EEG rhythmic and arrhythmic spectral components and functional connectivity at resting state may predict the development of synucleinopathies in idiopathic REM sleep behavior disorder.

STUDY OBJECTIVES: Idiopathic/isolated REM-sleep behavior disorder (iRBD) often precedes the onset of synucleinopathies. Here, we investigated whether baseline resting-state EEG advanced spectral power and functional connectivity differ between iRBD patients who converted towards a synucleinopathy at follow-up and those who did not. METHODS: Eighty-one participants with iRBD (66.89±6.91 years) underwent a baseline resting-state EEG recording, a neuropsychological assessment and a neurological examination. We estimated EEG power spectral density using standard analyses and derived spectral estimates of rhythmic and arrhythmic components. Global and pairwise EEG functional connectivity analyses were computed using the weighted phase-lag index (wPLI). Pixel-based permutation tests were used to compare groups. RESULTS: After a mean follow-up of 5.01±2.76 years, 34 patients were diagnosed with a synucleinopathy (67.81±7.34 years) and 47 remained disease-free (65.53±7.09 years). Among patients who converted, 22 were diagnosed with Parkinson's disease and 12 with dementia with Lewy bodies. As compared to patients who did not convert, patients who converted exhibited at baseline higher relative theta standard power, steeper slopes of the arrhythmic component and higher theta rhythmic power mostly in occipital regions. Furthermore, patients who converted showed higher beta global wPLI but lower alpha wPLI between left temporal and occipital regions. CONCLUSION: Analyses of resting-state EEG rhythmic and arrhythmic components and functional connectivity suggest an imbalanced excitatory-to-inhibitory activity within large-scale networks, which is associated with later development of a synucleinopathy in iRBD patients.

Immortalization of primary sheep embryo kidney cells.

Sheep primary epithelial cells are short-lived in cell culture systems. For long-term in vitro studies, primary cells need to be immortalized. This study aims to establish and characterize T immortalized sheep embryo kidney cells (TISEKC). In this study, we used fetal lamb kidneys to derive primary cultures of epithelial cells. We subsequently immortalized these cells using the large T SV40 antigen to generate crude TISEKC and isolate TISEKC clones. Among numerous clones of immortalized cells, the selected TISEKC-5 maintained active division and cell growth over 20 passages but lacked expression of the oncogenic large T SV40 antigen. Morphologically, TISEKC-5 maintained their epithelial aspect similar to the parental primary epithelial cells. However, their growth properties showed quite different patterns. Crude TISEKC, as well as the clones of TISEKC proliferated highly in culture compared to the parental primary cells. In the early passages, immortalized cells showed heterogeneous polyploidy but in the late passages the karyotype of immortalized cells became progressively stable, identical to that of the primary cells, because the TISEKC-5 cell line has lost the large SV40 T antigen expression, this cell line is a valuable tool for veterinary sciences and biotechnological productions.

Association between depression and hostile attribution bias in hostile and non-hostile individuals: An ERP study.

BACKGROUND: Hostility and aggression have been found to be highly prevalent among depressed patients and are associated with higher comorbidity and illness severity levels. Although negative interpretation biases are a fundamental element of cognitive models of depression, few studies have examined the specific biases in information processing, mainly the hostile attribution bias, found in hostile individuals who present depressive symptoms. METHOD: Using pre-collected data from a sample of 72 (male=41,6%, female=58,3%) undergraduate and community-based hostile (n = 26) and non-hostile (n = 46) adult participants, the authors aimed to examine the association between depression and the hostile attribution bias by determining whether depression level scores were uniquely related to electrophysiological measures of the hostile attribution bias. RESULTS: The hostile group showed higher measured levels of depression and reactive aggression compared to the non-hostile group. Also, depression scores were significant predictors of the N400 effect in the non-hostile task condition, while reactive aggression was not, whereas in the hostile condition, the overall model was significant, with depression and reactive aggression levels both showing strong trends towards significance. LIMITATIONS: A small sample size limited the scope of our conclusions. Also, sample selection prevented us from examining specific group differences regarding the hostile attribution bias in depressed and non-depressed groups. CONCLUSION: Clinical and research implications include the necessity to apply cognitive restructuring techniques to counter biased interpretation processes in settings where depression and aggression intersect, and the need to consider alternatives to self-evaluative methodologies.

Evaluation of the effect of vincristine on platelet count in dogs with lymphoma.

OBJECTIVES: To determine the effect of vincristine administration on the platelet count, platelet morphology and incidence of thrombocytopenia in dogs diagnosed with lymphoma. MATERIAL AND METHODS: Medical records of 59 dogs with lymphoma receiving vincristine sulphate were reviewed retrospectively. RESULTS: Following vincristine administration the platelet count was higher and the number of thrombocytopenic patients was lower. No difference was found in the number of dogs with enlarged and elliptical platelets following vincristine treatment. CLINICAL SIGNIFICANCE: Vincristine administration increases platelet counts in dogs with lymphoma. It is not contra-indicated to administer vincristine to dogs with lymphoma that are thrombocytopenic.

Antibacterial activity of chemotherapeutic drugs against Escherichia coli and Staphylococcus pseudintermedius.

The ability of chemotherapeutic agents to affect the growth of common bacterial pathogens and the relationship between the effects of chemotherapeutics and antimicrobials is largely unknown. The purpose of this study was to describe the susceptibility of canine bacterial isolates to chemotherapeutic agents and to compare these results to their antimicrobial susceptibility. The effects of bleomycin, doxorubicin, cytarabine, cyclophosphamide, methotrexate, 5-fluorouracil and gemcitabine on the growth of 33 Staphylococcus pseudintermedius isolates and 32 Escherichia coli isolates from dogs was determined by agar dilution. In addition to MICs, the lowest drug concentration associated with a decreased colony size was recorded. Results were compared to the MICs of a panel of antimicrobial agents. Bleomycin consistently inhibited bacterial growth of S. pseudintermedius and E. coli. Doxorubicin inhibited S. pseudintermedius but not E. coli while the opposite was seen for gemcitabine. Reduction in colony size on exposure to 5-fluorouracil for both organisms, and methotrexate for S. pseudintermedius was seen. No observable effect of cyclophosphamide or cytarabine was observed. Associations between elevated MICs to chemotherapeutic drugs and antimicrobial resistance were not found. These results indicate that chemotherapeutic agents affect the growth of bacteria, but do not support a role in the selection of antimicrobial resistance. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that chemotherapy drugs commonly used in veterinary oncology have an effect of the growth of canine isolates of Escherichia coli and Staphylococcus pseudintermedius. No associations between susceptibility to chemotherapeutic drugs and antibiotics were found, which does not support selection of antimicrobial resistance by chemotherapy drugs.

Recommendations on breast cancer screening and prevention in the context of implementing risk stratification: impending changes to current policies.

In recent years, risk stratification has sparked interest as an innovative approach to disease screening and prevention. The approach effectively personalizes individual risk, opening the way to screening and prevention interventions that are adapted to subpopulations. The international perspective project, which is developing risk stratification for breast cancer, aims to support the integration of its screening approach into clinical practice through comprehensive tool-building. Policies and guidelines for risk stratification-unlike those for population screening programs, which are currently well regulated-are still under development. Indeed, the development of guidelines for risk stratification reflects the translational aspects of perspective. Here, we describe the risk stratification process that was devised in the context of perspective, and we then explain the consensus-based method used to develop recommendations for breast cancer screening and prevention in a risk-stratification approach. Lastly, we discuss how the recommendations might affect current screening policies.

Synthesis, characterization, antibacterial activity and cytotoxicity of hollow TiO2-coated CeO2 nanocontainers encapsulating silver nanoparticles for controlled silver release.

Biomaterials as implants are being applied more extensively in medicine due to their on-going development and associated improvements, and the increase in human life expectancy. Nonetheless, biomaterial-related infections, as well as propagating bacterial resistance, remain significant issues. Therefore, there is a growing interest for silver-based drugs because of their efficient and broad-range antimicrobial activity and low toxicity to humans. Most newly-developed silver-based drugs have an extremely fast silver-ion release, increasing adverse biological impact to the surrounding tissue and achieving only short-term antimicrobial activity. Nanoencapsulation of these drugs is hypothesized as beneficial for controlling silver release, and thus is the aim of the present study. Initially, an amorphous or crystalline (anatase) titania (TiO2) coating was synthesized around silver nanoparticle-containing (AgNP) ceria (CeO2) nanocontainers using a sonication method forming AgNP/CeO2/TiO2 nanocontainers. These nanocontainers were characterized by high-resolution transmission electron microscopy, scanning electron microscopy, powder X-ray diffraction, gas sorption experiments and energy-dispersive X-ray spectroscopy. Silver release, monitored by using inductively coupled plasma optical emission spectroscopy, showed that these containers prevented silver release in water at neutral pH, and released the silver in concentrated nitric acid solution (pH = 1.1). The AgNP/CeO2/TiO2 nanocontainers showed an antibacterial activity against E. coli, however a concentration-dependent cytotoxicity towards a model epithelial barrier cell type (A549 cells) was observed. These nanocontainers offer the concept of potentially controlling silver delivery for the prevention of implant-associated infections.

Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice.

Ghrelin is a stomach-derived peptide hormone that stimulates appetite and promotes adiposity through binding to the growth hormone secretagogue receptor (GHS-R1a). Administration of ghrelin in rodents increases weight gain due to stimulating food intake and reducing fat utilization. Therefore, reducing circulating ghrelin levels holds the potential to reduce weight gain. We developed a GHS-R1a-fusion constructs of a decoy protein containing the ligand-binding domains of the ghrelin receptor. Intramuscular injection of the GHSR/Fc plasmid decreased circulating levels of acylated-ghrelin. When challenged with the high fat diet, treated mice displayed reduced weight gain compared with controls, which was associated with reduced fat accumulation in the peritoneum but not lean mass. Quantitative PCR with reverse transcription showed increased PPARγ and hormone sensitive lipase transcripts levels in adipose tissue of treated animals, illustrating a preference for increased fat utilization. Intra-peritoneal glucose tolerance and insulin tolerance tests showed improved glucose clearance and insulin sensitivity in GHSR/Fc treated animals. We suggest that in vivo expression of the GHSR-based fusion protein prevents diet-induced weight gain, altering adipose gene expression and improving glucose tolerance. These findings, while confirming the role of ghrelin in peripheral energy metabolism, suggest that a strategy involving neutralization of the circulation ghrelin by intramuscular injection of the GHSR1/Fc fusion construct may find clinical application in the treatment of obesity.

Parkinson's Disease Genetic Loci in Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.

Psychological characteristics of patients with myotonic dystrophy type 1.

OBJECTIVES: Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy. It is associated with motor symptoms but patients also display non-motor symptoms such as particular personality traits. Studies have reported mixed results about personality characteristics which may be attributable to small sample sizes, different disease severity of groups studied, and use of different questionnaires or method. This study aimed to describe the psychological characteristics of a large cohort of patients with DM1, to characterize those at risk of developing a psychiatric disorder, and to compare characteristics between two DM1 phenotypes, a mild and more severe adult-onset phenotype. METHODS: Two hundred patients with DM1 (152 adult-onset; 48 mild) were asked to complete questionnaires assessing personality traits, psychological symptoms, self-esteem, and suicidal risk. Neurological and neuropsychological assessments were performed to compare personality characteristics to clinical and cognitive measures. RESULTS: Patients with DM1 globally showed personality traits and psychological symptoms in the average range compared to normative data, with normal levels of self-esteem and suicidal ideation. However, 27% of patients were found to be at high risk of developing a psychiatric disorder. Moreover, psychological traits differed across phenotypes, with the most severe phenotype tending to show more severe psychological symptoms. The presence of higher phobic anxiety and lower self-esteem was associated with lower education, a higher number of CTG repeats, more severe muscular impairment, and lower cognitive functioning (P < 0.001). CONCLUSIONS: Different phenotypes should thus be taken into account in clinical settings for individual management of patients and optimizing therapeutic success.

Integrating silver compounds and nanoparticles into ceria nanocontainers for antimicrobial applications.

Silver compounds and nanoparticles (NPs) are gaining increasing interest in medical applications, specifically in the treatment and prevention of biomaterial-related infections. However, the silver release from these materials, resulting in a limited antimicrobial activity, is often difficult to control. In this paper, ceria nanocontainers were synthesized by a template-assisted method and were then used to encapsulate silver nitrate (AgNO3/CeO2 nanocontainers). Over the first 30 days, a significant level of silver was released, as determined using inductively coupled plasma optical emission spectroscopy (ICP-OES). A novel type of ceria container containing silver NPs (AgNP/CeO2 containers) was also developed using two different template removal methods. The presence of AgNPs was confirmed both on the surface and in the interior of the ceria containers by X-ray diffraction (XRD), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Upon removal of the template by calcination, the silver was released over a period exceeding three months (>90 days). However, when the template was removed by dissolution, the silver release was shortened to ≤14 days. The antimicrobial activity of the silver-containing CeO2 containers was observed and the minimum bactericidal concentration (MBC) was determined using the broth dilution method. Investigation on human cells, using a model epithelial barrier cell type (A549 cells), highlighted that all three samples induced a heightened cytotoxicity leading to cell death when exposed to all containers in their raw form. This was attributed to the surface roughness of the CeO2 nanocontainers and the kinetics of the silver release from the AgNO3/CeO2 and AgNP/CeO2 nanocontainers. In conclusion, despite the need for further emphasis on their biocompatibility, the concept of the AgNP/CeO2 nanocontainers offers a potentially alternative long-term antibactericidal strategy for implant materials.

Cognitive impairment in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterised by repetitive cessation or reduction of airflow due to upper airway obstructions. These respiratory events lead to chronic sleep fragmentation and intermittent hypoxemia. Several studies have shown that OSA is associated with daytime sleepiness and cognitive dysfunctions, characterized by impairments of attention, episodic memory, working memory, and executive functions. This paper reviews the cognitive profile of adults with OSA and discusses the relative role of altered sleep and hypoxemia in the aetiology of these cognitive deficits. Markers of cognitive dysfunctions such as those measured with waking electroencephalography and neuroimaging are also presented. The effects of continuous positive airway pressure (CPAP) on cognitive functioning and the possibility of permanent brain damage associated with OSA are also discussed. Finally, this paper reviews the evidence suggesting that OSA is a risk factor for developing mild cognitive impairment and dementia in the aging population and stresses the importance of its early diagnosis and treatment.

Using near infrared spectroscopy and heart rate variability to detect mental overload.

Mental workload is a key factor influencing the occurrence of human error, especially during piloting and remotely operated vehicle (ROV) operations, where safety depends on the ability of pilots to act appropriately. In particular, excessively high or low mental workload can lead operators to neglect critical information. The objective of the present study is to investigate the potential of functional near infrared spectroscopy (fNIRS) - a non-invasive method of measuring prefrontal cortex activity - in combination with measurements of heart rate variability (HRV), to predict mental workload during a simulated piloting task, with particular regard to task engagement and disengagement. Twelve volunteers performed a computer-based piloting task in which they were asked to follow a dynamic target with their aircraft, a task designed to replicate key cognitive demands associated with real life ROV operating tasks. In order to cover a wide range of mental workload levels, task difficulty was manipulated in terms of processing load and difficulty of control - two critical sources of workload associated with piloting and remotely operating a vehicle. Results show that both fNIRS and HRV are sensitive to different levels of mental workload; notably, lower prefrontal activation as well as a lower LF/HF ratio at the highest level of difficulty, suggest that these measures are suitable for mental overload detection. Moreover, these latter measurements point toward the existence of a quadratic model of mental workload.

Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

OBJECTIVES: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells.

The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express AMPK. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that Metformin directly inhibits stomach ghrelin production and secretion through AMPK. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss.

Invited article: attosecond photonics: synthesis and control of light transients.

Ultimate control over light entails the capability of crafting its field waveform. Here, we detail the technological advances that have recently permitted the synthesis of light transients confinable to less than a single oscillation of its carrier wave and the precise attosecond tailoring of their fields. Our work opens the door to light field based control of electrons on the atomic, molecular, and mesoscopic scales.

How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder.

Parkinsonism, as a gradually progressive disorder, has a prodromal interval during which neurodegeneration has begun but cardinal manifestations have not fully developed. A systematic direct assessment of this interval has never been performed. Since patients with idiopathic REM sleep behaviour disorder are at very high risk of parkinsonism, they provide a unique opportunity to observe directly the development of parkinsonism. Patients with idiopathic REM sleep behaviour disorder in an ongoing cohort study were evaluated annually with several quantitative motor measures, including the Unified Parkinson's Disease Rating Scale, Purdue Pegboard, alternate-tap test and timed up-and-go. Patients who developed parkinsonism were identified from this cohort and matched according to age to normal controls. Their results on motor testing from the preceding years were plotted, and then assessed with regression analysis, to determine when markers first deviated from normal values. Sensitivity and specificity of quantitative motor markers for diagnosing prodromal parkinsonism were assessed. Of 78 patients, 20 developed parkinsonism. On regression analysis, the Unified Parkinson's Disease Rating Scale first intersected normal values at an estimated 4.5 years before diagnosis. Voice and face akinesia intersected earliest (estimated prodromal interval = 9.8 years), followed by rigidity (4.4 years), gait abnormalities (4.4 years) and limb bradykinesia (4.2 years). Quantitative motor tests intersected normal values at longer prodromal intervals than subjective examination (Purdue Pegboard = 8.6 years, alternate-tap = 8.2, timed up-and-go = 6.3). Using Purdue Pegboard and the alternate-tap test, parkinsonism could be detected with 71-82% sensitivity and specificity 3 years before diagnosis, whereas a Unified Parkinson's Disease Rating Scale score >4 identified prodromal parkinsonism with 88% sensitivity and 94% specificity 2 years before diagnosis. Removal of action tremor scores improved sensitivity to 94% and specificity to 97% at 2 years before diagnosis (cut-off >3). Although distinction between conditions was often difficult, prodromal dementia with Lewy bodies appeared to have a slower progression than Parkinson's disease (prodromal interval = 6.0 versus 3.8 years). Using a cut-off of Unified Parkinson's Disease Rating Scale >3 (excluding action tremor), 25% of patients with 'still-idiopathic' REM sleep behaviour disorder demonstrated evidence of possible prodromal parkinsonism. Therefore, using direct assessment of motor examination before parkinsonism in a REM sleep behaviour disorder, we have estimated a prodromal interval of ∼4.5 years on the Unified Parkinson's Disease Rating Scale; other quantitative markers may detect parkinsonism earlier. Simple quantitative motor measures may be capable of reliably detecting parkinsonism, even before a clinical diagnosis can be made by experienced movement disorders neurologists.

Synthesized light transients.

Manipulation of electron dynamics calls for electromagnetic forces that can be confined to and controlled over sub-femtosecond time intervals. Tailored transients of light fields can provide these forces. We report on the generation of subcycle field transients spanning the infrared, visible, and ultraviolet frequency regimes with a 1.5-octave three-channel optical field synthesizer and their attosecond sampling. To demonstrate applicability, we field-ionized krypton atoms within a single wave crest and launched a valence-shell electron wavepacket with a well-defined initial phase. Half-cycle field excitation and attosecond probing revealed fine details of atomic-scale electron motion, such as the instantaneous rate of tunneling, the initial charge distribution of a valence-shell wavepacket, the attosecond dynamic shift (instantaneous ac Stark shift) of its energy levels, and its few-femtosecond coherent oscillations.

Quadrivalent human papillomavirus (HPV) vaccine: a review of safety, efficacy, and pharmacoeconomics.

WHAT IS KNOWN AND BACKGROUND: The introduction of vaccines has lead to a significant reduction in morbidity and mortality from diseases such as measles, rubella and poliomyelitis, as well as the eradication of smallpox (Ertl HC, Xiang Z (1996) The Journal of Immunology, 156, 3579-3582). A recent vaccine approved by the Food and Drug Administration (FDA) is the recombinant quadrivalent human papillomavirus (HPV) vaccine (Merck, Gardasil®). Concerns raised with this preventive measure include safety and efficacy issues as well as the financial implications. Furthermore, the use of the vaccine in women outside the currently approved age ranges and in adolescent boys and men has also been a source of debate. OBJECTIVE: A review of two licensed HPV vaccines (Gardasil, Merck and Cervarix, GalxoSmithKline) in the light of these issues. METHODS: Literature searches were conducted using the MEDLINE (1966-December 2008) and PubMed databases in addition to the Centers for Disease Control and Prevention website. Bibliographies of selected references were also evaluated for relevant articles. Published guidelines and press releases were utilized as were the manufacturer's package inserts. The collection of information for this review was limited to the most recently available human data. RESULTS AND DISCUSSION: The HPV quadrivalent vaccine has been effective in the management of HPV by preventing vaccine subtype-related persistent infection and precancerous lesions as evidenced by numerous clinical trials. It is also regarded as a generally safe and well-tolerated vaccine, based on an assessment of reported adverse events submitted through governmental databases and analyzed by independent researchers. The majority of adverse events were non-serious and the vaccine has not been conclusively implicated with serious events. The FDA continues to focus on routine post-marketing surveillance monitoring of reported adverse events. The bivalent vaccine has also been shown to be effective in reported trials. Its adverse effect profile also appears acceptable. WHAT IS NEW AND CONCLUSION: The HPV vaccines appear safe and effective. Additional clinical research on the vaccines on women outside the currently approved age ranges and in males is necessary. Studies on longer-term outcomes, including cervical cancer and the emergence of new viral genotypes are also necessary.

Versatile apparatus for attosecond metrology and spectroscopy.

We present the AS-2 Attosecond Beamline at the Joint Laboratory for Attosecond Physics of the Max-Planck-Institut für Quantenoptik and Ludwig-Maximilians-Universität for time resolved pump/probe experiments with attosecond resolution. High harmonic generation and subsequent filtering of the generated extreme ultraviolet (XUV) continuum by means of metal filters and XUV multilayer mirrors serve for the generation of isolated attosecond laser pulses. After high harmonic generation, the remaining fundamental laser pulse is spatially separated from the attosecond XUV pulse, to what is to our knowledge for the first time, by means of a perforated mirror in a Mach-Zehnder interferometer. Active stabilization of this interferometer guarantees the necessary temporal resolution for tracking attosecond dynamics in real time. As a proof-of-principle, photoelectron streaking experiments are performed and experimental techniques for their realization are summarized. Finally we highlight the potential of the presented beamline system for future experiments in comparison with previously demonstrated attosecond beamlines.