Mild activation of poly(ADP-ribose) polymerase (PARP) is neuroprotective in rat hippocampal slice models of ischemic tolerance

Ischemic tolerance is a phenomenon in which exposure to a mild preconditioning stress results in resistance to a subsequent lethal ischemic insult. Here we investigated the role of poly(ADP-ribose) polymerase (PARP) in the development of ischemic tolerance by using organotypic rat hippocampal slices exposed to 30 min oxygen-glucose deprivation (OGD), which leads to selective injury of the CA1 subregion 24 h later. We developed models of pharmacological preconditioning by exposing slices to subtoxic concentrations of either N-methyl-D-aspartate (NMDA) or (S)-3,5-dihydroxyphenylglycine (DHPG) and then, 24 h later, to 30 min OGD. Under these conditions, we observed a significant reduction in OGD-induced CA1 damage. Exposure of slices to the PARP-1 and -2 inhibitors TIQ-A, PJ-34 and UPF 1069 during preconditioning prevented the development of OGD tolerance in a concentration-dependent manner. NMDA and DHPG preconditioning increased the activity of PARP, as detected by immunoblots using antibodies against the poly(ADP-ribose) polymer product, but was not associated with consumption of cellular NAD(+) or ATP. Neuroprotection induced by preconditioning was also prevented by the caspase inhibitor Z-VAD-FMK. The modest but significant increase in caspase-3/7 induced by preconditioning, however, was not associated with PARP-1 cleavage, as occurred with staurosporine. Finally, TIQ-A prevented the activation of ERK1/2 and Akt induced by NMDA preconditioning, suggesting that the protective mechanism evoked by PARP requires activation of these prosurvival mediators. Our results suggest that preconditioning with appropriate pharmacological stimuli may promote neuroprotective mechanisms triggered by the sublethal activation of two otherwise deleterious executioners such as PARP and caspase-3/7.     

Ablation of PGC1 beta prevents mTOR dependent endoplasmic reticulum stress response

Mitochondria dysfunction contributes to the pathophysiology of obesity, diabetes, neurodegeneration and ageing. The peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) coordinates mitochondrial biogenesis and function as well as fatty acid metabolism. It has been suggested that endoplasmic reticulum (ER) stress may be one of the mechanisms linking mitochondrial dysfunction and these pathologies. Here we investigate whether PGC-1β ablation affects the ER stress response induced by specific nutritional and pharmacological challenges in the CNS. By using flow cytometry, western blot, real time PCR and several pharmacological and nutritional interventions in PGC-1β knock out and WT mice, we confirmed that PGC-1β coordinates mitochondria function in brain and reported for the first time that a) ablation of PGC-1β is associated with constitutive activation of mTORC1 pathway associated with increased basal GRP78 protein levels in hypothalamus and cortex of animals fed chow diet; and b) in animals fed chronically with high fat diet (HFD) or high protein diet (HPD), we observed a failure to appropriately induce ER stress response in the absence of PGC-1β, associated with an increase in mTOR pathway phosphorylation. This contrasted with the appropriate upregulation of ER stress response observed in wild type littermates. Additionally, inefficient in vitro induction of ER stress by thapsigargin seems result in apoptotic neuronal cell death in PGC-1β KO. Our data indicate that PGC-1β is required for a neuronal ER response to nutritional stress imposed by HFD and HPD diets and that genetic ablation of PGC-1β might increase the susceptibility to neuronal damage and cell death.     

Agreement in Endovascular Thrombolysis Patient Selection Based on Interpretation of Presenting CT and CT-P Changes in Ischemic Stroke Patients

Background

To evaluate the agreement in patient selection based on computed tomography (CT) and CT-perfusion (CT-P) imaging interpretation between stroke specialists in stroke patients considered for endovascular treatment.

Methods

All endovascular-treated acute ischemic stroke patients were identified through a prospective database from two comprehensive stroke centers; 25 consecutively treated patients were used for this analysis. Initial CT images and CT-P data were independently interpreted by five board eligible/certified vascular neurologists with additional endovascular training to decide whether or not to select the patient for endovascular treatment. The CT/CT-P images were evaluated separately and used as the sole imaging decision making criteria, 2?weeks apart from each other (memory wash-out period). For each set of imaging data inter-rater and intra-rater agreement scores were obtained using Cohen??s kappa statistic to assess the proportion of agreement beyond chance.

Results

Kappa values for the treatment decisions based on CT images was 0.43 (range 0.14?C0.8) (moderate agreement), and for the decisions based on CTP images was 0.29 (range 0.07?C0.67) (fair agreement) among the five subjects. There was substantial variability within the group and between images interpretation. Observed agreement on decision to treat with endovascular therapy was found to be 75% with CT images and 59% with CT-P images (with no adjustment for chance). Kappa values for intra-rater agreement were ?0.14 (ranged ?0.27?C0.27) (poor agreement).

Conclusions

There is considerable lack of agreement, even among stroke specialists, in selecting acute ischemic stroke patients for endovascular treatment based on CT-P changes. This mandates a careful evaluation of CT-P for patient selection before widespread adoption.     

Reliability of side‐to‐side ultrasound cross‐sectional area measurements of lower extremity nerves in healthy subjects

Introduction: In peripheral nerve ultrasound, the healthy contralateral side may be used as internal control. Therefore, inherent side‐to‐side differences must be minimal. The goal of this study was to assess intrastudy, intraobserver, and interobserver reproducibility of ultrasound in comparative side‐to‐side evaluation of lower limb nerves. Methods: Lower limb nerves of 60 normal subjects were evaluated by 3 radiologists. Bilateral sciatic, tibial, common fibular, sural, lateral femoral cutaneous, femoral, obturator, and saphenous nerves were evaluated. Results: Overall, side‐to‐side differences were not statistically significant at any level. In the lower limb nerves, in a between‐limb comparison, the minimum detectable difference of cross‐sectional area ranged from 16.4 mm² (sciatic nerve at the level of piriformis muscle) to 0.4 mm² (saphenous nerve). Conclusion: In general, the healthy contralateral side can be used as an internal control. Muscle Nerve 46: 717–722, 2012     

Conflict-dependent dynamic of subthalamic nucleus oscillations during moral decisions

Although lesional, neuroimaging, and brain stimulation studies have provided an insight into the neural mechanisms of judgement and decision-making, all these works focused on the cerebral cortex, without investigating the role of subcortical structures such as the basal ganglia. Besides being an effective therapeutic tool, deep brain stimulation (DBS) allows local field potential (LFP) recordings through the stimulation electrodes thus providing a physiological "window" on human subcortical structures. In this study we assessed whether subthalamic nucleus LFP oscillations are modulated by processing of moral conflictual, moral nonconflictual, and neutral statements. To do so, in 16 patients with Parkinson's disease (8 men) bilaterally implanted with subthalamic nucleus (STN) electrodes for DBS, we recorded STN LFPs 4 days after surgery during a moral decision task. During the task, recordings from the STN showed changes in LFP oscillations. Whereas the 14--30 Hz band (beta) changed during the movement executed to perform the task, the 5--13 Hz band (low-frequency) changed when subjects evaluated the content of statements. Low-frequency band power increased significantly more during conflictual than during nonconflictual or neutral sentences. We conclude that STN responds specifically to conflictual moral stimuli, and could be involved in conflictual decisions of all kinds, not only those for moral judgment. LFP oscillations provide novel direct evidence that the neural processing of conflictual decision-making spreads beyond the cortex to the basal ganglia and encompasses a specific subcortical conflict-dependent component.     

Cimicifuga racemosa treatment and health related quality of life in post-menopausal Spanish women

Objective.?The effect of Cimicifuga racemosa (CR) treatment was evaluated in healthy symptomatic post-menopausal women using the Cervantes health-related quality of life (HR-QoL) scale.

Design.?A prospective observational study was carried out in 122 healthy symptomatic post-menopausal Spanish women with elevated body weight, aged between 45 and 59 years. Three groups were formed according to age intervals. Each patient completed the Cervantes HR-QoL scale before and after CR treatment (20 mg, twice a day for 3 months). Changes in Cervantes scale global quality of life scores as well as in their domains (menopause and health, psychic, sexuality and couple relationship) were analysed.

Results.?The CR treatment ameliorated global quality of life in both the whole group of patients and when women were analysed by age subgroups. There were significant positive changes in Z scores for the Cervantes HR-QoL scale ‘menopause and health’, and ‘psychic’ domains in both the entire population and by age groups. The ‘sexuality domain’ significantly improved when the entire population was assessed, but not when each age-group was separately analysed; while there were no changes in ‘couple relationship domain’ scores.

Conclusion.?CR treatment increased both global quality of life and the four domains of the Cervantes HR-QoL scale, being an effective treatment to reduce symptoms in post-menopausal woman with elevated body weight.     

Oral appliances for the treatment of obstructive sleep apnea in patients with low C-PAP compliance: a long-term case series

Objectives:

To assess the effectiveness of mandibular advancement devices (MADs) for the treatment of obstructive sleep apnea syndrome (OSAS) over a long-term follow-up in patients non-compliant with continuous positive airway pressure (CPAP) and to identify potential predictive factors of response to MADs.

Methods:

Fifteen OSAS patients were enrolled. Apnea-hypopnea index (AHI) and daytime sleepiness were assessed at baseline and at the end of follow-up. Potential baseline predictors of treatment effectiveness were assessed.

Results:

AHI and Epworth Sleepiness Scale (ESS) scores improved significantly with MADs. Sixty per cent of patients were ‘responders’, of whom 33% were ‘full responders’. Sixty-seven per cent of patients showed total compliance. No correlations between the potential predictors and the response to MAD therapy were found.

Discussion:

Effectiveness of MAD therapy was shown over a long-term follow-up in OSAS patients with low compliance to CPAP. Efforts to identify predictive success factors fell short.     

Skeletal versus conventional intraoral anchorage for the treatment of class II malocclusion: dentoalveolar and skeletal effects

Background

The purpose of this retrospective study is to investigate the dentoalveolar and skeletal effects of two distalizing protocols featuring different anchorage systems used in patients with class II malocclusion: the MGBM system (skeletal anchorage) and Pendulum (intraoral anchorage).

Methods

The sample comprised 57 patients who were assigned to one of the two treatments: the MGBM group (30 patients, mean age 13.3 ± 2.3 years) or the Pendulum group (27 patients, mean age 12.8 ± 1.7 years). Three serial cephalograms were obtained at baseline (T0), after molar distalization (T1), and after fixed appliance treatment (T2). Esthetic, skeletal, and dental parameters were considered. Pancherz''s superimposition method was used to assess sagittal dental changes. The initial and final measurements and treatment changes were compared by means of a paired t test or a paired Wilcoxon test. Statistical significance was tested at p < 0.05, p < 0.01, and p < 0.001.

Results

In the MGBM group, the upper molar distalization was achieved in 7 months and showed a mean value of 4.9 mm (ms-PLO); the amount of molar relationship correction was 5.9 mm. In the Pendulum group, the upper molar distalization was obtained in 9 months and showed a mean value of 2.5 mm (ms-PLO), while the molar relationship correction amounted to 4.9 mm. Anterior anchorage loss occurred in both groups, although in the MGBM group, there was less mesial movement of the premolars.

Conclusions

The MGBM system and the Pendulum appliance are both effective in the correction of class II malocclusions. The MGBM system was found to be more efficient than the Pendulum appliance, producing greater molar distalization in a shorter treatment time.     

Concentrations of and application protocols for hydrogen peroxide bleaching gels: Effects on pulp cell viability and whitening efficacy

Objectives

To assess the whitening effectiveness and the trans-enamel/trans-dentinal toxicity of experimental tooth-bleaching protocols on pulp cells.

Methods

Enamel/dentine discs individually adapted to trans-well devices were placed on cultured odontoblast-like cells (MDPC-23) or human dental pulp cells (HDPCs). The following groups were formed: G1 – no treatment (control); G2 to G4 – 35% H₂O₂, 3 × 15, 1 × 15, and 1 × 5 min, respectively; and G5 to G7 – 17.5% H₂O₂, 3 × 15, 1 × 15, and 1 × 5 min, respectively. Cell viability and morphology were evaluated immediately after bleaching (T1) and 72 h thereafter (T2). Oxidative stress and cell membrane damage were also assessed (T1). The amount of H₂O₂ in culture medium was quantified (Mann–Whitney; α = 5%) and colour change (ΔE) of enamel was analysed after 3 sessions (Tukey's test; α = 5%).

Results

Cell viability reduction, H₂O₂ diffusion, cell morphology alteration, oxidative stress, and cell membrane damage occurred in a concentration-/time-dependent fashion. The cell viability reduction was significant in all groups for HDPCs and only for G2, G3, and G5 in MDPC-23 cells compared with G1. Significant cell viability and morphology recovery were observed in all groups at T2, except for G2 in HDPCs. The highest ΔE value was found in G2. However, all groups presented significant ΔE increases compared with G1.

Conclusion

Shortening the contact time of a 35%-H₂O₂ gel for 5 min, or reducing its concentration to 17.5% and applying it for 45, 15, or 5 min produce gradual tooth colour change associated with reduced trans-enamel and trans-dentinal cytotoxicity to pulp cells.

Clinical significance

The experimental protocols tested in the present study provided significant tooth-bleaching improvement associated with decreased toxicity to pulp cells, which may be an interesting alternative to be tested in clinical situations intended to reduce tooth sensitivity and pulp damage.     

Inferior frontal white matter volume and suicidality in schizophrenia

The neurobiology of suicidality in schizophrenia is largely unknown. We therefore assessed gray and white matter volumes associated with past suicidality and current self-aggression in schizophrenia. Fifty-five outpatients with schizophrenia (n=55) and healthy controls (n=55), matched for age, gender and handedness, were recruited. Ten patients had a life-time history of one or more suicide attempts. Current self-aggression was assessed using the Modified Overt Aggression Scale. High resolution structural magnetic resonance images were analyzed by voxel-based morphometry. We found significantly larger inferior frontal white matter volumes bilaterally in patients with a previous suicide attempt as compared with those patients without a history of suicidality. No other significant white or gray matter volume differences were observed. White matter volume in these regions did not differ between healthy controls and those patients without a previous suicide attempt. Furthermore, among patients, the level of current self-aggression showed a significant positive correlation with white matter volume in the same regions. Inferior frontal white matter alterations in fronto-temporo-limbic circuits may be associated with suicidality and self-aggression in schizophrenia.