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Importance: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens., Objectives: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA., Design, Setting, and Participants: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing., Interventions: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher)., Main Outcomes and Measures: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes., Results: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%)., Conclusions: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common., Trial Registration: ClinicalTrials.gov Identifier: NCT02908308.

Background: Even though treatment of Class II malocclusion with premolar extractions and incisor retraction might affect incisor inclination and soft tissue profile, the effects of bracket prescription on this have not been thoroughly assessed., Methods: Fifty patients (mean age: 13.6 years; 34% male) receiving extraction-based treatment with either standard Edgewise or pre-adjusted appliances were included. Between-group differences in the incisor inclination assessed with lateral cephalograms were analyzed statistically with linear/logistic regression at 5%., Results: Treatment-induced changes included retroclination of the upper/lower incisors (-3.0° and -2.0°, respectively), retraction of the upper/lower incisors (-3.4 mm and -1.5 mm, respectively), retraction of the upper/lower lip (-2.1 mm and -2.0 mm, respectively), and enlargement of the nasolabial angle (+1.6°). Analysis of the data adjusting for confounders indicated that the pre-adjusted group, after treatment, had larger inclination of the upper or lower incisors (+3.2° and +4.5°, respectively), more prominent upper incisors relative to the facial plane (+1.3 mm), and smaller interincisal angle (-7.3 or -7.7°). Post-treatment upper incisor inclination fell within the cephalometric norm significantly more in the pre-adjusted than in the standard Edgewise group (odds ratio 4.3; 95% confidence interval 1.1-16.6). No differences were found in lower incisor prominence, upper/lower lip prominence, or nasolabial angle., Conclusions: Pre-adjusted appliances were associated with increased inclination of the upper and lower incisors, with more prominent upper incisors, and with more acute interincisal angle after retraction compared with standard Edgewise appliances. However, such differences did not translate in greater retraction of the upper/lower lips and greater nasolabial angle., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Permanent canines are amongst the teeth most affected by impaction and ectopic eruption. Although impacted canines are often subjected to surgical exposure and alignment with either the open or the closed technique for many decades, their treatment effects have not yet been systematically asssessed., Objectives: The aim of this systematic review was to critically assess whether significant differences exist in the outcomes of the open or closed surgical exposure of impacted canines., Search Methods: An unrestricted electronic search of nine databases from inception to December 2016 was performed., Selection Criteria Methods: Included were randomized or prospective non-randomized studies comparing open versus closed exposure of impacted canines in human patients., Data Collection and Analysis: After duplicate study selection, data extraction, and risk of bias assessment according to the Cochrane guidelines, random-effects meta-analyses of mean differences (MDs) and odds ratios (ORs), including their 95 per cent confidence intervals (CIs) were performed, followed by subgroup and sensitivity analyses., Results: A total of eight unique studies and a total of 433 (30.1% male/59.9% female) patients were included, with an average age of 15.2 years and a total of 453 impacted canines (48.6% and 51.4% in the open and closed exposure, respectively). Open exposure of impacted canines was associated with reduced duration of canine alignment (two studies; MD = -2.14 months; 95% CI = -4.23 to -0.05 months; P < 0.05; moderate heterogeneity and moderate quality) and lower odds of tooth ankylosis (one study; OR = 0.15; 95% CI = 0.03-0.83; P < 0.05; low quality) compared to closed exposure; both findings being independent of canine localization. However, initial alignment of palatally impacted canines took overall significantly longer than labially impacted canines (8.87 versus 4.17 months)., Conclusions: Based on existing evidence, open surgical exposure seems to be superior in treatment duration and ankylosis risk over the closed technique. Due to the limited number of small included trials, further research is needed for robust clinical recommendations., Registration: PROSPERO (CRD42016051916)., (© The Author 2017. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Rationale: Although brain-derived neurotrophic factor (BDNF) is part of a homeostatic pathway involved in the development of alcohol dependence, it is not clear whether this is also true after recreational ethanol consumption., Objectives: We examined BDNF expression and signaling in the cortico-striatal network immediately and 24 h after either a single intravenous (i.v.) ethanol operant self-administration session or the last of 14 sessions., Methods: To compare contingent and non-contingent ethanol exposure, we incorporated the "yoked control-operant paradigm" in which rats actively taking ethanol (S-Et) were paired with two yoked controls receiving passive infusions of ethanol (Y-Et) or saline., Results: A single ethanol exposure transiently reduced BDNF mRNA levels in the medial prefrontal cortex (mPFC) of Y-Et. Immediately after the last of 14 sessions, mRNA and mature BDNF protein levels (mBDNF) were reduced in the mPFC in both S-Et and Y-Et while mBDNF expression was raised in the nucleus accumbens (NAc), suggesting enhanced anterograde transport from the mPFC. Conversely, 24 h later mBDNF expression and signaling were raised in the mPFC and NAc of S-Et rats but reduced in the NAc of Y-Et rats, with concomitant reduction of downstream signaling pathways., Conclusions: Our findings indicate that recreational-like i.v. doses of ethanol promote early changes in neurotrophin expression, depending on the length and modality of administration, the brain region investigated, and the presence of the drug. A rapid intervention targeting the BDNF system might be useful to prevent escalation to alcohol abuse.

Increases in alpha calcium/calmodulin-dependent protein kinase type II (αCaMKII) activity in the nucleus accumbens shell has been proposed as a core component in the motivation to self-administer cocaine and in priming-induced drug-seeking. Since cocaine withdrawal promotes drug-seeking, we hypothesized that abstinence from cocaine self-administration should enhance αCaMKII as well. We found that short-term abstinence from contingent, but not non-contingent, cocaine i.v. self-administration (2 h/d for 14 d; 0.25 mg/0.1 ml, 6 s infusion) elevates αCaMKII autophosphorylation, but not the kinase expression, in a dynamic, time- and brain region-dependent manner. Increased αCaMKII autophosphorylation in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), but not dorsolateral striatum (dlS), was found 24 h, but not immediately, after the last cocaine self-administration session. Notably, in the mPFC, but not NAc and dlS, αCaMKII autophosphorylation was still enhanced 7 d later. The persistent enhancement in the mPFC of abstinent rats may represent a previously unappreciated contribution to initial incubation of cocaine-seeking.

Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (S(D)s) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, S(D) s and CSs. Re-exposure to nicotine or sucrose S(D+)/CS(+), but not non-reward S(D-)/CS(-), revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to S(D+)/CS(+) reduced nicotine-seeking; however, this effect was transient, with return to S(D+)/CS(+) responding at 72 hours. Full recovery to S(D+)/CS(+) responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding., (© 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.)

Brain-derived neurotrophic factor (BDNF) dynamic changes were investigated in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) during use and the early phases of cocaine abstinence after 14 sessions (2 h self-administration/d; 0.25 mg/0.1 ml.6 s infusion) by employing a 'yoked control-operant paradigm'. The effect on BDNF was region-specific and dependent on the withdrawal time. In the NAc, BDNF protein levels increased immediately after the last self-administration session, with a larger increase in passively cocaine-exposed rats. In the mPFC, BDNF expression was elevated 24 h after the last self-administration session, independently of how the drug was encountered. No changes were found in NAc and mPFC 7 d after the last self-administration session. Analysis of transcript levels in the mPFC indicated that action on exon I might contribute to BDNF's cortical induction. These findings indicate a finely tuned modulation of BDNF expression during use and early phases of cocaine abstinence.

Rationale: With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-administration., Objectives: The study aimed to develop an operant model of oral alcoholic beer self-administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABA(B) agonist, and BHF177, a GABA(B) positive allosteric modulator, on alcoholic beer self-administration., Methods: Mice were trained to self-administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30-min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-administration., Results: Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-administration increased (0.8-1.0 g/kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9% alcoholic beer self-administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-also reduced near-beer self-administration., Conclusions: The operant model of oral alcoholic beer self-administration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.

Background: MeCP2 (CpG-binding protein 2) is a nuclear multifunctional protein involved in several cellular processes, like large-scale chromatin reorganization and architecture, and transcriptional regulation. In recent years, a non-neuronal role for MeCP2 has emerged in cell growth and proliferation. Mutations in the MeCP2 gene have been reported to determine growth disadvantages in cultured lymphocyte cells, and its functional ablation suppresses cell growth in glial cells and proliferation in mesenchymal stem cells and prostate cancer cells. MeCP2 interacts with lamin B receptor (LBR) and with Heterochromatin Protein 1 (HP1) at the nuclear envelope (NE), suggesting that it could be part of complexes involved in attracting heterochromatin at the nuclear periphery and in mediating gene silencing. The nuclear lamins, major components of the lamina, have a role in maintaining NE integrity, in orchestrating mitosis, in DNA replication and transcription, in regulation of mitosis and apoptosis and in providing anchoring sites for chromatin domains.In this work, we inferred that MeCP2 might have a role in nuclear envelope stability, thereby affecting the proliferation pattern of highly proliferating systems., Results: By performing knock-down (KD) of MeCP2 in normal murine (NIH-3 T3) and in human prostate transformed cells (PC-3 and LNCaP), we observed a strong proliferation decrease and a defect in the cell cycle progression, with accumulation of cells in S/G2M, without triggering a strong apoptotic and senescent phenotype. In these cells, KD of MeCP2 evidenced a considerable decrease of the levels of lamin A, lamin C, lamin B1 and LBR proteins. Moreover, by confocal analysis we confirmed the reduction of lamin A levels, but we also observed an alteration in the shape of the nuclear lamina and an irregular nuclear rim., Conclusions: Our results that indicate reduced levels of NE components, are consistent with a hypothesis that the deficiency of MeCP2 might cause the lack of a key "bridge" function that links the peripheral heterochromatin to the NE, thereby causing an incorrect assembly of the NE itself, together with a decreased cell proliferation and viability.

Peripheral neuropathy is one of the most frequent and severe complications of diabetes. Hydroxytyrosol (HT), the major antioxidant polyphenolic compound of olive oil, has been investigated as a new potential treatment to counteract the progression of peripheral diabetic neuropathy in rats. An established model of streptozotocin-induced diabetes has been used. After confirmation of hyperglycemia, diabetic and nondiabetic animals were randomized to receive either a low dose or a high dose of HT, or the corresponding vehicle, for 6 weeks. At the end of the 6-week period of treatment, HT blunted plasma thiobarbituric acid-reactive substances increase (p < 0.05) and significantly reduced nerve conduction velocity (p < 0.05) and thermal nociception impairment in diabetic rats (p < 0.05). Sciatic nerve Na(+), K(+)-ATPase activity reduction was also abolished by HT (p < 0.05). The present study provides evidence of the therapeutic potential of the natural substance hydroxytyrosol in the early stage of diabetic neuropathy.

Background: : Minimally invasive aortic valve surgery is usually performed through a right parasternal incision or a modification of partial sternotomy. We explored the feasibility of using a video-assisted small right lateral thoracotomy (RLT) to approach the aortic valve., Methods: : From August 2003 to December 2004, 12 patients with aortic stenosis (9) or regurgitation (3) underwent an aortic valve replacement through an 8 cm RLT in the 4th intercostal space. There were 4 men and 8 women with a mean age of 61 years (range 30-79 years). Nine mechanical and 3 biologic prostheses were implanted. Endotracheal narcosis was combined with high thoracic epidural anesthesia. Transesophageal echocardiographic monitoring was performed in all cases. Cannulation was done via the right femoral artery and vein and right jugular vein. The video-assisted operation was performed in moderate hypothermia (30°C) and in cardioplegic arrest. Transthoracic aortic clamping was used in all cases., Results: : Mean operation, perfusion, and clamping times were 223 minutes, 132 minutes, and 73 minutes, respectively. There was no mortality. One patient required conversion to sternotomy due to discovery of a calcium fragment entrapped in a mechanical prosthesis. One patient developed a groin seroma that was treated surgically. All patients, except one were extubated in the operative room and transferred to the intermediate care unit after 6 hours; all had an uneventful recovery., Conclusions: : Aortic valve replacement through an RLT is feasible and safe. Operative time, perfusion, and cross-clamping times are only marginally longer than a conventional operation, and recovery is rapid.

The executive deficit hypothesis of treated phenylketonuria (PKU) suggests that dopaminergic depletion in the lateral prefrontal cortex leads to selective executive impairment. This was examined by comparing adults with PKU on a lifelong diet with a matched healthy control group. Those with PKU were impaired on selective and sustained attention, working memory (Self-Ordered Pointing), and letter fluency. However, they failed to show differential sensitivity to increased cognitive load on the attentional and working memory tasks, and they did not differ significantly on the remaining executive tasks (rule finding, inhibition, and multitasking). Nor did they differ significantly on recall or recognition memory. Overall, the findings provided little support for the executive deficit hypothesis. A possible explanation in terms of slowed information processing speed is explored.