 0.037 mM). The essay tubes contained either: (i) no reactive material (blank), (ii) 0-9.0 g/L of each reactive material (systems I, II and III), or (iii) 5g/L Fe(0) and 0 to 9.0g/L GAC or MnO(2) (systems IV and V). The essay tubes were immobilized on a support frame and shaken for 0.8-5 days. Non-shaken experiments lasted for duration up to 50 days. Results show increased MB discoloration with increasing shaking intensities below 50 min(-1), a plateau between 50 and 150 min(-1), and a sharp increase of MB discoloration at shaking intensities >or=200 min(-1). At 300 min(-1), increased MB discoloration was visibly accompanied by suspension of dissolution products of Fe(0)/MnO(2) and suspension of GAC fines. The results suggest that, shaking intensities aiming at facilitating contaminant mass transfer to the Fe(0) surface should not exceed 50 min(-1).

Comet assay analysis of single-stranded DNA breaks in circulating leukocytes of glaucoma patients.

PURPOSE: To investigate the amount of single-stranded DNA breaks in circulating leukocytes of primary open-angle glaucoma (POAG) patients. METHODS: A comparative quantification of DNA breaks was performed in circulating leukocytes of POAG patients and healthy controls. The following groups of subjects were compared: (1) POAG patients having primary vascular dysregulation (PVD), (2) POAG patients without PVD, (3) healthy controls with PVD, and (4) healthy controls without PVD. The damage to DNA resulting in single-stranded breaks was assessed by means of the alkaline comet assay in which the damaged DNA migrates out of the nucleus forming a tail, which can be quantified using image analysis. Damage was quantified as the comet tail moment, which represents the extent of DNA damage in individual cells. RESULTS: Leukocytes of POAG patients exerted a significantly higher amount of comet tails, which are indicative of DNA damage, in comparison to control leukocytes (p<0.001). DNA breaks occurred particularly in the subgroup of POAG patients with PVD in comparison to glaucoma patients without PVD (p=0.002). In the control group, there was no significant difference between controls with PVD and controls without PVD (p=0.86). CONCLUSIONS: POAG patients with PVD have a significantly higher rate of DNA breaks than both POAG patients without PVD and healthy controls with and without PVD.

Endogenous retroviruses and cancer.

The genomes of vertebrates contain sequences that are similar to present-day exogenous retroviruses. Such sequences, called endogenous retroviruses (ERVs), have resulted from ancestral germ line infections by exogenous retroviruses which have thereafter been transmitted in a Mendelian fashion. By analogy to exogenous tumorigenic retroviruses, ERVs have been implicated in the pathogenesis of cancer. Cumulative evidence from animal models indicates that ERVs may participate in the process of malignant transformation or promote tumor growth, e.g. through insertional mutagenesis or via counteracting tumor immunosurveillance. Here, we review the role of ERVs in tumorigenesis with focus on human ERVs (HERVs) in human cancer. Although available data suggest a potential role of HERVs in human cancers, in particular germ cell tumors, the contributions of HERVs to human tumorigenesis warrant further elucidation. (Part of a multi-author review).

Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study.

OBJECTIVE: The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). METHODS: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. TRIAL REGISTRATION: NCT00099216. RESULTS: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. CONCLUSION: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.