Pseudo-spontaneous nystagmus has been reported in patients with direction-changing positional nystagmus (DCPN). Recently, the concept of a “light cupula” has been introduced as a pathophysiology that can exhibit persistent geotropic DCPN. Patients with persistent DCPN could have different characteristics of nystagmus. Therefore, we investigated the pseudo-spontaneous nystagmus in patients with transient  and persistent (belong to light cupula theory) geotropic DCPN.In this study, prospectively, 49 patients with persistent geotropic DCPN and 67 patients with transient geotropic DCPN were enrolled. We compared the incidence of pseudo-spontaneous nystagmus between persistent and transient DCPN patients and characteristics of pseudo-spontaneous nystagmus and positional nystagmus by the head roll test in these patients. A prospective study was conducted at a dizziness clinic.Patients with persistent geotropic DCPN exhibited significantly higher incidence of pseudo-spontaneous nystagmus than patients with transient geotropic DCPN. Patients with transient DCPN showed a significantly higher mean SPV value during the head roll test than patients with persistent DCPN. All patients exhibiting pseudo-spontaneous nystagmus in patients with persistent DCPN had a null plane, and all patients had nystagmus beats to the opposite side of the null plane or the lesion side.Our results support the possibility that the mechanism between persistent and transient geotropic DCPN may be different. However, more studies are needed on the pathogenesis and mechanism of the two diseases, including the occurrence of pseudo-spontaneous nystagmus in the disease entity. Benign paroxysmal positional vertigo (BPPV) is characterized by short-lasting vertigo that develops when the dependent position of the head changes . BPPV isDirection-changing positional nystagmus (DCPN) is typically observed in patients with lateral semicircular canal BPPV when the head is turned to either side in the supine position. In canalolithiasis-type lateral semicircular canal-BPPV, the DCPN beats towards the lowermost ear .Several recent studies have reported the occurrence of spontaneous nystagmus in the sitting position in patients with lateral semicircular canal-BPPV –6. BecauAlso, recently, the concept of a “light cupula” in the lateral semicircular canal, revealing a relatively long-duration geotropic (persistent) DCPN that was different from typical transient geotropic DCPN , has been introduced as a variant of lateral semicircular canal-BPPV ,8–10. WeIn the present study, we investigated the spontaneous nystagmus in the patients with persistent and transient geotropic DCPN, and we examined the difference in spontaneous nystagmus incidence and compared the characteristics of nystagmus between two groups.The study was approved by the Institutional Review Board of Hallym Dongtan Sacred Heart Hospital(2015-518-I). Forty-nine patients with persistent geotropic DCPN and Sixty-seven with transient geotropic DCPN seen between December 2015 and September 2017 were investigated. All patients underwent detailed medical history-taking and audiological and vestibular evaluations, including auditory evoked potential, video head impulse test, and caloric test. We tried to exclude all possible diseases that could cause DCPN. Patients with other labyrinthine diseases, recent head trauma, sudden hearing loss, recent surgery, or concomitant otologic pathology were excluded.Neurological examination revealed no abnormality in any of the patients. Eye movement was examined in various head positions and recorded using goggles fitted to an infrared camera . Nystagmus was documented using a video-based system  in some patients in order to calculate the slow-phase velocity (SPV) of the horizontal nystagmus.All patients were assessed for the presence of spontaneous nystagmus in the sitting position, and underwent in the order of head roll test and Dix-Hallpike test after observing spontaneous nystagmus. Spontaneous horizontal nystagmus was observed for at least 30 seconds without any head movement and mean SPV values during 10 second were measured for right and left head turns in the head-roll test.The diagnostic criteria for persistent DCPN were the presence of geotropic DCPN for over 2 min after a supine head-roll test and the presence of a null plane . PatientLateralization of the patients with transient DCPN was based on the stronger side of positional nystagmus during the head roll test, and lateralization of patients with persistent DCPN was based on identification of a null plane and the head roll test.We compared the incidence rate of spontaneous nystagmus (pseudo-spontaneous nystagmus) between patients with transient and persistent DCPN, and examined the clinical characteristics of patients with pseudo-spontaneous nystagmus. We also compared the mean SPV during the head roll test between the two groups.t-test or the chi-squared test. All statistical analyses were conducted using SPSS version 17.0 , with statistical significance set at p < 0.05.Clinical parameters, pseudo-spontaneous nystagmus incidence rate, and mean SPV in the two groups were compared using an independent The demographic and clinical data of groups with transient and persistent geotropic DCPN are summarized in Pseudo-spontaneous nystagmus in the sitting position was observed in 5 (7.5%) of the 67 patients with transient DCPN and in 12 (24.5%) of the 49 patients with persistent DCPN, and patients with persistent DCPN showed significantly higher incidence of pseudo-spontaneous nystagmus Click here for additional data file.


The prefrontal cortex (PFC) is crucial for maintaining relevant information in working memory and resisting interference. PFC neurons are strongly regulated by dopamine, but it is unknown whether dopamine receptors are involved in protecting target memories from distracting stimuli. We investigated the prefrontal circuit dynamics and dopaminergic modulation of targets and distractors in monkeys trained to ignore interfering stimuli in a delayed-match-to-numerosity task. We found that dopamine D1 receptors (D1Rs) modulate the recovery of task-relevant information following a distracting stimulus. The direction of modulation is cell-type-specific: in putative pyramidal neurons, D1R inhibition enhances and D1R stimulation attenuates coding of the target stimulus after the interference, while the opposite pattern is observed in putative interneurons. Our results suggest that dopaminergic neuromodulation of PFC circuits regulates mental representations of behaviourally relevant stimuli that compete with task-irrelevant input and could play a central role for cognitive functioning in health and disease. Dopaminergic activity in prefrontal cortex is important for working memory but the neural mechanisms of its action are not known. Jacob and colleagues show that dopamine D1 receptors regulate neural responses to relevant stimuli in a cell-type-specific manner in the presence of distractors. The primate prefrontal cortex (PFC) is a major brain hub for guiding intelligent behaviour1345A large body of experimental evidence has shown that frontal lobe executive functions are strongly regulated by midbrain dopamine neurons891112One of the most intensively studied dopamine-dependent PFC functions is spatial working memory171921To investigate how prefrontal D1Rs modulate working memory for multiple stimuli, we trained two rhesus monkeys to memorize the number of visual items (numerosity) of a target stimulus while resisting other, distracting numerosities16We trained two monkeys on a modified version of a delayed-match-to-numerosity task26We previously reported a detailed analysis of the two monkeys' behavioural performance in an extended version of the distractor task, showing that both animals had learned to respond to the sample numerosity despite memory interference by the task-irrelevant stimulus16n=47 sessions) or the D1R agonist SKF38393 (n=54 sessions) through up to three pipettes to the ventral and dorsal bank of the principal sulcus in lateral PFC  encoded the sample numerosity in at least one trial epoch  with factors sample , distractor , and iontophoresis condition (control or SCH22390/SKF38393), evaluated at P<0.01) and were subjected to further in-depth analysis.While the animals performed the task, we iontophoretically applied the selective D1R antagonist SCH23390  were successfully classified : SCH23390 6.3, control 5.4, SKF38393 4.8; P=0.33; Interneurons and pyramidal cells are thought to play complementary roles in shaping prefrontal cognitive processing, in particular in working memory tasks28assified . The dissified 30. NS neurWe had previously reported that the neuronal representation of the irrelevant distractor stimulus in PFC is not actively suppressed in this taskAn example sample-selective BS neuron was tuned to numerosity in several trial epochs under control conditions  and D1R stimulation (n=42) influenced the neurons' responses to preferred target numerosities, but had little effect on the representation of non-preferred stimuli . In the population of sample-selective BS neurons, D1R inhibition .The changes in the separation of preferred stimuli from non-preferred stimuli resulted in drug-induced differences in coding strength in the population of BS neurons. As observed in single BS neurons , ROC valn=18) and SKF38393 application (n=12), the responses to the preferred stimuli were clearly different , but not during its recovery . In contrast, modulation indices for BS neurons were consistently positive in both the first half  and second half of the trial .Comparable effects of D1R modulation on the representation of the preferred numerosity in NS neurons were seen in the sample and first memory epochs: while the mean responses to non-preferred stimuli were almost indistinguishable for SCH23390  or attenuated  the recovery of target information required to complete the task.P<0.01 in the distractor and second memory epoch; note that the number of task epochs during which a neuron might become selective for the distractor was half that for the sample). The difference between distractor-selective BS and NS neurons was significant . To determine whether distractor information is also modulated by D1R, we analysed the effects of SCH23390 and SKF38393 on the responses to the task-irrelevant stimulus in the same population of neurons as above. Comparable results were obtained when the analysis was performed for all distractor-selective neurons, irrespective of whether they encoded the sample or not .A large proportion of sample-selective neurons also encoded the distractor  ensures that a change in neuronal activity that only depends on the numerosity of either one of the stimuli would factor out when trials are sorted by the other stimulus. Instead, dual modulation before the animals' behavioural choice indicates that neuronal firing rates in this trial epoch are determined by a conjunction of activity, reflecting the maintenance of both the sample and distractor numerosity in working memory.Midbrain dopamine neurons fire phasic bursts in response to behaviourally relevant sensory events124224151915161445While D1Rs represent the dominant dopamine receptor family in PFC and are expressed by about one-quarter of all prefrontal neurons, the D2R family is concentrated in layer V and has therefore mainly been associated with motor output signals1447Our results support an active role of prefrontal D1Rs, beyond passive stimulus maintenance, at the center of cognitive control operations. It is tempting to speculate that unregulated dopamine signals could constitute an important factor in the generation of mental disorders. For example, one of the most influential theories to explain the psychotic symptoms in schizophrenia is the concept of aberrant salience23Macaca mulatta, monkey R and monkey W) were implanted with a titanium head post and a right-hemispheric recording chamber centered over the principal sulcus of the lateral prefrontal cortex (PFC), anterior to the frontal eye fields, guided by anatomical MRI and stereotaxic measurements. Chambers were angled to be able to penetrate the cortical surface perpendicularly. Surgery was conducted using aseptic techniques under general anaesthesia. All experimental procedures were in accordance with the guidelines for animal experimentation approved by the responsible authority, the Regierungspräsidium Tübingen.Two adult male rhesus monkeys  while suppressing a salient task-irrelevant, interfering numerosity 7. The anLow-level, non-numerical visual features could not systematically influence task performanceIn each recording session, up to three custom-made tungsten-in-glass electrodes flanked by two pipettes each24Data analysis was performed with MATLAB. None of the reported analyses depended on the exact choice of trials to include or time windows to analyse. Repeating analyses with a different set of parameters yielded comparable results.Sample-selective neurons. Neurons were included in the analysis if the following criteria were met: first, their average firing rate across trials was at least 1 spike per s; and second, they were recorded for at least 1 correct trial in all 24 conditions (3 sample numerosities × 4 interfering numerosities including the blank [0] stimulus × 2 iontophoresis conditions (control or drug)). A total of n=246 neurons fulfilled these criteria.P<0.01; n=122) were classified as sample selective.A three-way ANOVA was calculated with main factors sample numerosity , interfering numerosity  and iontophoresis condition (control or drug) using average firing rates in the sample, first memory, distractor and second memory periods, including correct trials only. Neurons with a significant main effect of sample numerosity in any trial period  was smoothed with a Gaussian kernel . For the population responses, we first normalized (Z-scored) the responses of a given unit by subtracting the mean response from its firing rate and by dividing the result by the s.d. of the responses. Both the mean and the s.d. were computed by combining the unit's responses across all trials and time bins  using correct trials only. We then defined a neuron's preferred and non-preferred numerosity by its maximum and minimum firing rate, respectively, for every bin individually and averaged normalized firing rates across neurons.ROC analysis. Neuronal coding strength (selectivity) was quantified using receiver operating characteristic (ROC) analysisP<0.01 after correcting for multiple comparisons by dividing the original significance threshold by the number of comparisons made across each window).Drug modulation index. The modulation index (MI) describes whether SCH23390 or SKF38393 application had a greater effect on the firing rates for the preferred (MI>0) or non-preferred numerosity (MI<0). For all analysed neurons, we calculated the average absolute difference in Z-scores between drug and control trials for the preferred and non-preferred stimulus . We used absolute values to account for reversals in the direction of firing rate modulation in the course of the trial (Zpref–ΔZnpref)/(ΔZpref+ΔZnpref).he trial . The MI Extracellular waveforms. Recorded single units were categorized into narrow-spiking (NS) and broad-spiking (BS) neurons, that is, putative interneurons and pyramidal cells, using a linear classifier 24Behavioural data. Only sessions with at least 25 correct control and 25 correct drug trials were analysed. The moving average of behavioural performance  was calculated for SCH23390 and SKF38393 sessions  using a window size of 40 trials. We controlled for slow trends in behavioural performance .


The intervention is likely to be cost-saving, with 1.4 times higher total cost-savings and 1.5 times higher health benefits in the most disadvantaged socioeconomic group ; total cost-savings AUD126.3M (95% UI AUD58.7M–196.9M) over the lifetime) compared to the least disadvantaged socioeconomic group ; total cost-savings AUD90.9M (95% UI AUD44.3M–136.3M)). Legislation to restrict HFSS TV advertising is likely to be cost-effective, with greater health benefits and healthcare cost-savings for children with low SEP.Television (TV) advertising of food and beverages high in fat, sugar and salt (HFSS) influences food preferences and consumption. Children from lower socioeconomic position (SEP) have higher exposure to TV advertising due to more time spent watching TV. This paper sought to estimate the cost-effectiveness of legislation to restrict HFSS TV advertising until 9:30 pm, and to examine how health benefits and healthcare cost-savings differ by SEP. Cost-effectiveness modelling was undertaken (i) at the population level, and (ii) by area-level SEP. A multi-state multiple-cohort lifetable model was used to estimate obesity-related health outcomes and healthcare cost-savings over the lifetime of the 2010 Australian population. Incremental cost-effectiveness ratios (ICERs) were reported, with assumptions tested through sensitivity analyses. An intervention restricting HFSS TV advertising would cost AUD5.9M (95% UI AUD5.8M–AUD7M), resulting in modelled reductions in energy intake (mean 115 kJ/day) and body mass index (BMI) (mean 0.352 kg/m Childhood obesity is a significant public health issue worldwide . ObesityA diet high in fat, salt and sugar (HFSS) is a key modifiable risk factor for childhood obesity and diet-related non-communicable diseases. In 2010, the World Health Organization (WHO) concluded that television (TV) advertising influences children’s food preferences, purchase requests and consumption patterns and published a set of recommendations on food marketing to children (of which TV advertising is one component) .Evidence also suggests there is a socioeconomic gradient in TV viewing patterns ,7,8. AusSeveral countries have introduced regulatory schemes to reduce or restrict HFSS advertising. Statutory regulations have resulted in bans on TV advertising to children in countries or jurisdictions such as Quebec, Sweden and Norway . CommercThe effectiveness of combinations of government and self-regulation in reducing the exposure of children to HFSS TV advertising is however limited . Critics2 [2 [Despite the strong program logic that links exposure to HFSS TV advertising to increased HFSS consumption and obesity, establishment of the effectiveness of its restriction is challenging . Real wo2  to −1 kg2 [2 ,20  undertaking analyses using a synthesis of the evidence; (ii) accounting for differences in benefits and costs by SEP; and (iii) exploring thresholds for minimum BMI effect required to achieve cost-effectiveness. This will provide important information on the potential population level impact of the intervention, plus new information on the intervention’s potential to reduce health inequities across socioeconomic groups.Australian legislation currently prohibits TV advertising during ‘P’ classified programs . TV netwThe proposed intervention was defined as legislation to implement time-based restrictions of unhealthy food and beverage marketing to children under 16 years of age on FTA TV until 9:30 pm ,29. PeakA scoping review of the literature was conducted to inform the evidence of effect. Searches were conducted by one author (VB), using the Scopus and EBSCOHost academic databases. “Gold standard” evidence to inform modelling would consist of BMI effect estimates from reduced exposure to HFSS TV advertising from high-quality randomised controlled trials (RCTs) conducted in natural settings ,23. A seBecause of this absence of “gold standard” evidence, we defined the assessment of benefit of the intervention using a method previously used , wherebyI2. Full meta-analysis methods and the characteristics of included studies are reported in A scoping search was conducted for reviews and systematic reviews reporting the effects of TV advertising on consumption in children and adolescents . ResultsStudies included in the meta-analysis reported effects from acute exposure in controlled settings. Consumption under experimental conditions may not necessarily reflect consumption in natural settings, due to factors such as scrutiny, context and differences in time horizons and choice sets . HoweverFixed costs were estimated as the cost of passing legislation  Table 1Table 1. Cost-effectiveness modelling was undertaken from a limited societal perspective, with the time horizon for estimating costs, cost-savings and health benefits being rest-of-life or 100 years for the 2010 Australian population. Costs, cost-savings and health benefits were discounted at 3% and were presented as 2010 values.Modelling was undertaken as (i) a whole population analysis, and (ii) an analysis by area-level SEP, using the Socio-Economic Indexes for Areas (SEIFA) IRSD quintiles 1 (most disadvantaged) and 5 (least disadvantaged) . A propoAll modelling was undertaken in Microsoft Excel 2016. Uncertainty analysis around key input parameters was estimated using Monte Carlo simulation (2000 iterations) using the Excel add-in Ersatz (version 1.35)  to estimThe base case assumes no loss of advertising revenue for broadcasters, given the likelihood of new advertising contracts to fill existing advertising periods. The effect of this assumption was tested in sensitivity analyses, assuming a short-term (one year) loss of revenue before networks recoup these costs through new advertising contracts  Supplem.Multi-variate sensitivity analysis was undertaken by varying key input parameters in a “worst-case” analysis . Worst-cGiven the relative uncertainty around the evidence of effect, a threshold analysis was undertaken to determine the minimum effect size required to return a mean ICER less than the AUD50,000 per HALY threshold . AnalysiThe broader impacts of an intervention that may not necessarily be captured within an economic evaluation should also be considered in order to take into account the wide range of factors important to decision-makers when setting priorities . Cost-ef2) at the population level (Results suggest that an intervention restricting TV advertising of HFSS food and beverages to children would cost AUD5.9M (95% UI AUD5.8M–AUD7M). The intervention would result in a small mean decrease in energy intake (approximately 115 kJ/day) and a small mean BMI reduction  compared to the least disadvantaged areas (Q5) . The cos2, The intervention would also be dominant when short-term loss of revenue to TV networks is included  . Worst-c2 would result in a mean ICER under the AUD50,000 cost-effectiveness threshold ). Under the base case scenario for intervention benefits, short-term loss of revenue to TV networks could be more than seven times higher (~$700 million), and the intervention would remain dominant (mean ICER per HALY saved 95% UI dominant-AUD7215).Threshold analysis demonstrated that the effect size (expressed as the relationship between ‘minutes of exposure to TV ads for HFSS food’ and ‘energy intake’) could be reduced by more than two orders of magnitude  for the intervention to remain cost-effective. In this scenario, assuming base case intervention cost, a BMI reduction of 0.0004 kg/mAn intervention restricting the exposure of Australian children to TV advertising of HFSS food and beverages is likely to be cost-saving over the lifetime of the cohort under the base case and all sensitivity analyses modelled, with greatest health benefits and cost-savings accrued by children living in the most disadvantaged areas (Q1) compared to children living in the least disadvantaged areas (Q5). To the best of our knowledge, this is the first time that an intervention restricting HFSS TV advertising to children has been modelled taking into account differences in advertising exposure by SEP.Results suggest the significant potential of legislation to restrict HFSS TV advertising to children in addressing health inequities, in a cost-effective manner. Given that the differences in effect estimates by SEP were determined by differences in TV viewing time within our analysis, the differences in health benefits and total cost-savings by measure of area-level disadvantage may actually be under-estimates. However, if the content of what children are watching on TV also differs by SEP , the differences in health benefits and total cost-savings between children with low SEP and children with high SEP may vary in other ways. More evidence quantifying the differential level and type of exposure of HFSS advertising to children by SEP is required to better inform this analysis. Further, this study only examined differences between SEP quintile one and five. Analysis across the entire socioeconomic spectrum is required, in order to gain a complete understanding of the equity-related effects of legislation to restrict HFSS TV advertising across all socioeconomic groups.The most significant challenge to date remains the availability of rigorous evidence of effect of the intervention to better inform analysis . While tOur cost-effectiveness results are in keeping with previously published findings in Australia , The UniBy limiting the intervention population to children aged five to 15 years, we may have under-estimated the cost-effectiveness of the intervention at the population level. Studies have suggested that HFSS TV advertising may also have an effect on food-related behaviours and attitudes in older adolescents and adults, however at this time the evidence is inconclusive  and therLimitations of our study include the assumption of maintenance of BMI effect into adulthood and the modelled effect estimate used for base case and sensitivity analyses, taken from meta-analysis of a small number of studies conducted in highly controlled experimental conditions. We have tried to compensate for this suspected bias by adjusting the effect estimate for a more plausible translation to a real-world setting, and for compensatory meal behaviours of children who snack. Adjustments were made using best-available evidence and logic pathways, however a more rigorous understanding of the effects of TV advertising on the consumption of HFSS food and beverages in children is clearly an area for significant future research.It is likely that the food industry would oppose the introduction of more stringent TV advertising legislation, and this is recognised as a potential barrier to the implementation of this public health policy . Whilst Finally, television advertising is only one medium used for marketing of HFSS food and beverages, and although traditional TV viewing is still the most dominant promotional channel, it may be waning . ChangesThis study indicates the significant potential of legislation restricting TV advertising of HFSS food and beverages to Australian children as a cost-effective intervention, with greatest benefits for the most socioeconomically disadvantaged. All modelled scenarios and sensitivity analyses resulted in dominance . Our analysis by measure of area-level socioeconomic disadvantage demonstrates greater health benefits and total cost-savings in those living in the most disadvantaged socioeconomic areas compared to those living in the least disadvantaged areas. Furthermore, results from our threshold analysis demonstrate the very small population level effect size required for the intervention to be considered cost-effective.


Little is known about the impact of different forms of childhood adversity (CA) on outcomes in first episode psychosis (FEP) patients beyond the first year of treatment. We investigated associations between different types of CA and 5-year outcomes in a well-characterised sample of FEP patients.A total of 237 FEP cases aged 18–65 years were followed on average for 5 years after first presentation to psychiatric services in South-London, UK. CA was assessed at service entry using the Childhood Experience of Care and Abuse Questionnaire. Using electronic clinical notes, extensive information was collected on clinical and social outcomes, service use, and self-injurious behaviours. As case analysis with missing data provides the most severely biased results we conducted multiple imputations to handle the missing data. We imputed the missing values using multiple imputations by chained equations (MICE). MICE has been shown to be a robust method for dealing with missing data across empirical and longitudinal studies.72.1% of the sample reported at least one form of CA. Childhood parental separation was associated with greater likelihood of non-compliance with antipsychotic medications , compulsory admission , and living alone  by the end of the follow-up. Institutional care was associated with longer total length of inpatient stay ; parental death was associated with compulsory admissions  during the follow-up.Our findings suggest some specificity in the detrimental impact of CA on service use and social functioning over a 5-year period following first contact with mental health services for psychosis. Clinicians should screen patients for CA and tailor interventions accordingly to improve outcomes.


According to World Health Organization estimation about 18 million people worldwide are suffering from Alzheimer's disease (AD) and figures would shoot up to 34 million by 2025 in aging population. The onset and propagation of AD is unrelenting from cellular to molecular levels, governed by multitude of factors leading to a continual decrease in cognitive abilities  showed some promising results in animal models of AD. Interestingly treatment of L-NBP  to APP/PS1 mice resulted in amelioration of Aβ induced damage to synapse. Improvement in synaptic plasticity which is considered as an essential factor modulating cognitive functions in AD has also been observed after L-NBP. Pictorial results from electron microscopy revealed the significant increase in number of synapse and spines in hippocampus regions following treatment with L-NBP. It could be reasoned that multiple molecular events have been amended to bring about changes in synaptic strength. These changes might range from removal of synaptic plaques to anti oxidative and anti-inflammatory mechanisms. However, it is very hard to distinguish whether removal of synaptic plaques provides anti oxidative and anti-inflammatory relief or vice versa. In this study Zhang et al.  to form clumps known as neuritic or senile plaques is considered as hallmark of AD. The buildup of these plaques seems to be a crucial as they lead to oxidative stress coupled with mitochondrial dysfunction and barrage of inflammatory cascade causing neuronal cell death. Studies carried by Zhang et al.  on L-3-ng et al.  exploredg et al. .Interestingly, L-NBP influence on inflammatory responses during AD has been previously reported involving decreased expression of IBA-1 and inhibition of microglia activation in APP/PS1 mice. Furthermore, significant decrease in Aβ deposition linked with decreased gliosis has also been observed on after L-NBP exposure highlighting potential effects of the compound in ameliorating inflammation. Anti-inflammatory potential of L-NBP is well documented wherein it reduced neuro inflammation in lipopolysaccharide-treated C57BL/6 mice. The anti-inflammatory response could be beneficial in long term therapy in case of neurodegenerative disorders (Lei et al., Mitochondria are considered a target in neurodegenerative disorder since reactive oxygen species generated during ATP generation tip the balance toward neuronal damage and apoptosis Figure . ElevateTaken together, the findings suggest that the neurotherapeutic potential of L-NBP as a disease modifier in AD is due to its multiple pharmacological properties. It may be hypothesized from the experimental findings that the specific feature of this compound is the ability to reduce the load of Aβ and to exert anti-oxidant properties by lowering the levels of ROS, maintaining optimum MMP with reduction in inflammatory markers. For the first time Zhang et al.  have demPB, PP, BP, FA, and VK write the study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In Dentistry, restorative materials and oral bacteria are believed to be responsible for restoration failure. To make long-lasting restorations, antibacterial agents should be made. Inorganic nanoparticles and their nano composites are applied as good antibacterial agents.  The purpose of this study was to investigate the effect of silver nanoparticles on composite shear bond strength using one etch and rinse and one self-etch adhesive systems. Silver nanoparticles were prepared. Transmission electron microscope and X-ray diffraction were used to characterize the structure of the particles. Nanoparticles were applied on exposed dentin and then different adhesives and composites were applied. All samples were tested by universal testing machine and shear bond strength was assesed. Particles with average diameter of about 20 nm and spherical shape were found. Moreover, it was shown that pretreatment by silver nanoparticles enhanced shear bond strength in both etch and rinse, and in self-etch adhesive systems (p≤0.05). Considering the positive antibacterial effects of silver nanoparticles, using them is recommended in restorative dentistry. It seems that silver nanoparticles could have positive effects on bond strength of both etch-and-rinse and self-etch adhesive systems. The best results of silver nanoparticles have been achieved with Adper Single Bond and before acid etching. The antimicrobial, antifungal and antiviral action of silver or silver compounds depends on the level of released bioactive silver ions (Ag+) and its availability to interact with bacterial or fungal cell membranes14. Silver NPs have the potential to serve as a bactericidal agent because of the inherent antimicrobial influences of silver ion. NPs are insoluble particles that are smaller than 100 nm in diameter25. They benefit smaller particles that demonstrated stronger antibacterial activity compared to larger particles due to their higher surface area and, thus, enhanced interaction with organic and inorganic molecules. However, many properties of metal NPs are still unknown27. The potency of the antibacterial effects corresponds to the nanoparticle size. Smaller particles have more antibacterial properties because of the equivalent silver mass content23. Silver NPs adhere and penetrate the bacterial cell wall, thereby causing structural changes in the cell membrane, such asin cell membrane permeability and cell apoptosis. There is a formation of pits on the cell surface, and there is accumulation of NPs on the cell surface9. Silver NPs may have potential toxicities at some concentrations and can produce many health problems if used inappropriately. Metal NPs have been recently applied in Dentistry because of their bactericidal and bacteriostatic effects11.Silver nanoparticles (NPs) have called the researcher’s attention because of their unique properties, for example, their optical, antimicrobial, and electrical properties5. These preventive measures consist of antimicrobial bonding agents, antibacterial mouth rinses, and remineralizing agents adjacent to oral appliances. It has been demonstrated that the presence of silver in dental restorative materials is effective against caries producing bacteria, such as streptococci and lactobacillus19. It can also be effective as an antibacterial additive to dental restorations. We do not know exactly whether the incorporation of silver NPs would interfere with bond strength of dental restorative materials19. Until now, only few studies have determined the effect of silver NPs on composite shear bond strength (SBS). Adhesion mechanism is based on the penetration of resin molecules into enamel and dentin22. Bond strength of dental composites to dentin is one of the main criteria in clinical durability of composite restoration. Various bonding systems have been introduced in order to fulfill a reliable bond to tooth structure based on two main methods: the etch-and-rinse and the self-etching adhesive systems7. Smear layer removal and formation of collagen fibril layer by means of acid conditioner to form hybrid layer are the main adhesion mechanisms in etch-and-rinse systems3. The self-etching adhesive system is subdivided into two groups: two-step and one-step self-etching. Self-etching adhesive systems employ an acidic monomer as conditioner. In self-etch adhesives, acidic functional monomers react to the mineral content of tooth surface24. Self-etch adhesives are less time-consuming and technique-sensitive. Etch-and-rinse adhesive systems are still considered as a golden standard among bonding systems. However, dentists have a tendency to use adhesive systems with a simplified application procedure12.Caries preventive measures with the purpose of reducing demineralization should be independent of the patient’s complianceTherefore, in this study we examined whether an additional pretreatment with silver NPs provides any supplementary effect on bond strength of self-etch commercial adhesive (Clearfil SE Bond) and etch-and-rinse (Adper Single Bond) using standard SBS methodology.3 with sodium dodecyl sulfate (SDS) (Merck) were mixed in an aqueous solution under a N2 atmosphere. SDS molecules were applied to disperse the silver NPs and also to stabilize the formation of shaped silver NPs. Deposition was carried out at different reaction times. Oxygen was removed from water by nitrogen bubbling and the electrolyte was combined under a nitrogen atmosphere. SDS was added at the 40 g/L level to avoid aggregation. The products were washed with distilled water and collected by centrifugation at 15,000 rpm for 10 min . A transmission electron microscope (TEM)  was used to determine size, shape, and size distribution of silver NPs. Silver NPs were prepared by placing a drop of working solution on a TEM grid and dryed for TEM analysis. X-ray diffraction (XRD) was used as a secondary or complementary technique to determine particle size by analyzing diffraction peaks. XRD pattern of silver NPs was obtained by a DX-1000 X-ray powder diffractometer 17.Portions of 1 g/L AgNONinety extracted, noncarious human premolar teeth were cleaned and stored in 0.1% thymol solution for one week. The teeth were prepared using a diamond bur  and a high-speed handpiece under water coolant up to the nearmost half of the DEJ to the pulp, which is the proposed location for measuring bond strength of composites, so that no pulp exposure occur in the preparation site. Then the exposed superficial dentin surface was polished using silicon carbide paper (600 grit) under water coolant to standardize the smear layer. The teeth were rinsed with distilled water to remove any debris and then mounted in acrylic resin (2×3×5 cm) and randomly divided into six groups (n=15).The specimens’ preparation was based on the type of employed adhesive system and tested silver NPs as follows:Group 1: Acid etching + Adper single Bond + Composite Z250Group 2: Silver NPs + Acid etching + Adper single Bond + Composite Z250Group 3: Acid etching + Silver NPs + Adper single Bond + Composite Z250Group 4: Clearfil SE Bond Primer + Clearfil SE Bond + Composite Z250Group 5: Silver NPs + Clearfil SE Bond Primer + Clearfil SE Bond + Composite Z250Group 6: Clearfil SE Bond Primer + Silver NPs + Clearfil SE Bond + Composite Z2502)26.In all groups tested the application of silver NPs were followed by a 60-second rinse with water. Adhesive systems were applied following the manufacturer’s instructions . Subsequ4.Specimens were stored in distilled water at 37°C for one week and then they were tested in shear mode using a rod attached to the universal testing machine  at a cross-head speed of 0.5 mm/min until the bond fractured and the shear force were evaluated. The force was measured in Newtons (N). SBS values were calculated by converting Newtons into megapascals (MPa)Statistical analysis was performed using SPSS 18.0.0 software . The statistically significant difference among groups was determined using analysis of variance (ANOVA) and Tukey test with the level of significance at p=0.05.The size and morphology of particles were assessed using a TEM . TEM imaA typical XRD pattern of the as-prepared silver NPs is shown in 21. Antibacterial properties of silver NPs and their compounds have been used in various medical and recently dental branches16. Due to the potential of microorganisms to stick to composite resins and adhesives compared to other restorative materials, the present study made an attempt to evaluate the effect of silver NPs on composite SBS with different adhesion protocols. In this study, etch-and-rinse adhesive with the application of silver NPs before acid etching showed better results. The use of silver NPs also had no adverse effect on bond strength in other groups.Nanotechnology is making advances in many fields, specially in Dentistry. In this technology, the specific material is converted into nanometric sizes for showing new properties16. Smaller silver NPs (<100 nm) can interact very closely with microbes. They provide a larger surface area for antimicrobial activity because of greater ratio of surface-to-volume than larger particles1. A variety of preparation methods have been demonstrated for the synthesis of silver NPs; some of them are laser ablation, electron irradiation, gamma irradiation, microwave processing, chemical reduction, photochemical methods, and biological synthetic methods. The most common method for the preparation of silver NPs is chemical reduction that produce stable, colloidal dispersions in water or organic solvents15. In Dentistry, two mechanisms are applied for bacterial reduction: a) combining dental materials with NPs; and b) coating surfaces with NPs to prevent microbial adhesion13. In this study, we used the second mechanism and for the first time silver NPs were applied with etch-and-rinse and self-etch adhesive systems as pretreatment. The rationale was to achieve benefits of antibacterial properties and perhaps positive effects on bond strength.Silver is a safe bactericidal metal because it is biocompatible to animal cells but is very toxic to bacteria16.Although discoloration and color changing to a tone of gray are common problems in all materials containing silver, especially composite resins, in the present study we did not see silver spots by visual eye check on any tooth, but we did not check it with the microscope either. It is showed in the previous study that using low concentrations of metal NPs can prevent severe discoloration of composite resins. Therefore, according to previous studies we chose concentrations of 1% silver NPs to impart the less detrimental effect of these NPs on the color of composite resins18. Bacteria at the interface of the tooth-restoration margins could harm the dental pulp and also affect bond strength. The primer could be an important vehicle to deliver antimicrobial agents such as silver NPs to kill bacteria in the tooth cavity because it has direct contact with dentin30. Silver NPs has a strong antibacterial activity, low cytoxicity and acceptable biocompatibility with human cells, and a long-term antibacterial effect by means of sustained silver ion release6. The development of new self-etch adhesives offers some promising opportunities. Unlike with etch and rinse adhesives, not all hydroxyapatites are removed from the hybrid layer in dentin as the demineralization by mild self-etch adhesives occurs. Depth and extent of demineralization by mild self-etch adhesives is limited compared to etch-and-rinse28. Researches have shown that functional monomers in self-etch adhesives can chemically interact with hydroxyapatite within a clinically acceptable time7, and this chemical interaction has been hypothesized to be improved by possible infiltration of silver NPs into dentinal tubules and perhaps it could provide better resistance against degradation by prevention of micro- and nanoleakage.From this study it can be concluded that the bonding effectiveness of Clearfil SE Bond can be improved by selectively use of silver NPs on the walls of the cavity. An antibacterial bonding agent at the tooth-restoration interface is very important because usually there are bacteria in the prepared tooth cavity. In previous studies, primer and adhesives that contain silver NPs could kill the residual bacteria2. However, we added silver NPs with different protocols. Bonding agents seemed to have infiltrated and wetted the dentin surface well, after silver NPs application. It might perhaps change the etching pattern of phosphoric acid and form the long resin tags from well-filled dentinal tubules. They also found that an experimental composite adhesive containing silica nanofillers and silver NPs can help prevent enamel demineralization around bracket surfaces without compromising physical properties2. Yoshida, et al.29 (1999) demonstrated that a resin composite incorporated with silver NPs had a long-term effect against Streptococcus mutans. In addition, they showed that a resin composite that has fillers containing Ag ions had antibacterial effects on oral streptococci with no adverse effect on adhesive mechanical properties, allowing thus their use in restorative treatments29.The present study demonstrated that bond strength of etch-and-rinse adhesive, (Adper Single Bond) was higher than self-etch (Clearfil SE Bond) adhesive, using silver NPs, under SBS test. Therefore, it seems that the effect of etching in the etch-and-rinse adhesive on cavity surfaces has an important role in producing high bond strength. In a previous study, 250 ppm and 500 ppm of silver NPs with a size smaller than 5 nm in combination with nanosized silica particles were added to self mixed experimental composite adhesives. They found that silver NPs did not significantly affect SBS among adhesivesin vitro study, we did not investigate the release of silver NPs into oral cavity and saliva, but these studies should be considered. It seems good to emphasize that more researches are needed to confirm these results, in which other types of adhesives and other methods that can produce similar conditions of degradation of the adhesive interface in the oral cavity should be performed. Furthermore, the results of this study were developed in vitro, therefore, clinical investigations are required to establish these findings and provide clinical recommendations.The present study measured dentin bond strength after one week of water-aging. More studies should be conducted to investigate the long-term bond durability of adhesive systems after long-term water-aging to investigate the effects of silver ion release and its effects on dental hard tissue remineralization, antibacterial characteristics, and the durability of the resin-dentin bond. In our Considering the positive antibacterial effects of silver NPs, using them is recommended in restorative Dentistry. It seems that silver NPs could have positive effects on bond strength of both etch-and-rinse and self-etch adhesive systems. The best results of silver NPs have been achieved with Adper Single Bond and before acid etching.


Phosphoproteomic experiments are increasingly used to study the changes in signaling occurring across different conditions. It has been proposed that changes in phosphorylation of kinase target sites can be used to infer when a kinase activity is under regulation. However, these approaches have not yet been benchmarked due to a lack of appropriate benchmarking strategies.in vivo, in vitro or in silico) supporting these influence the predictions.We used curated phosphoproteomic experiments and a gold standard dataset containing a total of 184 kinase-condition pairs where regulation is expected to occur to benchmark and compare different kinase activity inference strategies: Z-test, Kolmogorov Smirnov test, Wilcoxon rank sum test, gene set enrichment analysis (GSEA), and a multiple linear regression model. We also tested weighted variants of the Z-test and GSEA that include information on kinase sequence specificity as proxy for affinity. Finally, we tested how the number of known substrates and the type of evidence (Most models performed well with the Z-test and the GSEA performing best as determined by the area under the ROC curve (Mean AUC = 0.722). Weighting kinase targets by the kinase target sequence preference improves the results marginally. However, the number of known substrates and the evidence supporting the interactions has a strong effect on the predictions.The KSEA implementation is available in https://github.com/ evocellnet/ksea. Additional data is available in http://phosfate.comBioinformatics online. The functional plasticity of the proteome is modulated by specific post-translational modifications (PTMs) such as phosphorylation, glycosylation or ubiquitination. Reversible modification of proteins controls signal transduction and information processing within the cell, mediating molecular processes such as protein enzymatic regulation, complex associations, protein degradation and changes in subcellular localization . ThroughPrevious studies of cell decision-making mediated by protein phosphorylation have been limited by the reduced number of phosphosites and kinase activities that were possible to measure, most frequently using phospho-specific antibodies .Despite the heterogeneity of the biological samples, as well as the technical variation introduced by different experimental setups, high reproducibility is expected in the quantitative response of the direct kinase regulations included in the gold standard. As was done in our previous study .The parametric one-sample Z-test compares the mean fold change of all substrates of a given kinase to the mean and variance of all fold changes in the same condition. The non-parametric methods instead, assess the phosphorylation differences between the substrate and the non-substrate fold-change distributions using different metrics: the KS-test estimates the maximum distance between the cumulative probability distributions and the Wilcoxon test evaluates the rank differences among both distributions. The Z-test was implemented in R as previously described in  and Precision-Recall (PC) curves. Area Under ROC Curve (AUC) and the observed precision at recall 0.5 were systematically used as performance metrics. The benchmark robustness was evaluated by comparing the summary metrics obtained in each of the 60 negative set randomizations. Additionally, the technical variance introduced by each of the methods was assessed by creating 10 permuted sets of kinase-substrate relationships maintaining the same number of substrates per kinase.https://github.com/omarwagih/matchtm). The MSS—ranging from 0 to 1—can be interpreted as an approximation of the kinase-substrate binding preferences. The kinase substrate fold changes were then multiplied by their corresponding MSS to obtain their weighted fold changes. As a consequence, differentially regulated substrates not showing affinity for the known kinase-binding motif would see their fold changes diminished. The weighted fold changes were then used to perform the Z-test and the GSEA algorithm as described previously. The fold changes of the sites whose phosphorylation is not catalyzed by the kinase under prediction remained unaltered. When benchmarking the weighted version of the methods we only considered kinases with at least 10 known substrates available to build the PWM. This decreases the benchmark set to 135 positive kinase-condition pairs including 21 kinases covering 57 different perturbations.The weighted Z-test and GSEA methods introduced in this study modify the original statistics to re-rank the substrate quantifications in order to include binding specificities as a proxy for their binding affinities. To calculate the estimated affinity, we constructed a library of position weight matrices (PWMs) from the amino-acid sequences surrounding the known kinase substrates (±7 residues). Next, we calculated the matrix similarity scores (MSS) to measure the identity between each substrate flanking sequence and their corresponding kinase-PWM . It is noteworthy that some kinases in the negative set also present significant regulation under specific conditions, potentially due to other regulatory events not included in the gold standard. These could include, for example, downstream activation/inhibition of kinases or off-target effects in the cases of drugs. All methods were benchmarked using ROC and PC analysis  if the number of quantifications remains below five substrates.To evaluate the robustness of the methods to the number of quantified substrates, we compared the aforementioned performances with those obtained only for kinases with ≤ 5 quantified substrates and those with more than 5 . OverallP-value = 8.4 × 10−10) and GSEA-weighted versus GSEA  . These were used to score each target site based on their sequence and the values incorporated into the Z-test and GSEA (see ‘Methods’ section). In these ‘weighted’ versions of the methodologies, phosphosites that best match the kinase preference were more strongly considered when predicting the regulation of the kinase. We observed a small but significant improvement in AUC and Precision at recall 0.5 whereby these changes tended to perform better than the initial implementations: Z-test-weighted versus Z-test  .in vivo, in vitro and in silico supported substrates. Kinase activities predicted using GSEA or Z-test using in vivo characterized substrates perform better than predictions using in vitro supported substrates   . Moreovelest set . Also inar trend . The pooon score . Howeveret al., 2016) or to study kinase pathway changes occurring after specific stimulations (http://phosphate.com) allowing others to easily compare alternative approaches. We also provide an R package including one of the best performing methods (GSEA at http://github.com/evocellnet/ksea).The progress and developments in MS have led to the unbiased exploration of cell signaling changes via phosphoproteomics. Single experiments are now reporting how changes of thousands of phosphorylation sites occur across tens to hundreds of conditions .Conflict of Interest: none declared.Supplementary DataClick here for additional data file.


De novo assembly of whole genome shotgun (WGS) next-generation sequencing (NGS) data benefits from high-quality input with high coverage. However, in practice, determining the quality and quantity of useful reads quickly and in a reference-free manner is not trivial. Gaining a better understanding of the WGS data, and how that data is utilized by assemblers, provides useful insights that can inform the assembly process and result in better assemblies.de novo genome assemblies, primarily via their k-mer frequencies and GC composition. KAT enables users to assess levels of errors, bias and contamination at various stages of the assembly process. In this paper we highlight KAT’s ability to provide valuable insights into assembly composition and quality of genome assemblies through pairwise comparison of k-mers present in both input reads and the assemblies.We present the K-mer Analysis Toolkit (KAT): a multi-purpose software toolkit for reference-free quality control (QC) of WGS reads and https://github.com/TGAC/KAT.KAT is available under the GPLv3 license at: Bioinformatics online. A frequK-mer spectra reveal information not only about the data quality  but also of genomic complexity .KAT, the K-mer Analysis Tookit, is a suite of tools for rapidly counting, comparing and analysing spectra for k-mers of arbitrary length directly from sequence data (see Supplementary section 2 for a discussion on choice of de novo assembly of a dataset will be sufficient to run KAT on the dataset (see Supplementary section 4 for details). K-mer counting in KAT is performed by an integrated and modified version of Jellyfish2 . In addition, KAT provides the sect tool necessary to study specific assembled sequences and track the k-mer coverage across both the read and the assembly spectra. This can help identify assembly artefacts such as collapsing or expanding events, or detect repeat regions. Fraxinus excelsior assemblies created from the same dataset using the comp and sect tools. The plots highlight different strategies taken by the assembler, in (a) and (c) we see some homozygous content being duplicated, and in (b) and (d) some heterozygous content eliminated.The KAT hist tool for computing spectrum from a single sequence set and the gcp tool to analyse gc content against k-mer frequency. The filter tool can be used to isolate sequences from a set according to their k-mer coverage or gc content from a given spectrum . These tools can be used for various tasks including contaminant detection and extraction both in raw reads and assemblies, analysis of the GC bias and consistency between paired end reads and other types of libraries.KAT also includes the de novo genome assembly QC and validation.KAT is a user-friendly, scalable toolkit for rapidly counting, comparing and analyzing k-mers from various data sources. The tools in KAT assist the user with a wide range of tasks including error profiling, assessing sequencing bias and identifying contaminants and Supplementary DataClick here for additional data file.


The prion protein (PrP) has been extensively studied because of its central role in a group of neurodegenerative conditions collectively known as prion diseases. While a wealth of information is available for the pathology and transmission of these diseases, the molecular mechanisms involved are not yet clearly defined.So, how do we learn about the molecular mechanisms underlying the pathogenic role of the PrP in disease? What have we learned about the physiological role of the PrP? Defining PrP function may shed light on pathological processes involved in prion diseases. The PrP has been shown to participate in several biological processes, including neuritogenesis, neuronal homeostasis, cell signalling, cell adhesion, and a protective role against stress. This pleiotropism has led to confusion about the precise molecular function(s) of the PrP. This essay shall attempt to clarify the most relevant physiological roles of the protein in the context of the central and peripheral nervous system.C) and the pathogenic isoform denoted as prion . The latter plays a key role in the pathological outcome of prion diseases, while the former is a ubiquitous protein expressed in most cell types in mammals.The PrP can exist in 2 distinct conformations: the host-encoded, physiological cellular prion protein (PrPC is encoded by the Prnp gene located on chromosome 20 in humans (PRNP) and chromosome 2 in mice. Depending on the species considered, the Prnp gene contains either 2 or 3 exons, with the entire coding region being contained in the last exon, thus excluding possible alternative splicing .C may be subjected to proteolytic processing. One of the cleavage sites is present in the central region of the protein and produces the N-terminal N1 soluble fragment and the GPI-anchored C-terminal C1 fragment. PrPC may also be present as a soluble full-length isoform, resulting either from a phospholipase cleavage of the GPI anchor or from proteolytic processing at the C-terminus. These varieties of post-translational modifications can give rise to several different isoforms and this could hamper efforts on defining PrPC function(s) [Via additional post-translation modifications, PrPction(s) .Purkinje cells in the cerebellum, the evidence that most mouse models’ knockout for the PrP do not show gross abnormalities indicates that PrPC may be dispensable for embryonic development and adulthood. Nevertheless, several mouse models in which the Prnp gene is disrupted have been developed [C in circadian rhythms and sleep dysfunctions [With the exception of 3 PrP knockout mouse models, in which ectopic expression in the central nervous system of the PrP paralogue Doppel leads to loss of eveloped . Early sunctions , alteredunctions , neuritounctions , and myeunctions .C involvement in synaptic plasticity and N-methyl-d-aspartate receptors (NMDARs) regulation [In addition, more recent work has characterized PrPgulation , 11.C function and despite their limitations, they are still used in characterizing PrPC physiological roles in the central and peripheral nervous system.Overall, these knockout models have been instrumental for defining PrPC is its involvement in cell signalling. Because of its extracellular localization, the protein could mediate environmental molecular signals to the cell. Transduction of the signals cannot be mediated directly by PrPC because it is GPI anchored to the cellular membrane without direct access to the cytosol but would require interactions with other transmembrane proteins.One of the most intriguing function(s) of PrPC may be involved in mediating extracellular signals is the description of a caveolin-1-dependent coupling of PrPC to the proto-oncogene tyrosine-protein kinase Fyn (Fyn) [C could exert its function by partnering with other membrane proteins to convey cellular signalling. The neural cell adhesion molecule (NCAM) was identified as one preferential interactor of PrPC [C can promote neuritogenesis via the tyrosine kinase Fyn [C is essential for regulating the neurite outgrowth and guidance function, indicating that the N-terminus of the protein, which includes the octarepeats region, is essential for its function [C has been used for focal stimulation of neurite outgrowth and guidance [Perhaps the most important study and the first evidence that PrPyn (Fyn) . Since t of PrPC . Throughnase Fyn –17. In tC plays a critical role in NCAM-dependent neuronal differentiation of neural stem/precursor cells [In addition, in another work it has been shown that PrPor cells .C is developmentally regulated and its high expression in the immature brain could be relevant in regulating neurogenesis and cell proliferation [C plays a crucial role in regulating via protein kinase A (PKA) synaptic plasticity in the developing hippocampus, therefore contributing to proper synaptic formation in adulthood [PrPferation . A recendulthood .C expression is its involvement in myelin formation and maintenance. Aging PrP knockout mice present a clear phenotype in which the peripheral nervous system shows demyelinating disease [C acts as an agonistic ligand of the adhesion G-protein coupled receptor G6 (Adgrg6) receptor, the function of which is critical for myelin maintenance [An important function linked to PrP disease . Moleculntenance .C and copper ions in NMDAR S-nitrosylation and activity. By exploiting PrP knockout mice, the authors showed that the depletion of PrPC is associated with a reduction in the S-nitrosylation of the 2 NMDAR subunits GluN2A and GluN1, while not affecting the levels of the corresponding proteins at the synapse. The sensitivity of PrP knockout versus wild-type organotypic hippocampal cultures to N-methyl-d-aspartate (NMDA)-mediated excitotoxicity was monitored under a great variety of conditions that were selected in order to assess the involvement of calcium, copper, nitric oxide (NO), NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainite, or GluN2B receptors. These experiments unambiguously highlight a higher sensitivity of PrP knockout mouse cultures to NMDA-mediated excitotoxicity, which can be reversed upon exposure to the NO donor S-nitrosoglutathione (GSNO). Conversely, the results substantiate an increased sensitivity of wild-type cultures to NMDA-dependent excitotoxicity when copper or NO is chelated.One of the most detailed functional studies recently published deals with the involvement of the cellular form of the prion protein PrPC acts to regulate NMDAR S-nitrosylation regulation can be summarized as follows. Upon glutamate release from the presynaptic terminal, NMDARs are activated on the postsynaptic terminal, leading to calcium entry. Via a series of molecular mechanisms, NO and copper ions are released in the synaptic cleft. Released Cu2+ ions are rapidly bound by copper-binding proteins including PrPC, which is highly expressed in both presynaptic and postsynaptic terminals. PrPC has high affinity for both Cu2+ and Cu+ and it may reside in lipid raft domains, which also contain NMDAR. Synaptic NO can react with extracellular cysteine thiols of NMDAR subunits GluN1 and GluN2A, leading to cysteine S-nitrosylation. The S-nitrosylation inhibits NMDAR activation by closing the channel. The chemical reaction between NO and cysteine thiol requires the presence of an electron acceptor such as Cu2+. According to this model, PrPC positions Cu2+ ions that support the reaction of NO with thiols, leading to the S-nitrosylation of GluN1 and GluN2A, thus inhibiting NMDAR [The molecular mechanism by which PrPng NMDAR , 21  of PrPC, our understanding of the neuropathological processes underlying prion diseases may progress towards the development of novel therapeutic approaches to such devastating disorders [In recent years, several function(s) of PrPisorders .


The type of interaction was studied using the area under the survival curve ratios (AUC ratios) obtained by numerical integration. Comparison of the AUC ratio and the surviving fraction (SF) value after taxane alone was made using Student's t-test. The influence of the drug concentration was tested by one-way analysis of variance (Anova). A supra-additive or additive effect was seen when seven ovarian carcinoma cell lines were exposed to paclitaxel or docetaxel concomitantly with cisplatin. A supra-additive effect was found in four cell lines  after simultaneous use of cisplatin with all docetaxel concentrations tested, and in two cell lines (UT-OC-4 and SK-OV-3) when cisplatin was used concomitantly with paclitaxel. A more pronounced supra-additive effect was seen with the combination of cisplatin and docetaxel. The degree of supra-additivity was dose dependent, with increasing synergy after a higher taxane dose. The data obtained in this study suggest that a supra-additive or additive effect can be achieved in ovarian carcinoma with the concomitant use of cisplatin and a taxane. © 1999 Cancer Research CampaignThe purpose of this study was to compare the growth-inhibitory effect of cisplatin–paclitaxel with that obtained with a cisplatin–docetaxel combination and to assess the type of interaction. Concomitant use of taxanes and cisplatin was studied in seven human ovarian carcinoma cell lines, using the 96-well plate clonogenic assay. Chemosensitivity was expressed in terms of IC


The influence of photodynamic therapy (PDT) on vascular perfusion and the development of hypoxia was investigated in the murine RIF-1 tumour. Image analysis was used to quantify changes in perfusion and hypoxia at 5 min after interstitial Photofrin-mediated PDT. The fluorescent stain Hoechst 33342 was used as an in vivo marker of functional vascular perfusion and the antibody anti-collagen type IV as a marker of the tumour vasculature. The percentage of total tumour vasculature that was perfused decreased to less than 30% of control values after PDT. For the lower light doses this decrease was more pronounced in the centre of the tumour. The observed reduction in vascular perfusion showed a good linear correlation (r = 0.98) with previously published tumour perfusion data obtained with the 86Rb extraction technique. The image analysis technique provides extra information concerning the localisation of (non)-perfused vessels. To detect hypoxic tumour areas in vivo, an immunohistochemical method was used employing NITP [7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline]. A large increase in hypoxic areas was found for PDT-treated tumours. More than half the total tumour area was hypoxic after PDT, compared with < 4% for control tumours. Our studies illustrate the potential of image analysis systems for monitoring the functional consequences of PDT-mediated vascular damage early after treatment. This provides direct confirmation that the perfusion changes lead to tissue hypoxia, which has implications for the combined treatment of PDT with bioreductive drugs.


The 62 kDa protein product of the c-myc oncogene (p62 c-myc) is thought to be involved in the control of normal cellular proliferation and differentiation. We have measured oncoprotein levels using a flow cytometric assay in 141 operable breast cancers and have correlated levels with prognostic variables, patient survival and disease free intervals. High levels of p62 c-myc were associated with well differentiated tumours. There was no correlation with tumour DNA index, lymph node or oestrogen receptor status. C-myc oncoprotein levels were not predictive of patient survival or disease free interval. This relationship of oncoprotein levels with tumour histological grade is in keeping with the suggestion that the c-myc oncogene is important in the control of cellular differentiation. The other findings imply that measurement of c-myc oncoprotein levels does not yield useful prognostic information.


To date, functional imaging studies of treatment-induced recovery from chronic aphasia only assessed short-term treatment effects after intensive language training. In the present study, we show with functional magnetic resonance imaging (fMRI), that different brain regions may be involved in immediate versus long-term success of intensive language training in chronic post-stroke aphasia patients.Eight patients were trained daily for three hours over a period of two weeks in naming of concrete objects. Prior to, immediately after, and eight months after training, patients overtly named trained and untrained objects during event-related fMRI. On average the patients improved from zero (at baseline) to 64.4% correct naming responses immediately after training, and treatment success remained highly stable at follow-up. Regression analyses showed that the degree of short-term treatment success was predicted by increased activity (compared to the pretraining scan) bilaterally in the hippocampal formation, the right precuneus and cingulate gyrus, and bilaterally in the fusiform gyri. A different picture emerged for long-term training success, which was best predicted by activity increases in the right-sided Wernicke's homologue and to a lesser degree in perilesional temporal areas.The results show for the first time that treatment-induced language recovery in the chronic stage after stroke is a dynamic process. Initially, brain regions involved in memory encoding, attention, and multimodal integration mediated treatment success. In contrast, long-term treatment success was predicted mainly by activity increases in the so-called 'classical' language regions. The results suggest that besides perilesional and homologue language-associated regions, functional integrity of domain-unspecific memory structures may be a prerequisite for successful (intensive) language interventions. Detailed clinical and demographic information of the patients are provided in Additional file Prior to training, all patients completed a baseline assessment consisting of a neurological examination, speech and language tests, and neuropsychological testing. All patients had relatively preserved cognitive abilities except for the language domain  were examined twice within a two-week time interval on an overt naming task during fMRI to (a) establish the set of brain regions activated by healthy subjects during our naming task and (b) to control for effects of repeated testing .For the intensive anomia training, 50 concrete object names were individually selected for each patient ('trained objects'). Each trained object name had been named incorrectly at least twice during three baseline runs comprising a standardized set of 344 objects   served as a control set for the post assessments (immediately and eight months post training). During the post assessments, the 50 trained and 30 untrained objects were presented thrice outside the scanner.Performance for a respective object name was classified as correct when at least two of the three runs were correct . By definition, the baselines for trained and untrained object names were zero percent correct (one or less correct runs out of three for each of the object names).2* weighted single shot echo-planar (EPI) sequence . A high-resolution T1-weighted anatomical image was acquired for anatomical identification and coregistration into the Talairach space.MRI data were acquired in a 3 Tesla whole body scanner (Philips Intera T30) with nominal gradient strength 30 mT/m and maximal slew rate 150 mT/m/ms. A circularly polarized transmit/receive birdcage head coil with a HF reflecting screen at the cranial end was used for spin excitation and resonance signal acquisition. Functional images were acquired using a TThe object-naming task comprised the visual presentation of photos of concrete objects during fMRI. Patients attended three identical fMRI sessions: The first was prior to the training (pre), the second directly after the training (post1), and the third eight months after completion of training (post2). Please note that patient P06 did not attend the 'two weeks'-appointment due to health problems unrelated to the study. The 'eight months'-assessment for P08 could not be conducted due to a required scanner hardware upgrade after his initial training.During each fMRI session, the participants had to overtly name the same 90 individually selected objects Figure . Thirty ). Control subjects also overtly named ninety visually presented objects during fMRI that were selected from our standardized set of 344 object pictures, based on a name agreement of > 80 percent in a different sample of healthy adults [Naming performance was assessed during the respective fMRI session by means of a special MR dual-channel communication system, equipped with software to subtract gradient noise from the patient microphone channel .Imaging data were analysed with SPM2  process . During  process . The masData were analysed in the context of the general linear model, using the canonical hemodynamic response function (hrf) to model responses during the five seconds of overt object naming for each experimental condition. To account for movement artefacts, the estimated realignment parameters were entered in the design matrix as user specified regressors. Anatomical localization of activated brain regions was determined using the Talairach Demon .Planned contrasts-of-interest were calculated for each individual subject . These included the individual activity changes from pre to post training (post1-pre) or the comparison of the baseline scan with the third scan eight months after the training (post2-pre) for each object type separately . To detect areas with the greatest short- or long-term fMRI activity changes, which linearly correlated with behavioural improvement, we performed two linear regression analyses . Dependent variable was the individual activity change from pre to post training , respectively. The respective individual training success for trained items (post1 or post2) served as behavioural regressor.Technical difficulties, which could not be resolved by the fMRI microphone manufacturer, precluded the recording of the speech samples during scanning for later off-line analysis with application of a software filter to extract the speech signal from the scanner noise. Online assessment of patient's word production was not reliably possible because of the scanner background noise. Sound quality was, however, good enough to determine that all patients complied with task instructions and tried to name the objects presented during scanning.Thus, we decided to use the patients' performance outside of the scanner on the matched set of items  as behavioural regressors. Even though intra-scanner scores are considered to be the most appropriate measure of performance for language production tasks , our extTo ensure that the results are specific for overt naming of the trained objects and not due to therapy-unrelated activity changes over time , we used the results of the respective regression analyses for the matched set of untrained objects as exclusive masks . The behavioural regressor here was the performance improvement of each patient from pretraining to post1 or post2, respectively. Thus, this analysis allows assessing which areas are specifically related to training-induced improved word-retrieval in the patient group.To determine the brain activity pattern during overt picture naming in the nine healthy subjects, we performed a one sample t-test using the individual fMRI activation patterns during overt object naming (first fMRI session only). The nine healthy control subjects showed overt naming related activity in brain regions mediating the core processes of picture naming  for det. UnspeciZ-score > 3.00) for the patients because of the known stronger activations seen in chronic stroke patients compared to healthy controls in fMRI studies [Maximally activated voxels within significant clusters (p < 0.05) are reported at a voxel threshold of p < 0.05 and a minimum cluster size of 10 voxels if not otherwise stated. At least one voxel within a given cluster had to additionally survive a single-voxel statistical threshold of p < 0.001 , right inferior parietal (BA 40) regions, the right fusiform gyrus (BA 19), and the right caudate nucleus.increases of brain activity ('Session2 > Session1'), even at an uncorrected threshold of p < 0.05. Only activity decreases in the right inferior parietal lobe were observed from the first to the second assessment .In healthy control subjects, the comparison between the two fMRI sessions revealed no The present fMRI study determined for the first time both short- and long-term correlates of successful treatment-induced language recovery in chronic aphasia. We here show that success of an intensive language training in chronic aphasia patients depends both on immediate activity changes in visual, attention-, and memory-related brain structures as well as on slowly evolving activity changes (over the course of eight months) in right language homologue areas of the middle temporal lobe . This longitudinal study thus demonstrates that even in the chronic stage after a stroke, language reorganization is a highly dynamic process, comparable to the time course of language or motor recovery in the acute stage after stroke ,38.Patients behaviourally improved from zero percent correct naming responses at pre-training to a mean of 64.4 percent immediately after training, which amounts to a very large treatment effect compared to previous studies with chronic aphasia patients . This deinitial language learning, i.e., the acquisition of lexical [Immediate treatment success from baseline to immediately after training was best predicted by an fMRI activity increase in brain structures orchestrating memory encoding  . It may  lexical , semanti lexical , and syn lexical  knowledg lexical . The con lexical . Thus, iAdditionally, a right parahippocampal activity increase from pre to post training was a good correlate of language recovery in our patients. This presumably reflects the fact that language re-learning is more laborious in aphasia as compared to language learning in healthy subjects and may thus require the joint effort of both hemispheres. The right parahippocampus may also mediate the functional recruitment of right-sided homologue language regions following left hemisphere damage ,24.We also observed increased activity immediately after training in the right-sided precuneus and cingulate gyrus and bilaterally in the posterior fusiform gyri in patients with good naming recovery. This in line with previous functional imaging studies on treatment induced recovery of language functions in chronic aphasia  and thesA lack of treatment-induced hippocampal activity modulation in prior aphasia intervention neuroimaging studies may be due to the smaller extent of treatment induced language recovery in chronic aphasia e.g. ,18,19). ,19. 18,1spontaneous language recovery over the course of one year depended on regional cerebral blood flow increases bilaterally in the temporal lobes [The major novel aspect of the present study was the identification of brain structures mediating the long-term retention (after eight months) of the training outcome. Behaviourally, patients' naming performance remained highly stable throughout the eight months follow-up period . The long-term treatment success, however, was mediated by different brain structures than those involved in short-term language recovery. Greater treatment success in the long run was predominantly related to an activity increase in language regions of right temporal lobe  - when lowering the statistical threshold to account for the reduced statistical power in perilesional brain areas  - in peral lobes ,47. The The current study aimed to investigate the neural correlates of immediate versus long-term successes of intensive naming training in chronic aphasia patients. The results can therefore not be directly generalized to other types of language training (non-intensive) or other types of aphasic symptoms . Future studies may also consider obtaining complimentary information from different imaging techniques that have a better temporal resolution. For example, Laganaro et al.  used eleFurthermore, the core problem in our patients was the linking of semantic information with a particular word form . RM, MM, HK, MD, AB, HS, MT, KK, HL, AF, SK and CB contributed to the design of the study. RM, MM, HK, HS, KK and CB collected the imaging data. HL conducted the neuropsychological testing. RM, KK and MT administered the treatment. RM, MM, HK, MD and CB analyzed the fMRI data. RM, MM and CB drafted the manuscript. All authors were involved in revising the initial draft and approved the final version.Patient Information. Demographic and clinical information and language test results for the eight aphasia patientsClick here for fileSupporting information. Provides additional supportive information regarding patient characteristics, neuropsychological testing and functional imaging analyses and resultsClick here for fileBrain activity changes immediately after training and at the follow-up assessment. Brain activity changes in the patients and healthy controls: Brain areas showing a) positive and b) negative correlations between short-term training success and 'post1-pre' training activity changes for trained object names (masked with the respective results for untrained object names). Brain areas showing c) positive and d) negative correlations between long-term training success and 'post2-pre' training activity changes for trained object names (masked with the respective results for untrained object names). The corresponding results for the control group (Session1 versus Sesssion2) are displayed in italic fontClick here for file