OFF Phase Research Articles

Dynamical behaviors of vertical-cavity surface-emitting lasers with an embedded saturable absorber subjected to an on-off keying (OOK) current modulation

Abstract We numerically study the dynamics of VCSEL-SA when modulated by an analog on-off keying (OOK) current. It is found that the laser gives a pulse-like response when operated below the threshold current. After the threshold current, which is in the excitable phase, the laser generates single spikes (phasic spiking) and a series of spikes (tonic spiking) wherein the amplitude of the spikes varies as the form of the current. Complex dynamics such as bursting oscillations and chaotic dynamics are successfully generated at low frequencies (few MHz). After this excitable phase, the laser copies the OOK current with underdamped oscillations generated during the OFF phase of the OOK current.

The Effects of Safinamide Adjunct Therapy on Depression and Apathy in Patients With Parkinson's Disease: Post-hoc Analysis of a Japanese Phase 2/3 Study.

Background and PurposeNeuropsychiatric symptoms in Parkinson's disease (PD) have been shown to significantly affect quality of life (QOL). We investigated the impact of safinamide on depression and apathy when administered as an adjunct to levodopa in Japanese patients with PD.MethodsThis was a post-hoc analysis of data from a phase 2/3 clinical study of safinamide in Japanese patients with PD experiencing wearing-off (JapicCTI-153056; https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-153056). Patients received placebo, safinamide 50 mg, or safinamide 100 mg as an adjunct therapy. The endpoints for this analysis were changes from baseline to Week 24 in the Unified Parkinson's Disease Rating Scale (UPDRS) Part I item 3 (depression) and item 4 (apathy) scores and the Parkinson's Disease Questionnaire (PDQ-39) “emotional well-being” domain score. Subgroup analyses investigated the relationship between neuropsychologic symptoms and improvements in motor fluctuation and assessed which patient populations might be expected to obtain neuropsychologic benefit from safinamide.ResultsCompared with placebo, safinamide (both doses) significantly improved UPDRS Part I item 3 scores in the overall analysis population, and the 100-mg dose improved UPDRS Part I item 4 scores in the population with apathy at baseline. Changes in the PDQ-39 “emotional well-being” score showed numerical, but not significant, dose-related improvements. Notable reductions in depression were associated with a change in daily ON-time ≥1 h, pain during OFF-time at baseline, and female sex.ConclusionsThe results from this post-hoc analysis of the Japanese phase 2/3 study suggest that safinamide could bring benefits to patients with PD who have mild depression, pain during the OFF phase. In addition, safinamide might provide particular benefits for patients with PD who have mild apathy and female.

Current Knowledge on the Background, Pathophysiology and Treatment of Levodopa-Induced Dyskinesia-Literature Review.

Levodopa remains the primary drug for controlling motor symptoms in Parkinson’s disease through the whole course, but over time, complications develop in the form of dyskinesias, which gradually become more frequent and severe. These abnormal, involuntary, hyperkinetic movements are mainly characteristic of the ON phase and are triggered by excess exogenous levodopa. They may also occur during the OFF phase, or in both phases. Over the past 10 years, the issue of levodopa-induced dyskinesia has been the subject of research into both the substrate of this pathology and potential remedial strategies. The purpose of the present study was to review the results of recent research on the background and treatment of dyskinesia. To this end, databases were reviewed using a search strategy that included both relevant keywords related to the topic and appropriate filters to limit results to English language literature published since 2010. Based on the selected papers, the current state of knowledge on the morphological, functional, genetic and clinical features of levodopa-induced dyskinesia, as well as pharmacological, genetic treatment and other therapies such as deep brain stimulation, are described.

A Methylation-Directed, Synthetic Pap Switch Based on Self-Complementary Regulatory DNA Reconstituted in an All E. coli Cell-Free Expression System.

Pyelonephritis-associated pili (pap) enable migration of the uropathogenic Escherichia coli strain (UPEC) through the urinary tract. UPEC can switch between a stable 'ON phase' where the corresponding pap genes are expressed and a stable 'OFF phase' where their transcription is repressed. Hereditary DNA methylation of either one of two GATC motives within the regulatory region stabilizes the respective phase over many generations. The underlying molecular mechanism is only partly understood. Previous investigations suggest that in vivo phase-variation stability results from cooperative action of the transcriptional regulators Lrp and PapI. Here, we use an E. coli cell-free expression system to study molecular functions of the pap regulatory region based on a specially designed, synthetic construct flanked by two reporter genes encoding fluorescent proteins for simple readout. On the basis of our observations we suggest that besides Lrp, the conformation of the self-complementary regulatory DNA plays a strong role in the regulation of phase-variation. Our work not only contributes to better understand the phase variation mechanism, but it represents a successful start for mimicking stable, hereditary, and strong expression control based on methylation. The conformation of the regulatory DNA corresponds to a Holliday junction. Gene expression must be expected to respond if opposite arms of the junction are drawn outward.

Effects of safinamide adjunct therapy on pain in patients with Parkinson's disease: Post hoc analysis of a Japanese phase 2/3 study

IntroductionThe non-dopaminergic and dopaminergic actions of safinamide may alleviate pain in patients with Parkinson's disease (PD). We investigated the efficacy of safinamide for pain when administered as an adjunct to levodopa in Japanese patients with PD. MethodsThis was a post hoc analysis of a phase 2/3 clinical study of safinamide in Japanese patients with PD who were experiencing wearing-off. Pain was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part II ‘sensory symptoms’ item 17, on a scale of 0–4, and the 39-item Parkinson's Disease Questionnaire (PDQ-39) ‘bodily discomfort’ domain score. Subgroup analyses, according to baseline symptoms and concomitant medications, were also performed. ResultsLeast square (LS) mean changes in the UPDRS item 17 score from baseline to Week 24 in the placebo, safinamide 50-mg and safinamide 100-mg groups during the OFF phase were 0.08, −0.15 (p = 0.0133 vs placebo) and −0.18 (p = 0.0054), respectively, and during the ON phase were 0.04, −0.08 (p = 0.0529) and −0.08 (p = 0.0505), respectively. Changes from baseline to Week 24 in PDQ-39 ‘bodily discomfort’ scores were not significantly different in safinamide groups vs placebo. The presence of moderate-to-severe bradykinesia or early-morning dystonia at baseline resulted in numerically greater effect sizes in UPDRS item 17 scores during the OFF phase. ConclusionsSafinamide 50 mg and 100 mg reduced the UPDRS item 17 score in patients with PD, especially during the OFF phase. Patients with moderate-to-severe bradykinesia and early-morning dystonia may benefit from safinamide treatment.

Diurnal burden of spontaneous seizures in early epileptogenesis in the post-kainic acid rat model of epilepsy.

Patients with epilepsy can experience diurnal seizure patterns. However, few studies in rodent models of temporal lobe epilepsy (TLE) routinely quantify the diurnal pattern of spontaneous recurrent seizures (SRS), and those that have conducted such assessments used small groups. This study thus aimed to define whether there was a diurnal pattern of SRS in the early phases of epileptogenesis in a large cohort (n = 40) of post‐kainic acid (KA)‐induced status epilepticus (SE) male Sprague Dawley rats. Rats were monitored by continuous 24/7 video‐EEG in two‐week epochs up to 6 weeks post‐KA‐induced SE. The total number of SRS by 6 weeks post‐SE correlated to body weight at the time of SE insult (R 2 = .1465, P = .0143). The total number of spontaneous behavioral and electrographic seizures, seizure severity, and seizure burden was recorded during lights ON (light) or lights OFF (dark) phases. All measures significantly increased with time post‐SE; we detected significantly more seizures during the lights OFF phase of the post‐SE monitoring periods. Moreover, a subset of rats demonstrated marked seizure preference in the lights OFF phase. Our study confirms that a diurnal pattern of SRS is variably detectable in early epileptogenesis in this model of TLE.

Epigenetic Memories: The Hidden Drivers of Bacterial Persistence?

Epigenetic modifications, including DNA methylation, stably alter gene expression without modifying genomic sequences. Recent evidence suggests that epigenetic regulation coupled with a long-term 'memory' effect plays a major role within bacterial persistence formation. Today, emerging high-resolution, single-molecule sequencing technologies allow an increased focus on DNA modifications as regulatory epigenetic marks, which presents a unique opportunity to identify possible epigenetic drivers of bacterial persistence.

Efficacy and safety of safinamide as an add-on therapy to L-DOPA for patients with Parkinson's disease: A randomized, double-blind, placebo-controlled, phase II/III study

IntroductionSafinamide is a reversible and selective monoamine oxidase-B (MAO-B) and sodium channel inhibitor with demonstrated efficacy in mid-to late-stage Parkinson's disease (PD) as an adjunct to l-DOPA. This study aimed to confirm the efficacy and safety of safinamide in PD patients with wearing-off. MethodsThis 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study included Japanese PD patients with wearing-off on l-DOPA treatment. Patients were randomized to receive placebo (P), safinamide 50 mg/day (S50), or safinamide 100 mg/day (S100). The primary endpoint was the change from baseline in mean daily ON-time without troublesome dyskinesias (ON-time). Other measures included the changes in mean daily OFF-time, the unified Parkinson's disease rating scale (UPDRS) score, and the PDQ-39 summary index. ResultsA total of 406 subjects were randomized, of whom 349 completed the study. Baseline characteristics were balanced. Differences in the change of mean daily ON-time at Week 24 compared with the P group were 1.39 h (p = 0.0002) in the S50 group and 1.66 h (p < 0.0001) in the S100 group. Changes from baseline in mean daily OFF-time, UPDRS Part II total score (OFF phase), UPDRS Part III total score (ON phase), and UPDRS Part I also showed significant improvements. Adverse events occurred in 58.9%, 60.2%, and 61.4% of the P, S50, and S100 groups, respectively. The most common adverse drug reactions were dyskinesias (2.1%, 8.3%, and 10.6%) and visual hallucinations (1.4%, 3.0%, and 4.5%). ConclusionAs an adjunct to l-DOPA, safinamide safely increased ON-time and improved PD symptoms/signs in PD patients with wearing-off.

The research on active boost PFC

The current wave form of active boost PFC is simulated in time domain and frequency domain. With the voltage of 220 v, the inductance of 15 mH, the capacitance of 5040 μF, the load of 2500 W, the integrated power factor, fundamental power factor, and distortion are analyzed. The distortion is enhanced with the increase of frequency. Comparing high-order harmonic part under 10 mH and 15 Mh, it is demonstrated that the appropriate OFF phase angle changes with different requirement: the angle is 37 degree with distortion in least while the one is 34 degree with maximum integrated power factor. Topology and results are proposed. The results demonstrate that the power factor of real PFC circuit is up to 0.975.

The Immediate Effects of Vagus Nerve Stimulation in Intractable Epilepsy: An Intra-operative Electrocorticographic Analysis.

The purpose of this study was to investigate whether and how vagus nerve stimulation (VNS) reduces the epileptogenic activity in the bilateral cerebral cortex in patients with intractable epilepsy. We analyzed the electrocorticograms (ECoGs) of five patients who underwent callosotomy due to intractable epilepsy even after VNS implantation. We recorded ECoGs and analyzed power spectrum in both VNS OFF and ON phases. We counted the number of spikes and electrodes with epileptic spikes, distinguishing unilaterally and bilaterally hemispherically spread spikes as synchronousness of the epileptic spikes in both VNS OFF and ON phases. There were 24.80 ± 35.55 and 7.20 ± 9.93 unilaterally spread spikes in the VNS OFF and ON phases, respectively (P = 0.157), and 35.8 ± 29.21 and 10.6 ± 13.50 bilaterally spread spikes in the VNS OFF and ON phases, respectively (P = 0.027). The number of electrodes with unilaterally and bilaterally spread spikes in the VNS OFF and ON phases was 3.84 ± 2.13 and 3.59 ± 1.82 (P = 0.415), and 8.20 ± 3.56 and 6.89 ± 2.89 (P = 0.026), respectively. The ECoG background power spectra recordings in the VNS OFF and ON phases were also analyzed. The spectral power tended to be greater in the high-frequency band at VNS ON phase than OFF phase. This study showed the reduction of epileptogenic spikes and spread areas of the spikes by VNS as immediate effects, electrophysiologically.

Predictors of dementia-free survival after bilateral subthalamic deep brain stimulation for Parkinson's disease.

Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves motor complications and quality of life (QOL) in patients with Parkinson's disease (PD). However, it does not delay or prevent the occurrence of dementia. The deleterious effects of dementia on QOL and activities of daily living (ADL) underscore the importance of identifying predictors of dementia-free survival in PD patients considered for STN DBS. The baseline clinical and neuropsychological data and the occurrence of dementia recorded during the longitudinal follow-up of a cohort of patients with PD with at least 2 years follow-up after bilateral STN DBS, were reviewed. One hundred and sixteen patients operated between 1999 to 2014 satisfied the inclusion criteria. Their mean age was 56.5 (±10) years and the mean duration of PD at surgery was 11.2 (±4.2) years. During the 542 person-years of follow-up, 30 patients developed dementia. The mean dementia-free survival after surgery was 8.7 [95% confidence interval (CI): 7.8-9.6] years. In univariate analysis, the baseline factors of older age, longer disease duration, past history of depression or psychosis, freezing of gait in OFF phase, worse ADL scores in ON phase, lower levodopa response of the Unified Parkinson's Disease Rating Scale (UPDRS) III axial sub-scores, and poor performances in the Addenbrooke's Cognitive Examination and Wisconsin Card Sorting Test (WCST) were associated with a shorter dementia-free survival. Among these, only freezing of gait and poor performance in WCST were independent predictors. Presence of freezing of gait in the drug OFF state and executive dysfunction predict the occurrence of earlier dementia in PD patients who otherwise qualify for bilateral STN DBS.

A Novel Pharmacologic ‘Remote Control’ to Steer CAR-T Cell Function In Vivo

▪Background:Immunotherapy with chimeric antigen receptor T cells (CAR-T) is emerging as a transformative novel treatment for hematologic malignancies. In contrast to conventional agents, CAR-T are a living drug that is essentially out of the physician's (and patient's) control after infusion. At present, there is a lack of technologies to maintain control over CAR-T, both for steering efficacy and for preventing toxicity. Here, we present a novel strategy of pharmacologic ‘remote control’ to precisely steer CAR-T activity and function in real-time.Methods:We considered that an effective way for controlling CAR-T function was to interfere with signal transduction through the CAR. We assembled a library of tyrosine kinase inhibitors and screened for their ability to block CAR-T function without affecting CAR-T viability. We performed functional testing with CD8+ and CD4+ CAR-T (n=3 donors) in the presence of titrated doses of the lead compound, and employed CD19- and ROR1-specific CARs comprising 4-1BB or CD28 costimulatory moieties.Results:We identified a lead compound, TCI-1, that stood out through its ability to confer a dose-dependent (partial at lower, complete at higher doses) blockade of all CAR-T effector functions, i.e. cytolytic activity, cytokine secretion and proliferation. We confirmed that TCI-1 is effective in both CD8+ and CD4+ CAR-T, and capable of completely blocking CAR-T function independent from CAR specificity and costimulatory moiety included in the signaling module. The onset of CAR-T blockade is immediate after exposure to TCI-1 and is caused by interference with early phosphorylation events in the CAR-CD3zeta module as demonstrated by western blot, and by interference with the induction of transcription factors, as demonstrated with an NFAT-inducible reporter gene. Blockade of CAR-T function is effective for several days if TCI-1 is continuously supplied and instantaneously and fully reversible after removal of the compound. Short- and long-term exposure to TCI-1 does not lead to a reduction in CAR-T viability, and does not hinder the subsequent ability of CAR-T to exert their effector functions. We reasoned that in patients experiencing side effects like cytokine release syndrome (CRS), CAR-T are in a highly activated state and therefore performed comprehensive testing to demonstrate that TCI-1 is able to arrest activated CAR-T that are already in the process of executing their effector functions.For further proof-of-concept, we employed a xenograft model in immunodeficient mice (NSG/Raji) and demonstrate that TCI-1 is capable of controlling the function of CD19 CAR-T in vivo. In a first scenario, we administered TCI-1 between d3 and d5 after CAR-T infusion and show that TCI-1 is able to arrest activated CAR-T during this time interval and pause the antitumor effect. Importantly, CAR-T immediately resumed their antitumor function once administration of TCI-1 was discontinued (function ON-OFF-ON sequence). In a second scenario, we administered TCI-1 immediately after CAR-T infusion (function OFF-ON sequence). The data show that TCI-1 halts CAR-T activation during the OFF phase and prevents cytokine release, without affecting the subsequent antitumor potency of CAR-T during the ON phase in this lymphoma model.Conclusions:Our data introduce TCI-1 as a universally applicable pharmacologic ‘remote control’ for CAR-T. We show that TCI-1 is capable to exert real-time, ON/OFF control over CAR-T function in vitro and in vivo. TCI-1 has a favorable pharmacokinetic and safety profile in humans, suggesting the potential for rapid clinical implementation. The qualities of TCI-1 with rapid-onset mode of action in addition to complete but fully reversible CAR-T inhibition surpass the qualities of steroids that are toxic to T cells and provide only incomplete control, and complement the existing spectrum of safety technologies with suicide-gene that effectively control CAR-T but also terminate their antitumor effect. DisclosuresMestermann:University Hospital of Wuerzburg: Employment, Patents & Royalties: co-inventor on a patent related to TCI-1 that has been filed by the University of Wuerzburg. .

Effect of dual-chamber minimal ventricular pacing on paroxysmal atrial fibrillation incidence in myotonic dystrophy type 1 patients: A prospective, randomized, single-blind, crossover study

Atrial fibrillation (AF) is a common finding in the myotonic dystrophy type 1 (DM1) population. Pacemakers (PMs) may facilitate the diagnosis and management of frequent subclinical asymptomatic AF episodes. The purpose of this study was to evaluate the effect of minimal ventricular pacing on paroxysmal AF incidence in DM1 patients during a 24-month follow-up period. We enrolled 70 DM1 patients (age 43.4 ± 13.8 years; 39 women) who underwent dual-chamber PM implantation. Patients were randomized to minimizing ventricular pacing features (ON) or not (OFF). Patients crossed over to the opposite pacing programming 12 months later. We counted the number of DM1 patients with at least 1 episode of AF, the AF total duration, and the burden recorded by PM diagnostics during the MVP ON and OFF phases. Twenty-five DM1 patients (41.7%) showed at least 1 AF episode. Seven patients (11.7%) demonstrated AF episodes during MVP ON phase and 25 patients (41.7%) during MVP OFF phase (P<.001). Thirty-five patients had no AF during MVP ON or OFF phase, 3 patients had AF episodes only during MVP ON phase, 21 patients had AF episodes only during MVP OFF phase, and 4 patients had AF episodes during MVP ON and OFF phases. Activation of the MVP algorithm was associated with a 44% reduction in relative risk of developing AF. Furthermore, during the MVP ON phases, the study population showed a shorter total AF duration and a lower AF burden. MVP is an efficacy strategy for reducing the risk of AF in DM1 patients who have undergone PM implantation.

A “HOLTER” for Parkinson’s disease: Validation of the ability to detect on-off states using the REMPARK system

The treatment of Parkinson's disease (PD) with levodopa is very effective. However, over time, motor complications (MCs) appear, restricting the patient from leading a normal life. One of the most disabling MCs is ON-OFF fluctuations. Gathering accurate information about the clinical status of the patient is essential for planning treatment and assessing its effect. Systems such as the REMPARK system, capable of accurately and reliably monitoring ON-OFF fluctuations, are of great interest. ObjectiveTo analyze the ability of the REMPARK System to detect ON-OFF fluctuations. MethodsForty-one patients with moderate to severe idiopathic PD were recruited according to the UK Parkinson’s Disease Society Brain Bank criteria. Patients with motor fluctuations, freezing of gait and/or dyskinesia and who were able to walk unassisted in the OFF phase, were included in the study. Patients wore the REMPARK System for 3days and completed a diary of their motor state once every hour. ResultsThe record obtained by the REMPARK System, compared with patient-completed diaries, demonstrated 97% sensitivity in detecting OFF states and 88% specificity (i.e., accuracy in detecting ON states). ConclusionThe REMPARK System detects an accurate evaluation of ON-OFF fluctuations in PD; this technology paves the way for an optimisation of the symptomatic control of PD motor symptoms as well as an accurate assessment of medication efficacy.

Spontaneous locomotor activity and L-DOPA-induced dyskinesia are not linked in 6-OHDA parkinsonian rats.

Bradykinesia (slowness of movement) and other characteristic motor manifestations of Parkinson’s disease (PD) are alleviated by treatment with L-dihydroxyphenylalanine (L-DOPA). Long-term L-DOPA treatment, however, is associated with complications such as motor fluctuations and dyskinesia that severely impair the quality of life. It is unclear whether the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect share a common mechanism. To investigate the possible connection between these two effects, we analyzed the spontaneous locomotor activity of parkinsonian rats before surgery (unilateral injection of 6-OHDA in the right medial forebrain bundle), before treatment with L-DOPA, during L-DOPA treatment (the “ON” phase), and after the end of L-DOPA treatment (the “OFF” phase). We correlated the severity of dyskinesia (AIM scores) with locomotor responses in the ON/OFF phases of chronic L-DOPA treatment at two different doses. We treated three groups of parkinsonian animals with chronic injections of 8 mg/kg L-DOPA, 6 mg/kg L-DOPA, and saline solution and one group of non-lesioned animals with 8 mg/kg L-DOPA. At the end of the experiment, tyrosine hydroxylase (TH) immunoreactivity was analyzed in the striatum of all parkinsonian rats. We found no correlation between the severity of dyskinesia and spontaneous locomotor activity in the ON or OFF phase of L-DOPA treatment. The only observed correlation was between the pathological rotation induced by L-DOPA at the highest dose and locomotor activity in the ON phase of L-DOPA treatment. In addition, a L-DOPA withdrawal effect was observed, with worse motor performance in the OFF phase than before the start of L-DOPA treatment. These findings suggest that different neural mechanisms underlie the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect, with a different dose-response relationship for each of these two effects.

Leucine-responsive regulatory protein Lrp and PapI homologues influence phase variation of CS31A fimbriae.

CS31A, a K88-related surface antigen specified by the clp operon, is a member of the type P family of adhesive factors and plays a key role in the establishment of disease caused by septicemic and enterotoxigenic Escherichia coli strains. Its expression is under the control of methylation-dependent transcriptional regulation, for which the leucine-responsive regulatory protein (Lrp) is essential. CS31A is preferentially in the OFF state and exhibits distinct regulatory features compared to the regulation of other P family members. In the present study, surface plasmon resonance and DNase I protection assays showed that Lrp binds to the distal moiety of the clp regulatory region with low micromolar affinity compared to its binding to the proximal moiety, which exhibits stronger, nanomolar affinity. The complex formation was also influenced by the addition of PapI or FooI, which increased the affinity of Lrp for the clp distal and proximal regions and was required to induce phase variation. The influence of PapI or FooI, however, was predominantly associated with a more complete shutdown of clp expression, in contrast to what has previously been observed with AfaF (a PapI ortholog). Taken together, these results suggest that the preferential OFF state observed in CS31A cells is mainly due to the weak interaction of the leucine-responsive regulatory protein with the clp distal region and that the PapI homolog favors the OFF phase. Within the large repertoire of fimbrial variants in the P family, our study illustrates that having a fimbrial operon that lacks its own PapI ortholog allows it to be more flexibly regulated by other orthologs in the cell.

Spontaneous and electrically modulated spatiotemporal dynamics of the neocortical slow oscillation and associated local fast activity

The neocortical slow oscillation (SO; ~1Hz) of non-REM sleep and anesthesia reflects synchronized network activity composed of alternating active and silent (ON/OFF) phases at the local network and cellular level. The SO itself shows self-organized spatiotemporal dynamics as it appears to originate at unique foci on each cycle and then propagates across the cortical surface. During sleep, this rhythm is relevant for neuroplastic processes mediating memory consolidation especially since its enhancement by slow, rhythmic electrical fields improves subsequent recall. However, the neurobiological mechanism by which spontaneous or enhanced SO activity might operate on memory traces is unknown. Here we show a series of original results, using cycle to cycle tracking across multiple neocortical sites in urethane anesthetized rats: The spontaneous spatiotemporal dynamics of the SO are complex, showing interfering propagation patterns in the anterior-to-posterior plane. These patterns compete for expression and tend to alternate following phase resets that take place during the silent OFF phase of the SO. Applying sinusoidal electrical field stimulation to the anterior pole of the cerebral cortex progressively entrained local field, gamma, and multi-unit activity at all sites, while disrupting the coordination of endogenous SO activity. Field stimulation also biased propagation in the anterior-to-posterior direction and more notably, enhanced the long-range gamma synchrony between cortical regions. These results are the first to show that changes to slow wave dynamics cause enhancements in high frequency cortico-cortical communication and provide mechanistic clues into how the SO is relevant for sleep-dependent memory consolidation.

Prefrontal alterations in Parkinson's disease with levodopa‐induced dyskinesia during fMRI motor task

Levodopa-induced dyskinesia represents disabling complication of long-term therapy with dopaminergic drugs in treating Parkinson's disease (PD). Recently, our group demonstrated that PD patients with levodopa-induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa-induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa-induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia.

Intermittent Androgen Suppression in Prostate Cancer: Testosterone Levels and Its Implication

Intermittent androgen suppression (IAS) in patients affected by prostate cancer seems to lessen the severity of the side effects that are associated with continuous androgen ablation. This report monitors the effect of IAS on testosterone values, quality of life, and sexual function during phases of therapy. A total of 100 patients entered a prospective study of IAS. Androgen blockade was prolonged until a serum prostate specific antigen (PSA) nadir was reached and then resumed for a PSA threshold of 10 ng/mL, in repeated cycles. During I phase, we assessed testosterone levels, well-being with quality-of-life score, and sexual function. All patients were followed up every 3 months with PSA and total testosterone determinations, and with quality-of-life score using a 10-point questionnaire. Side effects were assessed using yes/no questions. Sexual function was assessed using yes/no questions and in the sexually active patients with International Index of Erectile Function-5 (IIEF). All patients completed I cycle of treatment (I ON plus I OFF phase). During the OFF phase, 46% of patients showed low testosterone levels, while the others recovered normal testosterone concentrations at a mean of 6.2 months after therapy. There is a negative correlation between baseline PSA values and length of OFF phase and testosterone recovery, and a negative correlation between length of OFF phase and testosterone value during OFF phase. Worsening in Quality of Life (QOL) was significant during active treatment with respect to baseline, but therapy withdrawal showed a positive impact with respect to treatment period. Improvement in quality of life correlated to testosterone recovery and time to testosterone recovery. Fifty-four percent of subjects had normal sexual intercourse at therapy withdrawal, with a correspondence to time to testosterone recovery. Quality of life and sexual function seem to follow testosterone normalization. These results could have implications in the analysis of IAS.

Time-resolved plasma parameters in the HiPIMS discharge with Ti target in Ar/O2 atmosphere

A High Power Impulse Magnetron Sputtering System (HiPIMS) equipped with a titanium target 5cm in diameter has been investigated by means of a time-resolved Langmuir probe and time-resolved ion flux probe. The plasma parameters have been measured in a distance of 70mm from the target face and below the racetrack. The ion flux at the substrate (placed at the same position as the Langmuir probe) has been determined from the voltage drop across a resistor connected with the planar probe. The planar probe was pulsed at a repetition rate of 50kHz, duty cycle 50%. The effects of working gas pressure and mean discharge current have been investigated.Fine temporal resolution of the measured probe characteristics revealed a decrease in the effective electron temperature Teff during pulse-ON time followed by a steady value at 0.6eV for all the pressures during the rest of the period. For the pressure of 2Pa, we observed a local maximum in Teff (0.9eV) at the end of cathode voltage pulse. Furthermore, during the pulse-OFF time we observed an exponential-like decay of the electron temperature for all the pressures. The plasma density demonstrated a steep increase during pulse-ON time followed by an exponential-like decrease during plasma OFF phase. The ion flux measurements have revealed approximately 3 times higher magnitude in the ion flux on the substrate at low pressure than at higher-pressures. The influence of these phenomena on the total energy flux at substrate and on thin film properties is discussed.