Controlling the Self-Injection Threshold in Laser Wakefield Accelerators.

Controlling the parameters of a laser plasma accelerated electron beam is a topic of intense research with a particular focus placed on controlling the injection phase of electrons into the accelerating structure from the background plasma. An essential prerequisite for high-quality beams is dark-current free acceleration (i.e., no electrons accelerated beyond those deliberately injected). We show that small-scale density ripples in the background plasma are sufficient to cause the uncontrolled (self-)injection of electrons. Such ripples can be as short as ∼50 µm and can therefore not be resolved by standard interferometry. Background free injection with substantially improved beam characteristics (divergence and pointing) is demonstrated in a gas cell designed for a controlled gas flow. The results are supported by an analytical theory as well as 3D particle in cell simulations.

A roadmap for graphene.

Recent years have witnessed many breakthroughs in research on graphene (the first two-dimensional atomic crystal) as well as a significant advance in the mass production of this material. This one-atom-thick fabric of carbon uniquely combines extreme mechanical strength, exceptionally high electronic and thermal conductivities, impermeability to gases, as well as many other supreme properties, all of which make it highly attractive for numerous applications. Here we review recent progress in graphene research and in the development of production methods, and critically analyse the feasibility of various graphene applications.

Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons.

Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC-exposed human neonates. Pericardial fat thickness (7.7±3.6 mm vs 3.1±1.1 mm, M±s.d.; P=0.022; n=5) and hepatic fatty acids (13.3±11.0% vs 2.5±2.2%; P=0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary.

Clinical outcome and global gene expression data support the existence of the estrogen receptor-negative/progesterone receptor-positive invasive breast cancer phenotype.

The presence or absence of estrogen and progesterone steroid hormone receptor expression (ER, PR) is an essential feature of invasive breast cancer and determines prognosis and endocrine treatment decisions. Among the four ER/PR receptor phenotypes, the ER-/PR+ is infrequent, and its clinical relevance has been controversially discussed. Thus, we investigated its clinical significance and gene expression pattern in large datasets. In a retrospective clinical study of 15,747 breast cancer patients, we determined the ER/PR subtype survival probabilities using Kaplan-Meier and Cox regression analyses. From The Cancer Genome Atlas (TCGA) breast cancer dataset, PAM50 expression signature and pathway analyses were performed to test for distinct molecular features. In our cohort, the ER-/PR+ phenotype has been observed at a frequency of 4.1 % and was associated with an improved 10-year survival for stage I cancers compared to the ER+/PR+ reference subtype (median; 95 % CI 88.1 %; 83-93 vs. 84.3 %; 82-86 %, P = 0.024) as was confirmed by multivariate analysis over the entire follow-up (HR 0.59, 95 % CI 0.38-0.92, P = 0.021). This association lacked significance when including all stages. ER-/PR+ patients treated with antihormonal agents (34.5 %) had shorter survival compared to their non-treated counterparts (Log-rank P = 0.0001). PAM50 signatures suggest a distinct configuration for the ER-/PR+ phenotype. This specific phenotype has been further separated by a set of 59 uniquely expressed genes. Our study supports the notion of the existence of an ER-/PR+ phenotype with clinical and molecular features distinct from the large group of ER+/PR+ patients.

Functional characterization of common protein variants in the efflux transporter ABCC11 and identification of T546M as functionally damaging variant.

Multidrug resistance protein 8 (ABCC11) is an efflux transporter for anionic lipophilic compounds, conferring resistance to antiviral and anticancer agents like 5-fluorouracil (5-FU). ABCC11 missense variants may contribute to variability in drug response but functional consequences, except for the 'earwax variant' c.538G>A, are unknown. Using the 'Screen and Insert' technology, we generated human embryonic kidney 293 cells stably expressing ABCC11 missense variants frequently occurring in different ethnic populations: c.57G>A, c.538G>A, c.950C>A, c.1637C>T, c.1942G>A, c.4032A>G. A series of in silico prediction analyses and in vitro plasma membrane vesicle uptake, immunoblotting and immunolocalization experiments were undertaken to investigate functional consequences. We identified c.1637C>T (T546M), previously associated with 5-FU-related toxicity, as a novel functionally damaging ABCC11 variant exhibiting markedly reduced transport function of 5-FdUMP, the active cytotoxic metabolite of 5-FU. Detailed analysis of 14 subpopulations revealed highest allele frequencies of c.1637C>T in Europeans and Americans (up to 11%) compared with Africans and Asians (up to 3%).

Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors.

Human organic anion transporter 7 (OAT7, SLC22A9) is a hepatic transport protein poorly characterized so far. We therefore sought to identify novel OAT7 substrates and factors contributing to variable hepatic OAT7 expression. Using OAT7-expressing cells, pravastatin was identified as a substrate. Hepatic SLC22A9/OAT7 mRNA and protein expression varied 28-fold and 15-fold, respectively, in 126 Caucasian liver samples. Twenty-four variants in SLC22A9 were genotyped, including three rare missense variants (rs377211288, rs61742518, rs146027075), which occurred only heterozygously. No variant significantly affected hepatic SLC22A9/OAT7 expression. The three missense variants, however, showed functional consequences when expressed in vitro. Hepatic nuclear factor 4-alpha (HNF4α) emerged as a major transcriptional regulator of SLC22A9 by a series of in silico and in vitro analyses. In conclusion, pravastatin is the first identified OAT7 drug substrate. Substantial inter-individual variability in hepatic OAT7 expression, majorly driven by HNF4α, may contribute to pravastatin drug disposition and might affect response.The Pharmacogenomics Journal advance online publication, 4 August 2015; doi:10.1038/tpj.2015.55.

Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration.

BACKGROUND AND PURPOSE: There is an urgent need for early predictive markers for the course of disease in prodromal α-synucleinopathies such as idiopathic rapid eye movement (REM) sleep behaviour disorder. Autonomic cardiac/vascular dysfunction is a prominent feature in advanced α-synucleinopathies, but its diagnostic value as an early neurodegenerative marker remains unclear. The latter may be complicated since synuclein-mediated neurodegeneration may involve central and peripheral components of the autonomic nervous system. METHODS: The diagnostic value of autonomic symptoms and central and peripheral autonomic markers of blood pressure and heart rate regulation were prospectively evaluated in 20 subjects with idiopathic REM sleep behaviour disorder and 20 age-matched healthy controls. RESULTS: Although subjects with REM sleep behaviour disorder showed no clinical autonomic symptoms, blood pressure (P ≤ 0.035) and heart rate response (P ≤ 0.065) were slightly diminished during orthostatic challenge. Autonomic dysregulation was distinctively reflected in lower resting heart rate (all components, P ≤ 0.05) and blood pressure variability (low frequency component, P ≤ 0.024) indicating peripheral cardiac/vascular denervation. In contrast, baroreflex sensitivity and central cardiac autonomic outflow (sympathovagal balance) were well preserved indicating intact central autonomic regulation. Heart rate variability [very low frequency component, receiver operating characteristic (ROC) area under the curve (AUC) 0.80, P ≤ 0.001] and blood pressure variability (low frequency component ROC AUC 0.73, P ≤ 0.01) but not baroreflex sensitivity and sympathovagal balance showed an excellent diagnostic accuracy in identifying subjects with REM sleep behaviour disorder and healthy controls. CONCLUSIONS: Cardiac/vascular dysfunction in prodromal α-synucleinopathy arises from peripheral rather than from central autonomic degeneration. Autonomic indices encoded in heart rate and blood pressure variability are precise functional markers of early synuclein-mediated neurodegeneration.

Stratified medicine for the use of antidiabetic medication in treatment of type II diabetes and cancer: where do we go from here?

At present, the global diabetes epidemic is affecting 347 million individuals, 90% of whom are diagnosed with type II diabetes mellitus (T2DM). T2DM is commonly treated with more than one type of therapy, including oral antidiabetic drugs (OADs) and agents used in the treatment of diabetic complications. Several pharmacological classes of OADs are currently available for the treatment of T2DM, of which insulin secretagogues (i.e. sulphonylureas and meglitinides), insulin sensitizers [thiazolidinediones (TZDs)] and biguanides are the most commonly prescribed. Although many of these OADs have been used for more than half a century in the treatment of T2DM, the pharmacogenomic characteristics of these compounds have only recently been investigated, primarily in retrospective studies. Recent advances in pharmacogenomics have led to the identification of polymorphisms that affect the expression and function of drug-metabolizing enzymes and drug transporters, as well as drug targets and receptors. These polymorphisms have been shown to affect the therapeutic response to and side effects associated with OADs. The aim of this review was to provide an up-to-date summary of some of the pharmacogenomic data obtained from studies of T2DM treatment, with a focus on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly prescribed OADs. In addition, the implications of pharmacogenomics in the use of the OAD metformin in cancer will be briefly discussed. Finally, we will focus on recent advances in novel 'omics' technologies and discuss how these might aid in the personalized management of T2DM.

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Direct Observation of the Injection Dynamics of a Laser Wakefield Accelerator Using Few-Femtosecond Shadowgraphy.

We present few-femtosecond shadowgraphic snapshots taken during the nonlinear evolution of the plasma wave in a laser wakefield accelerator with transverse synchronized few-cycle probe pulses. These snapshots can be directly associated with the electron density distribution within the plasma wave and give quantitative information about its size and shape. Our results show that self-injection of electrons into the first plasma-wave period is induced by a lengthening of the first plasma period. Three-dimensional particle-in-cell simulations support our observations.

A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine.

At the blood-brain barrier, overexpression of the drug efflux transporter ABCC2 (also known as MRP2) has been proposed as a mechanism for impaired carbamazepine (CBZ) treatment response in epilepsy. However, investigation of the impact of ABCC2 polymorphisms on CBZ treatment efficacy has produced conflicting and inconclusive results. A series of in vitro cell efflux and plasma membrane vesicle uptake assays were undertaken to investigate whether CBZ was an ABCC2 substrate. In addition, the effect of three common ABCC2 polymorphisms, -24C>T, c.1249G>A and c.3972C>T, on the efficacy of CBZ in epilepsy (assessed using the clinical end points time to first seizure and time to 12-month remission from the SANAD (Standard and New Antiepileptic Drugs) trial) was determined. CBZ was found not to be a substrate for human ABCC2 in vitro. Clinically, no significant association was observed for the ABCC2 genetic variants and CBZ treatment outcomes. This comprehensive analysis does not support a role for ABCC2 in CBZ treatment efficacy.

Combination of high on-treatment platelet aggregation and low deaggregation better predicts long-term cardiovascular events in PCI patients under dual antiplatelet therapy.

High on-treatment platelet reactivity is associated with short-term major cardiovascular (CV) events in patients undergoing percutaneous coronary intervention (PCI). Maximum and final aggregation assessed by light transmission aggregometry (LTA) have both been used to predict short-term outcome after PCI, however their long-term prognostic impact remains controversial. There is currently no information regarding the prognostic role of deaggregation and its added value in combination with established aggregation parameters. About 1279 patients with symptomatic coronary artery disease (CAD) undergoing PCI were enrolled in this monocentric study. On-treatment platelet aggregation under clopidogrel maintenance therapy, as well as deaggregation was determined by maximum and final aggregation (5 min after adding of the agonist). Deaggregation was defined as slope of the tangent between Aggmax +0.5 min. Primary endpoints were the composite of myocardial infarction, stroke, and CV death or stent thrombosis according to the ARC criteria. Low deaggregation, defined as values in the lowest tertile (<1.5), was more frequent in patients with acute coronary syndromes (ACS) compared to patients with stable angina pectoris (SAP), ACS: 29.6% vs. SAP: 22.0%, p = 0.001. The combination of high on-treatment platelet reactivity, defined by the upper tertile of Aggmax and low deaggregation, was associated with significantly increased risk for combined long-term CV events. The combination of low deaggregation and high on-treatment platelet reactivity is associated with higher risk for recurrent events in patients with CAD undergoing PCI. Thus, deaggregation might be a more sensitive parameter providing added value in terms of risk prediction for long-term recurrent CV events in relation with established aggregation parameters.

[Age and osteoporosis. Effects of aging on osteoporosis, the diagnostics and therapy]. / Alter und Osteoporose. Auswirkungen der Alterung auf die Osteoporose, deren Diagnostik und Therapie.

BACKGROUND: Osteoporosis is an age-associated disease, which is influenced by genetic, epigenetic and environmental factors. AIM: This article examines the evidence for specific aspects in osteoporosis diagnosis and management in higher age groups. MATERIAL AND METHODS: The study was based on extraction of data from literature databases and from the guidelines of the "Dachverband Osteologie" (DVO, Governing Body for Osteology). RESULTS: Age is a high risk factor for osteoporosis. Vitamin D insufficiency and reduced calcium absorption are common in the elderly. Loss of bone and muscle develop in a vicious circle of immobilization caused by underlying diseases. In addition deficits in cognition and coordination promote falls and fragility fractures. Clinical risk assessment including geriatric test batteries is recommended in all women > 70 and men > 80 years of age. Specific medication is indicated if the 10-year fracture risk exceeds 30 %, where in women > 75 and in men > 85 years of age bone density measurement can be relinquished. There is good evidence for the efficacy of antiosteoporotic medication even for the elderly. Prevention of falls requires multimodal management to enhance muscle power and coordination. It is essential to improve underlying cardiovascular, pulmonary and neurological diseases while critically evaluating the necessity of medication that boosts the risk of falls and fractures. There is good evidence for age and disease-adapted exercise programs such as Tai-Chi. Treating osteoporosis reduces the fracture risk, improves the quality of life, maintains independence and decreases mortality. CONCLUSION: Treating osteoporosis in the elderly is strongly recommended. Multimodal management and medication according to guidelines can be very successful, given that interdisciplinary and geriatric concepts consider the specific needs of the elderly population.

Genomics of ADME gene expression: mapping expression quantitative trait loci relevant for absorption, distribution, metabolism and excretion of drugs in human liver.

Expression quantitative trait loci (eQTL) analysis is a powerful approach toward identifying genetic loci associated with quantitative changes in gene expression. We applied genome-wide association analysis to a data set of >300 000 single-nucleotide polymorphisms and >48 000 mRNA expression phenotypes obtained by Illumina microarray profiling of 149 human surgical liver samples obtained from Caucasian donors with detailed medical documentation. Of 1226 significant associations, only 200 were validated when comparing with a previously published similar study. Potential explanations for low replication rate include differences in microarray platforms, statistical modeling, covariates considered and origin and collection procedures of tissues. Focused analysis revealed a subset of 95 associations related to absorption, distribution, metabolism and excretion of drugs. Of these, 21 were true replications and 74 were newly discovered associations in enzymes, transporters, transcriptional regulators and other genes. This study extends our knowledge about the genetics of inter-individual variability of gene expression with particular emphasis on pharmacogenomics.

Functional outcome in dogs undergoing hemilaminectomy for thoracolumbar disc extrusion but without nociception > 96 h: A prospective study.

This prospective study investigated the functional recovery of surgically treated dogs with thoracolumbar intervertebral disc extrusion (IVDE) without deep pain perception (DPP) for > 96 h. Dogs (n = 36) with paraplegia secondary to thoracolumbar intervertebral disc extrusion with loss of deep pain perception ranging from 4 to 60 days were enrolled. All dogs underwent hemilaminectomy and fenestration of the affected intervertebral disc and postoperative follow-up was provided for a maximum of 180 days. Recovery of motor function was satisfactory (based on the owner's assessment) in 22 dogs, 61.1% (47.2% with DPP, and 13.9% without DPP) and unsatisfactory in 38.9% of cases (n = 14). Postoperative physiotherapy, preoperative anti-inflammatory drugs, and age had no effect on recovery. In this study, the longer the time taken to regain pain perception, the longer the recovery time. The median time to recovery was 30 days. A total of 47.2% of dogs with paraplegia and absence of DPP secondary to thoracolumbar IVDE lasting > 96 h, recovered functional ambulation after decompressive surgery.

Heart rate variability - a potential early marker of sub-acute post-stroke infections.

OBJECTIVE: Infection is the most relevant complication after acute ischemic stroke. Activity of the autonomic nervous system seems to control post-stroke immunodepression. We investigated heart rate variability (HRV) indices that reflect autonomic readjustments as predictors of post-stroke infection. MATERIALS AND METHODS: Forty-three patients with acute ischemic stroke were enrolled in a prospective study. The predictability of sub-acute infections (day 4 ± 1 after admission) was investigated in 34 patients without acute infection by means of HRV indices obtained in the acute period (48 h after admission). RESULTS: Sub-acute infection could be predicted in patients without clinical or paraclinical (white blood cell count and C-reactive protein) signs of infection in the acute period at (i) day: increased HFnorm, reduced LFnorm and LF/HF; (ii) night: reduced LF and VLF (P < 0.05). CONCLUSIONS: HRV indices are candidates for early markers of developing post-stroke infections, preceding routine blood samples. Thus, HRV-based early diagnosis of post-stroke infection should be investigated in more detail as it may have implications as a novel tool for timely and appropriate treatment. A corresponding continuous HRV-based risk assessment using the ECG provided by the routine stroke monitoring system would be possible without any additional burden for patients and staff.

[Implementation and results of a geriatric medication database]. / Aufbau und Ergebnisse einer geriatrischen Medikamentendatenbank.

BACKGROUND: The aim of this project was to obtain information about drug therapy in geriatric units. PATIENTS AND METHODS: Members of the geriatrics in Bavaria database (GiB-DAT) collected data on discharge medication and transferred them to the database. A total of 88,840 data sets of geriatric rehabilitation clinics and acute geriatric units were evaluated according to the anatomical therapeutic chemical (ATC) system. RESULTS: Patients (mean age: 81.1 years, female 67.7%) had an average of 10.4 diagnoses and took 8.0 drugs at discharge. A peak number of prescribed drugs was reached at the age of 60-70 years with a decrease in the following decades of life. Female patients received more drugs, significantly those in the decades from 71 to 80 and 81 to 90 years old. The bulk of the drugs were from the ATC groups "Cardiovascular system" (89.9%), "Nervous system" (82.3%) and "Alimentary tract and metabolism" (78%).

Modulators of neuronal migration and neurite growth.

A multitude of molecules have been identified over the past few years that promote neurite outgrowth in vitro. The concept that these molecules work mainly by providing an adhesive surface for neuronal growth cones has been challenged by evidence from recent experiments. Some of the substrate molecules have diverse actions on cell migration and neurite growth. In addition, there is now evidence that there are molecules that specifically inhibit growth cone locomotion. This has given rise to the hypothesis that growth cones integrate a variety of growth-promoting and inhibitory signals and translate them into directed locomotion.