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Deep brain stimulation (DBS) is an established therapy for appropriately selected patients with movement disorders and neuropsychiatric conditions. Although the exact mechanisms and biology of DBS are not fully understood, it is a safe and well‐tolerated therapy for many refractory cases of neuropsychiatric disease. Increasingly, DBS has been explored in other conditions with encouraging results. In this paper, available data is reviewed and new DBS targets, challenges and future directions in neurological disorders are explored. A detailed search of the medical literature discussing the potential use of DBS for neurological disorders excluding accepted indications was conducted. All reports were analyzed individually for content and redundant articles were excluded by examining individual abstracts. The level of evidence for each indication was summarized. Multiple studies report promising preliminary data regarding the safety and efficacy of DBS for a variety of neurological indications including chronic pain, tinnitus, epilepsy, Tourette syndrome, Huntington's disease, tardive dyskinesia and Alzheimer's disease. The initial results of DBS studies for diverse neurological disorders are encouraging but larger, controlled, prospective, homogeneous clinical trials are necessary to establish long‐term safety and effectiveness. The field of neuromodulation continues to evolve and advances in DBS technology, stereotactic techniques, neuroimaging and DBS programming capabilities are shaping the present and future of DBS research and use in practice. [ABSTRACT FROM AUTHOR]

Background Adalimumab is a tumour necrosis factor-alpha antibody approved for treatment of moderate to severe chronic plaque psoriasis. Objective To characterise population pharmacokinetics of adalimumab 40 mg every other week dosing regimen and impact of immunogenicity on pharmacokinetics, efficacy and safety in psoriasis patients. Methods Patients were enrolled in a Phase 3 study comprising a 16-week double-blind, placebo-controlled period, a 17-week open-label period for Week 16 Psoriasis Area and Severity Index ( PASI) 75 responders, and a 19-week double-blind, placebo-controlled period for Week 33 PASI 75 responders. Serum adalimumab and anti-adalimumab antibody ( AAA) concentrations were measured and a population pharmacokinetic model devleoped to identify patient/disease factors affecting adalimumab pharmacokinetics. Impact of immunogenicity on treatment efficacy and safety was also assessed. Results Week 33 mean adalimumab concentration was 5.2 μg/mL. Week 16 responders had higher adalimumab concentrations than non-responders (6.3 vs. 2.2 μg/mL). Bodyweight and study were significant covariates in population pharmacokinetic model with weight accounting for 19% and 29% of variability in adalimumab clearance and volume of distribution, respectively. A total of 8.8% of adalimumab-treated patients tested AAA positive and had twofold higher adalimumab clearance. PASI 75 response rate was comparable between AAA+ and AAA− patients at Weeks 33 and 52 (Week 33: 36% vs. 22.5%, Week 52: 21.1% vs. 17.8%) and adverse events incidence was similar between the two groups. Conclusions Patient weight and study significantly affect adalimumab clearance and volume of distribution in psoriasis patients. Development of AAAs result in lower adalimumab exposure and efficacy with no effect on adverse events incidence. [ABSTRACT FROM AUTHOR]

Background Published evaluations of skin disease signs and health-related quality of life ( HRQoL) upon therapy withdrawal and retreatment in psoriatic patients are limited to results of drug withdrawal after short-term treatment. Analyses are lacking that evaluate patients' response to retreatment for patients treated successfully long-term. Objective To study the efficacy and safety of adalimumab in patients with long-term clinical responses to adalimumab who then discontinue therapy and are retreated with the same dosing regimen as the initial course. Skin disease signs and patients' HRQoL are evaluated. Methods This post hoc analysis of an open-label study ( NCT00195676) included patients who had responded favourably to adalimumab during initial treatment (≥75% improvement in Psoriasis Area and Severity Index [ PASI 75 response]) and had maintained good clinical response for an extended period (up to 252 weeks); patients had Physician's Global Assessment (PGA) 0 or 1 before treatment interruption. Following drug withdrawal (up to 40 weeks), all patients were retreated with adalimumab 80 mg initial dose, followed by 40 mg every-other-week for 16 weeks. PASI response and HRQoL were evaluated. Results Of the 133 patients in this analysis, 24 (18%) relapsed during therapy withdrawal. After 16 weeks of retreatment, 75% who relapsed and 89.9% who did not relapse, had a PASI 75 response; 89.5% achieved European Consensus Programme treatment goals after 16 weeks of retreatment. During drug withdrawal, HRQoL disproportionally worsened compared to skin disease signs; HROoL also considerably worsened for patients who did not relapse. Patients regained HRQoL upon retreatment with adalimumab. No new safety signals were identified in this study. Conclusion Retreatment with adalimumab was successful in improving psoriasis skin signs and HRQoL in this subgroup with initial and extended responses to therapy followed by relapse after treatment withdrawal. Patient's HRQoL should be considered, as it may substantially worsen during therapy interruption. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the effects of unilateral and bilateral ventralis intermedius (Vim) deep brain stimulation (DBS) on mood and motor function. Methods: Thirty-one consecutive medication refractory patients with essential tremor who underwent unilateral or bilateral Vim DBS at University of Florida and returned for at least 6 -month follow-up completed the Visual Analog Mood (VAMS), the Beck Depression Inventory (BDI), and the Tremor Rating Scale (TRS) before and after surgery. We excluded all patients who were implanted at other institutions. Results: The tense subscale of the VAMS improved significantly in both the unilateral and bilateral DBS groups ( P < 0.001). On the VAMS afraid subscale, only the bilateral group trended toward improvement ( P = 0.075). There were no significant changes for either group for the happy, confused, sad, angry, energetic or tired VAMS scores. TRS subscale scores all improved after unilateral and bilateral Vim DBS surgery ( P < 0.001). Conclusions: Feelings of tenseness, tremor severity and ADLs improved following unilateral or bilateral Vim DBS for ET. [ABSTRACT FROM AUTHOR]

In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2, encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD. [ABSTRACT FROM AUTHOR]

Following a quantitative review examining the relative influence of positive and negative social exchanges on emotional health, a second-order factor model of negative social exchange was tested and supported in a sample of 906 college students. Structural equation analysis exploring the unique effects of negative social exchange and perceived support satisfaction on depression revealed both variables to predict this outcome, over and above the contribution of personality and coping variables. In addition to the direct effects of the Big Five personality dimensions on depression, indirect effects of the Big Five via negative social exchange, support satisfaction, and avoidant coping also were observed. Although the prevailing belief among support researchers is that the negative effects of conflictual social interactions outweigh the positive effects of social support, the results of the quantitative review suggest boundary conditions that qualify this conclusion. In addition to corroborating a hierarchical measurement model of negative social exchange, the results of the present investigation suggest that how social support and social negativity are measured substantially influences conclusions concerning their relative impact on psychological distress. [ABSTRACT FROM AUTHOR]

Researchers recently have proposed that various empathy-related reactions are differentially related to individual differences in emotional intensity and regulation. This idea was tested with a sample of elderly hospital volunteers. As predicted, dispositional sympathy was associated with high levels of both dispositional regulation and negative emotional intensity. Personal distress was linked with low regulation and high negative emotional intensity, and cognitive perspective taking was associated with high regulation. Perspective taking moderated the relation of emotional intensity to sympathy and personal distress. In addition, elders' negative affect when volunteering at a hospital was correlated with low regulation and high levels of regulation and dispositional sympathy. The results demonstrate the findings pertaining to vicarious emotional responding are generalizable to nonstudent populations engaged in planned, sustained helping behavior. [ABSTRACT FROM AUTHOR]

Aims The objective of this study was to determine the validity of sharpness of lateral margins (an important component of the pattern analysis method) as a criterion for the histological distinction of naevi from malignant melanoma. Methods and results The sharpness of lateral borders in a series of histologically unequivocal malignant melanomas, Spitz naevi and compound naevi, chosen at random from dermatopathology slide archives, was determined. The incidence of poor demarcation of lateral borders in malignant melanomas was about equal to that of Spitz naevi and was significantly less than in compound naevi. The sharpness of lateral borders frequently varies with level of sectioning. Conclusions The proposal that malignant melanomas have a significantly greater incidence of poor demarcation of lateral borders than benign melanocytic neoplasms (Spitz naevi and compound naevi) was shown to be without validity on cited empirical grounds as well as theoretical grounds (the lack of constancy of pattern from a 3-dimensional standpoint). [ABSTRACT FROM AUTHOR]

The differential diagnosis of melanocytic lesions is fraught with difficulty and a common source of litigation either if a lesion misreported as ‘benign’ recurs locally or re-presents with nodal metastases or if an atypical naevus is called ‘malignant’ leading to a cosmetically unsatisfactory wider resection, unwarranted anxiety about prognosis and adverse life insurance prospects. Several authors have claimed that there are valid morphological criteria which, alone or in combination, enable reliable distinction between benign and malignant melanocytic lesions. Others question these criteria and, doubting the extent to which unequivocal diagnoses can be rendered in all cases, believe that the diagnosis is purely subjective and that most diagnostic errors are non-negligent. To address these issues, expert opinions were commissioned from three sets of authors. Okun, Edelstein & Kasznica emphasize that a significant minority of melanocytic lesions are so borderline morphologically that diagnostic uncertainty is allowable and that such uncertainty can be handled responsibly. Kirkham, in favouring the methodical use of criteria, concedes that they are ‘largely opinion-based rather than evidence-based, but do go beyond mere subjective pattern analysis’. In agreement with Okun and his colleagues, Slater emphasises that no single feature is reliable by itself and that all aspects, including clinical details, should be interpreted together; he has no hesitation in reporting the diagnosis as ‘uncertain’ in doubtful cases. In the absence of a specific marker pathognomonic of melanocytic malignancy, the diagnosis will continue to rely on the judicious application of morphological criteria with a small proportion of elusive cases in which diagnostic uncertainty should not be concealed. [ABSTRACT FROM AUTHOR]

Background: Few clinical trials have evaluated long-term treatment of nail psoriasis with biologics., Objective: Safety and efficacy of adalimumab [ADA; Humira AbbVie Inc, North Chicago, IL, USA)] long-term treatment (52 weeks) was evaluated in a phase-3, randomized trial in patients with moderate-to-severe plaque psoriasis and concomitant moderate-to-severe fingernail psoriasis. Results from the first 26 weeks (Period A) have been reported., Methods: Patients receiving 40 mg ADA every other week or placebo in Period A, continued with or switched to 40 mg ADA every-other-week treatment in the subsequent 26-week open-label extension (OLE) period. Main efficacy evaluations were ≥75% improvement in total-fingernail modified Nail Psoriasis Severity Index (mNAPSI 75) and achievement of Physician's Global Assessment for Fingernail Psoriasis of clear or minimal disease (PGA-F 0/1) with a ≥2-grade improvement from baseline, across the trial for patients who continued ADA from Period A through the OLE (Continuous-ADA Population). Safety was evaluated during the OLE and for patients receiving ADA at any time during the study (All-ADA Population)., Results: Of the 217 patients initially randomized in Period A, 188 (86.6%; 94 in each treatment group) entered the OLE after completion of or early escape from Period A. For the Continuous-ADA Population (N = 109), endpoint achievement rates improved from OLE entry (Week 26) to Week 52, including total-fingernail mNAPSI 75 (47.4-54.5%); PGA-F 0/1 (51.1-55.6%) and total-fingernail mNAPSI = 0 (6.6-17.9%). Serious adverse event and serious infection rates for the All-ADA Population (N = 203) were 6.9% and 3.4%, respectively., Conclusions: In this population of psoriasis patients with concomitant, moderate-to-severe nail psoriasis, long-term efficacy and improvement in signs and symptoms of nail disease were demonstrated after every-other-week ADA treatment, including incremental improvements in rate of total clearance of nail disease. No new safety risks were identified for patients receiving at least one ADA dose across 52 weeks., (© 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: This phase 3 trial is the first to evaluate the efficacy and safety of treatment with the systemic TNF-α inhibitor, adalimumab, for Chinese patients with moderate-to-severe plaque psoriasis., Methods: In the 12-week, double-blind, placebo-controlled Period A, patients were randomized 4 : 1 to receive adalimumab 40 mg every-other-week (following a single 80 mg dose), or placebo every-other-week. In the subsequent 12-week, open-label, Period B, all patients received adalimumab 40 mg every-other-week starting at week 13, following a single, blinded dose at week 12 of adalimumab 80 mg or matching placebo (for patients receiving placebo or adalimumab in Period A respectively). In Period A, efficacy was analysed for all randomized patients and safety for all patients receiving ≥1 dose of the study drug., Results: For the 425 patients in this study (87 placebo; 338 adalimumab), a higher percentage randomized to adalimumab achieved the primary endpoint of ≥75% improvement from baseline in PASI score (PASI 75) at week 12: placebo 11.5% (10/87); adalimumab 77.8% (263/338; P < 0.001). Physician's Global Assessment of clear to minimal was achieved at week 12 by 14.9% placebo (13/87) and 80.5% adalimumab (272/338; P < 0.001). For patients who received adalimumab at any time during the study (All-adalimumab Population), treatment-emergent adverse events (AEs) were reported by 63.4%; the most common was upper respiratory infection (16.1%). Serious AEs were reported by 3.5% of the All-adalimumab Population, and serious infectious AEs by 1.2%, which include lung infection, pneumonia and tuberculosis [2 (0.5%) patients each]. There was one death (chronic heart failure)., Conclusion: In these Chinese patients with moderate-to-severe psoriasis, a significantly greater percentage treated with adalimumab compared with placebo achieved efficacy endpoints at week 12 and efficacy was sustained to week 24. Safety results were consistent with the known adalimumab safety profile; no new safety signals were identified in the 24 weeks of treatment., (© 2016 The Authors. Journal of European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venerology.)

Thalamic gating of sensory inputs to the cortex varies with behavioral conditions, such as sleep-wake cycles, or with different stages of anesthesia. Behavioral conditions in turn are accompanied by stereotypic spectral content of the EEG. In the rodent somatosensory system, the receptive field size of the ventral posteromedial thalamic nucleus (VPM) shrinks when anesthesia is deepened. Here we examined whether evoked thalamic responses are correlated with global EEG activity on a fine time scale of a few seconds. Trial-by-trial analysis of responses of VPM cells to whisker stimulation in lightly anesthetized rats indicated that increased EEG power in the delta band (1-4 Hz) was accompanied by a small, but highly significant, reduction in spontaneous and evoked thalamic firing. The opposite effect was found for the gamma EEG band (30-50 Hz). These significant correlations were not accompanied by an apparent change in the size of the receptive fields and were not EEG phase-related. The correlation between EEG and firing rate was observed only in neurons that responded to multiple whiskers and was higher for the non-principal whiskers. Importantly, the contributions of the two EEG bands to the modulation of VPM responses were to a large extent independent of each other. Our findings suggest that information conveyed by different whiskers can be rapidly modulated according to the global brain activity., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)