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Two letters to the editor are presented including one in response to the article "Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial" in the 2010 issue and the other in response by Andreas Goebel and colleagues to an editorial to their article.

Patients' fears of anesthesia mostly focus on a possibly inadequate anesthetic effect, on postoperative wound pain and/or nausea and vomiting (PONV). Concerning the possibility of an inadequate anesthetic effect, patients usually express two different kinds of fears: first, that they might stay conscious during surgery («Awareness») without it being noticed, and second that they might not wake up again after the operation or that they might sustain neurological damages or deficits after the anesthesia. Last but not least patients are afraid they might suffer from substantial pain after waking up from the anesthesia. In this article we take a closer look at these aspects and discuss ways and possibilities of handling them, suggesting useful approaches for the general practitioner when talking these issues through with his patients prior to an operation.

Background: Recently, a single point mutation in the presenilin 1 (PSEN1) gene of the first described Alzheimer's disease (AD) patient Auguste D was reported by Müller and co-workers. However, the sequencing results of the DNA from a 100-year-old tissue contained some uncertainties., Methods: We heat extracted DNA from an original histological slice of Auguste D's brain and used nested polymerase chain reaction for the amplification of different exons of genes known to be affected in familial forms of AD., Results: Our sequencing analysis did not validate the reported mutation. Furthermore, an extended sequencing analysis of Auguste D's DNA revealed no indication of a nonsynonymous hetero- or homozygous mutation in the exons of APP, PSEN1, and PSEN2 genes comprising the already known familial AD mutations., Conclusion: Despite the wealth of data from Müller and co-workers, our results emphasize the requirement of more detailed analysis of Auguste D's DNA in future., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Ropivacaine is a local anesthetic widely used for regional anesthesia. One of its advantages is low toxicity at plasma concentrations reached systemically during continuous peripheral or central nervous block. The objective of this study was to test the effect of systemic ropivacaine on pain, hyperalgesia, dynamic allodynia, and flare response., Methods: This randomized, double-blinded, placebo-controlled, crossover study was carried out in at the Clinical Trials Centre, University of Zurich, Switzerland. Twenty healthy male volunteers were included in the study. Exclusion criteria were contraindications or hypersensitivity to local anesthetics, vulnerable subjects (intellectually or mental impaired), drug, alcohol or nicotine abuse, known peripheral neuropathies, diabetes mellitus and/or congestive heart disease. Ropivacaine and saline were infused intravenously during a subcutaneous electrical stimulation. The stimulation software adjusted the stimulus strength according to the rating on a numeric rating scale (NRS; 0-10) maintaining a NRS of 5. Areas of punctate hyperalgesia, dynamic allodynia, and flare response were measured before and after the infusion., Results: The area of hyperalgesia increased significantly with saline (303 ± 380%, P < 0.05) and ropivacaine (186 ± 137%, P < 0.05). The area of allodynia (253 ± 299%, P < 0.05) and flare response (112 ± 24%, P < 0.05) increased only during the placebo infusion., Conclusion: The results of this study imply that systemic ropivacaine may diminish pain sensitization processes.

Objectives: The conformational state of voltage-gated sodium channels is an important determinant for the efficacy of both local anesthesia and electrical neuromodulation techniques. This study investigated the role of subthreshold preconditioning ramp currents on axonal nerve excitability parameters in the presence of sodium channel blockers in myelinated A and unmyelinated C fibers., Materials and Methods: A- and C-fiber compound action potentials were recorded extracellularly in vitro in saphenous nerve from adult rats. Nerve fibers were stimulated with a supramaximal current pulse either alone or after a 300-msec conditioning polarizing ramp current (between -10% and +100% of the original threshold current) in the presence and absence of lidocaine and tetrodotoxin (TTX). A computerized threshold tracking program (QTRAC), Institute of Neurology, University College London, London, UK) was used to determine the membrane thresholds., Results: Preconditioning ramp currents of weak strengths increased membrane excitability. Stronger preconditioning ramp currents enhanced the potency of lidocaine and TTX to increase excitability thresholds. In A and C fibers stimulated with ramp currents of 110% (A fibers) and 40% (C fibers), lidocaine (80 μM) induced a 168 ± 15% (p < 0.001) and 302 ± 23% (p < 0.001) increase in threshold, respectively (no ramp current: 135 ± 9% and 124 ± 4%, respectively). TTX (16 nM) induced an increase in threshold of 455 ± 45% (p < 0.001) and 214 ± 22% (p = 0.005), respectively (no ramp current: 205 ± 12% and 128 ± 6%, respectively)., Conclusions: Slow preconditioning ramp stimuli inactivate sodium currents. In the presence of sodium channel blockers, stronger ramp stimuli cause an increase in threshold, which is larger than that caused by the sodium channel blocker alone. Therefore, we conclude that small depolarizing ramp currents could be used to increase excitability threshold in the presence of low concentrations of local anesthetics. These additive effects might represent a target to address with peripheral nerve stimulation in order to suppress afferent pain signaling., (© 2013 International Neuromodulation Society.)

Introduction: Pharmacotherapy in patients with neuropathic pain syndromes (NPS) can be associated with long periods of trial and error before reaching satisfactory analgesia. The aim of this study was to investigate whether a short intravenous (i.v.) infusion of lidocaine may have a predictive value for the efficacy of oxcarbazepine., Methods: In total, 16 consecutive patients with NPS were studied in a prospective, uncontrolled, open-label study design. Each patient received i.v. lidocaine (5 mg/kg) within 30 min followed by a long-term oral oxcarbazepine treatment (900-1,500 mg/day). During an observation period of 28 days, treatment response was documented by a questionnaire including the average daily pain score documented on a numeric rating scale (NRS)., Results: A total of 6 out of 16 patients (38%) were lidocaine responders (defined as pain reduction >50% during the infusion), and 4 of 16 (25%) were oxcarbazepine responders. In total, 6 out of 16 participants (38%) discontinued oxcarbazepine treatment due to side effects. In an interim analysis predictive value of the lidocaine infusion was low with a Kendall's tau correlation coefficient of 0.29 and coefficient of determination R(2) of 0.119 (95% confidence interval -0.29 to 0.72). As a consequence of this low correlation, the study was discontinued for ethical reasons., Conclusion: In conclusion, lidocaine infusion has a low predictive value for effectiveness of oxcarbazepine-if at all.

Background: Medication overuse headache (MOH) has been recognized as an important problem in headache patients although the pathophysiological mechanisms remain unclear. The diagnosis of MOH is based on clinical characteristics defined by the International Headache Society. The aim was the evaluation of the diagnostic criteria of MOH in a mixed population of chronic pain patients to gain information about the prevalence and possible associations with MOH., Methods: Data of all patients referred to the interdisciplinary pain clinic at the University Hospital of Zurich between September 2005 and December 2007 were retrospectively analyzed. Demographic data (age, sex, history of migration), as well as data about duration of pain disease, category of pain disease (neurological, psychiatric, rheumatologic, other), use of medication, history of trauma, and comorbidity of depression and anxiety have been collected., Results: Totally 178 of 187 consecutive chronic pain patients were included in the study. A total of 138 patients (78%) used analgesics on 15 or more days per month. Chronic headache was more prevalent among patients with analgesic overuse (39.8%) than without analgesic overuse (18%). The prevalence of MOH was 29%. The odds ratio (OR) for a patient with medication overuse to have chronic headache was 13.1 if he had a history of primary headache, compared to a patient without a primary headache syndrome. Furthermore, history of headache (OR 2.5, CI [1.13;5.44]), history of migration (OR 2.9, CI [1.31;6.32]) and comorbid depression (OR 3.5, CI [1.46;8.52]) were associated with overuse of acute medication, in general., Conclusions: Primary headaches have a high risk for chronification in patients overusing analgesics for other pain disorders. Whereas history of headache, history of migration and comorbidity of depression are independentely associated with analgesic overuse in this group of patients.

Little information is available on the pH sensitivity of the excitability properties of mammalian axons. Computer-assisted threshold tracking in humans has helped to define clinically relevant changes of nerve excitability in response to hyperventilation and ischaemia, but in vivo studies cannot directly differentiate between the impact of pH and other secondary factors. In this investigation, we applied an excitability testing protocol to a rat saphenous skin nerve in vitro preparation. Changes in extracellular pH were induced by altering pCO(2) in the perfusate, and excitability properties of large myelinated fibres were measured in the pH range from 6.9 to 8.1. The main effect of protons on nerve excitability was a near linear increase in threshold which was accompanied by a decrease in strength-duration time constant reflecting mainly a decrease in persistent sodium current. In the recovery cycle, late subexcitability following 7 conditioning stimuli was substantially reduced at acid pH, indicating a block of slow but not of fast potassium channels. Changes in threshold electrotonus were complex, reflecting the combined effects of pH on multiple channel types. These results provide the first systematic data on pH sensitivity of mammalian nerve excitability properties, and may help in the interpretation of abnormal clinical excitability measurements., (© 2012 Peripheral Nerve Society.)

The dopaminergic system has been previously associated to behavioral facilitation and aggression, hence making the pathway a good candidate for suicidal behavior. We studied gene variants in the tyrosine hydroxylase (rs3842727, rs6356) and DOPA decarboxylase (rs1451371, rs1470750, rs998850) genes in a sample of 571 individuals consisting of 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide and 312 German control subjects. TH variants were not associated with suicide (uncorrected P = 0.023) and related traits. Some marginal associations could be observed for DDC with suicide, violence, anger, and aggression. In conclusion, our study does not support the involvement of TH gene variants as major contributors to suicide, whereas DDC variants could mediate some features related to suicide and be involved in violent suicidal behavior., (Copyright 2007 Wiley-Liss, Inc.)

Objective: The pharmacokinetics of ropivacaine 0.2% were evaluated during a 48-hour continuous extrapleural infusion with 2 different infusion rates in patients undergoing cardiovascular surgery. The hypotheses that no toxic plasma concentrations of ropivacaine would be reached and that proportionality exists among plasma concentrations and dosage used were tested., Design: A prospective, randomized, nonblinded study., Setting: The investigation was performed as a single-center study in the Division of Cardiovascular Anesthesia, University Hospital of Zurich, in Switzerland., Participants: Seventeen consenting adults scheduled for elective cardiovascular surgery, with or without extracorporeal bypass, via the lateral thoracotomy approach were enrolled., Interventions: For postoperative pain relief, patients were randomly assigned to receive continuous extrapleural infusion of ropivacaine 0.2% at a rate of either 6 or 9 mL/h over 48 hours., Measurements and Main Results: Plasma concentrations of ropivacaine reached toxic levels (>2.2 mg/L) in 25% of cases. No proportionality of plasma concentrations of ropivacaine existed when the 2 dosing regimens were compared., Conclusions: Plasma concentrations of ropivacaine, administered at the given dose and rates during continuous extrapleural infusion, are unpredictable and may reach toxic levels in patients undergoing major cardiothoracic surgery.

The neurobiological basis of suicidal behaviour is multifactorial and complex. Several lines of evidence indicate that environmental factors as well as multiple genes and interactions of both are implicated in its aetiology. The aim of this study was to establish the transcriptomic expression profile of post-mortem brain tissue of suicide victims in order to identify new candidate genes and biological patterns for suicidal behaviour. Post-mortem orbitofrontal cortex tissue was derived from 11 suicide victims and 10 non-psychiatric controls carefully selected from a brain bank of over 150 brains, and the expression of more than 23000 messenger RNAs was assessed in this case-control study. Validation experiments were carried out using quantitative RT-PCR as an independent method. A classification of the differentially expressed genes according to their biological function and statistical analyses of the data were performed in order to identify biological pathways that are over-represented in the suicide group. In total, 124 transcripts demonstrated significant changes (fold changes > or = 1.3, p value < or = 0.01), with 59 showing under-, and 65 over-expression in the suicide group. The results could be validated for nine particularly interesting transcripts (CDCA7L, CDH12, EFEMP1, MLC1, PCDHB5, PTPRR, S100A13, SCN2B, and ZFP36). The pathway analysis showed that the Gene Ontology categories 'central nervous system development', 'homophilic cell adhesion', 'regulation of cell proliferation' and 'transmission of nerve impulse' were significantly enriched. The differentially expressed genes and significant biological processes might be involved in the pathophysiology of suicide and warrant further attention.

Nitric oxide (NO) is a neurotransmitter which modulates depressive and aggressive behaviors. We studied gene variants of NOS-I (rs2682826;rs1353939;rs2293049;rs693534) and NOS-III (rs2070744;rs1799983;rs891512) in a total of 571 cases (167 German suicide attempters, 92 Caucasian suicide completers and 312 German healthy subjects). A NOS-I risk haplotype C-G-G (rs2682826-rs1353939-rs693534) was associated with suicidal behavior (P = 0.01), and more specifically with suicide attempts (P = 0.01). Sliding windows analysis showed similar results for the haplotype G-G (rs1353939-rs693534) being a risk factor for suicidal behavior (P = 0.01) again especially in suicide attempters (P = 0.004). Additionally, the G-allele of rs693534 was associated with suicidal behavior (P = 0.005) and more specifically with suicide attempts (P = 0.003). Interestingly, the same haplotype (G-G) as well as the rs693534 G-allele were also associated with increased aggression. Regarding NOS-III, a protective haplotype C-T-A (rs2070744-rs1799983-rs891512) was observed (P = 0.01) with a pronounced effect against suicide completion (P = 0.005). Sliding window analysis showed the same effect of haplotype T-A (rs1799983-rs891512) (P = 0.01) which was again protective against suicide completion (P = 0.006). Single marker analysis showed the same protective effect of the rs891512 A-allele (P = 0.009) again especially against suicide completion (P = 0.007). Additionally, a second haplotype (T-T-G) was associated with increased aggression (P = 0.0002; sliding haplotype T-G, P = 0.002). In conclusion, our study suggests a possible involvement of NOS-I and NOS-III gene variants in suicidal behavior and related intermediate phenotypes., ((c) 2007 Wiley-Liss, Inc.)

Objective: To establish an in vitro model for measurement of the excitability properties of cutaneous sensory axons., Methods: We used a saphenous skin-nerve preparation from adult rat in combination with computerized threshold tracking. We measured strength-duration time constant, the recovery of excitability after a supramaximal stimulus and the accommodation to conditioning subthreshold polarizing stimuli (threshold electrotonus, current-threshold relationship) and compared these with previously published recordings from sensory axons in human median nerve., Results: Threshold electrotonus and the amplitude of superexcitability were indistinguishable between human median nerve in vivo and rat saphenous nerve in vitro, but several excitability parameters were significantly different in the rat: strength-duration time constant was significantly shorter (0.19+/-0.01 vs. 0.53+/-0.02 ms); the refractory period was shorter (1.9+/-1.1 ms vs. 3.5+/-1.0 ms) and late subexcitability was smaller (6.3+/-0.3% vs. 11.3+/-0.5%); thirdly, during recording of current-threshold relationship, rat nerves displayed more inward rectification to strong hyperpolarizing currents. Parameters were stable over more than 3h., Conclusions: Excitability changes of sensory Abeta-fibres can be reliably studied in the rat in vitro and are qualitatively similar to humans., Significance: This rat model will facilitate pharmacological studies of nerve excitability and work on models of neuropathy.

Context: Working memory (WM) deficits in patients with schizophrenia have mainly been associated with prefrontal dysfunction. However, the contribution of perceptual deficits and abnormalities in sensory areas has not been explored. The present study closes this important gap in our understanding of WM dysfunction in schizophrenia by monitoring neural activity during WM encoding and retrieval with event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI)., Objective: To investigate the neurophysiological changes that contribute to WM impairment in early-onset schizophrenia at perceptual and cognitive stages using the ERP components P1, P3a, P370, and P570 and fMRI data from extrastriate visual areas., Design: We conducted the study between June 1, 2003, and December 20, 2006. Electroencephalographic and fMRI data were acquired separately during a visual delayed discrimination task. Participants encoded up to 3 abstract shapes that were presented sequentially for 600 milliseconds each and decided after a 12-second delay whether a probe matched 1 of the sample stimuli., Setting: Between-group study at an inpatient psychiatric hospital and outpatient psychiatric facilities., Participants: Seventeen adolescents with early-onset schizophrenia according to DSM-IV criteria and 17 matched controls participated in the study., Main Outcome Measures: Amplitude of the ERP components P1, P3a, P370, and P570 and the fMRI signal from extrastriate visual areas., Results: The P1 amplitude was reduced in patients during encoding and retrieval. The P1 amplitude increased with WM load during encoding only in controls. In this group, a stronger P1 amplitude increase predicted better WM performance. The P1 reduction was mirrored by reduced activation of visual areas in patients in fMRI. The P370 amplitude during encoding and retrieval was also reduced in patients., Conclusions: The P1 amplitude reduction indicates an early visual deficit in adolescents with schizophrenia. Our findings suggest that P1 is of particular relevance for successful WM encoding. Early visual deficits contribute to impaired WM in schizophrenia in addition to deficits in later memory-related processes.

Neuroinflammation is observed in neurodegenerative diseases like Alzheimer's disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T-cell reactivity in AD patients and in an AD mouse model. Mitogenic activation via ligation of the T-cell receptor (TCR) with PHA-L was measured in T lymphocytes from AD patients and Thy1(APP 751SL) x HMG(PS1 M146L)-transgenic mice (APP x PS1). In order to uncover failures in TCR signaling, the TCR was also bypassed by PMA and ionomycin treatment. All patients were sporadic late onset cases and the transgenic mice expressed no mutant APP in lymphocytes, so that direct interactions of mutant APP on T-cell function can be excluded. CD4+ and CD8+ T-cell showed increased reactivity (tyrosine phosphorylation, CD69 expression, and proliferation) in AD, while APP x PS1 transgenic mice displayed hyporeactive CD8+ T-cells after TCR ligation. Increased levels of CD8+ T memory cells and down regulation of CD8 receptor were found in AD and the animal model. Anergic TCR uncoupling was associated with loss of MAPK signaling (p38, ERK1 and ERK2) in APP x PS1. Our data implicate the generation of reactive memory T-cell in AD and of anergic memory T-cells in transgenic mice and should be taken into concern when designing immunotherapy.

The validity and reliability of using psychological autopsies to diagnose a psychiatric disorder is a critical issue. Therefore, interrater and test-retest reliability of the Structured Clinical Interview for DSM-IV Axis I and Personality Disorders and the usefulness of these instruments for the psychological autopsy method were investigated. Diagnoses by informant's interview were compared with diagnoses generated by a personal interview of 35 persons. Interrater reliability and test-retest reliability were assessed in 33 and 29 persons, respectively. Chi-square analysis, kappa and intraclass correlation coefficients, and Kendall's tau were used to determine agreement of diagnoses. Kappa coefficients were above 0.84 for substance-related disorders, mood disorders, and anxiety and adjustment disorders, and above 0.65 for Axis II disorders for interrater and test-retest reliability. Agreement by personal and relative's interview generated kappa coefficients above 0.79 for most Axis I and above 0.65 for most personality disorder diagnoses; Kendall's tau for dimensional individual personality disorder scores ranged from 0.22 to 0.72. Despite of a small number of psychiatric disorders in the selected population, the present results provide support for the validity of most diagnoses obtained through the best-estimate method using the Structured Clinical Interview for DSM-IV Axis I and Personality Disorders. This instrument can be recommended as a tool for the psychological autopsy procedure in post-mortem research., (Copyright 2004 Elsevier Ireland Ltd.)

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells.

Depressive symptoms are often found in dementia (up to 86 %). Therefore, adequate treatment is necessary. Depressive symptoms appear significantly more often in vascular dementia than in dementia in Alzheimer's disease, but severity and profile of depressive symptomatology are independent of the etiology of dementia. The aim of this review is to help clinicians to select appropriate psychometric instruments to identify and measure depressive symptomatology in dementia. Frequently used scales are described, e.g. the Dementia Mood Assessment Scale and the Cornell Scale for Depression in Dementia - specific scales developed for rating severity of depression in dementia - and the Geriatric Depression Screening Scale. Methodological problems and limitations of psychopathological assessment in dementia caused by restriction of self-report, information gathered by collateral sources, manifestations of age and interference of somatic symptoms are discussed.