Dental health in advanced age and Alzheimer's Disease: A possible link with bacterial toxins entering the brain?

We investigated a possible link between bacterial infestation of the oral cavity, dental health and Alzheimer's dementia (AD). Resistant germs on the surface of the maxillary molars are the cause of a complex biofilm of bacteria with the effect of a colonization of germs between oral cavity and maxillary sinus. Bacterial toxins may lead to subsequent inflammatory processes transgressing to neighboring central nervous system structures that are suspected to be crucial in the inception of AD, such as the entorhinal cortex and the hippocampus.

Pain Assessment Discrepancies: A Cross-Sectional Study Highlights the Amount of Underrated Pain.

BACKGROUND: Inadequately treated postoperative pain can lead to longer healing processes, longer hospital stays, and the development of chronic pain. In a 900-bed university hospital in Switzerland, pain scores were assessed systematically. The study's primary aim was to define whether the routine pain assessment on the ward is accurate and reproducible. Subsequently the obtained data were used for a benchmark analysis to determine the hospital's performance in pain assessment quality compared with similar centers. METHODS: During a 3-month period, PAIN OUT questionnaires were used for patients' interviews. Patients were included randomly according to the daily surgical schedule. Pain scores were assessed routinely by nursing staff on the wards and compared to PAIN OUT data. The ascertained data were analyzed by descriptive statistics as well as the Wilcoxon test for nonparametric values using IBM SPSS. RESULTS: 658 patients were included in the study. Comparing routine pain measurements with PAIN OUT results revealed that within the first 24 hours on the ward, pain scores were significantly lower than measured with PAIN OUT questionnaires. This difference increased with increasing pain scores. The quality of pain management of the hospital in which this study was performed ranged around the 50th percentile when compared to similar centers. CONCLUSION: The cross-sectional data comparison of pain assessment by the ward staff and by interviews with the PAIN OUT questionnaire showed a large gap of underrated pain. The benchmark analysis with the method of PAIN OUT suggests a decent pain management among reference groups.

Factors Influencing Quality of Pain Management in a Physician Staffed Helicopter Emergency Medical Service.

BACKGROUND: Pain is frequently encountered in the prehospital setting and needs to be treated quickly and sufficiently. However, incidences of insufficient analgesia after prehospital treatment by emergency medical services are reported to be as high as 43%. The purpose of this analysis was to identify modifiable factors in a specific emergency patient cohort that influence the pain suffered by patients when admitted to the hospital. METHODS: For that purpose, this retrospective observational study included all patients with significant pain treated by a Swiss physician-staffed helicopter emergency service between April and October 2011 with the following characteristics to limit selection bias: Age > 15 years, numerical rating scale (NRS) for pain documented at the scene and at hospital admission, NRS > 3 at the scene, initial Glasgow coma scale > 12, and National Advisory Committee for Aeronautics score < VI. Univariate and multivariable logistic regression analyses were performed to evaluate patient and mission characteristics of helicopter emergency service associated with insufficient pain management. RESULTS: A total of 778 patients were included in the analysis. Insufficient pain management (NRS > 3 at hospital admission) was identified in 298 patients (38%). Factors associated with insufficient pain management were higher National Advisory Committee for Aeronautics scores, high NRS at the scene, nontrauma patients, no analgesic administration, and treatment by a female physician. In 16% (128 patients), despite ongoing pain, no analgesics were administered. Factors associated with this untreated persisting pain were short time at the scene (below 10 minutes), secondary missions of helicopter emergency service, moderate pain at the scene, and nontrauma patients. Sufficient management of severe pain is significantly better if ketamine is combined with an opioid (65%), compared to a ketamine or opioid monotherapy (46%, P = .007). CONCLUSIONS: In the studied specific Swiss cohort, nontrauma patients, patients on secondary missions, patients treated only for a short time at the scene before transport, patients who receive no analgesic, and treatment by a female physician may be risk factors for insufficient pain management. Patients suffering pain at the scene (NRS > 3) should receive an analgesic whenever possible. Patients with severe pain at the scene (NRS ≥ 8) may benefit from the combination of ketamine with an opioid. The finding about sex differences concerning analgesic administration is intriguing and possibly worthy of further study.

Abnormal Connectional Fingerprint in Schizophrenia: A Novel Network Analysis of Diffusion Tensor Imaging Data.

The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal-frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder.

[Anxieties of patients before anesthesia - what information can the family physician provide?]. / Ängste der Patienten vor einer Anästhesie - welche Informationen kann der Hausarzt geben?

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 («Awareness¼) 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.

Les craintes des malades avant une anesthésie ont trait principalement à un effet anesthésiant insuffisant en cours de l'intervention ainsi que de la survenue d'une douleur ou de nausées et de vomissements dans la période post-opératoire. En ce qui concerne la crainte d'un effet anesthésiant insuffisant, elle comporte deux aspects: d'une part la crainte de devenir conscient pendant l'opération sans que cela se remarque et d'autre part de ne pas se réveiller après l'opération ou de développer des atteintes ou es déficits neurologiques. Finalement il y a aussi une crainte non négligeable concernant l'existence d'une douleur en post-opératoire. Dans ce travail sont discutées en détail les craintes potentiellement engendrées lors de la planification d'une anesthésie. Est proposée également une approche utile de discuter de ces craintes entre la malade et le médecin généraliste en préparation de l'intervention.

Consolidation time affects performance and neural activity during visual working memory.

We tested the effects of variation of stimulus onset asynchrony (SOA) on visual working memory (WM) performance across different load levels and the underlying brain activation patterns using functional magnetic resonance imaging (fMRI) in 48 healthy participants. Participants were instructed to memorise arrays of coloured squares and had to perform a match/non-match judgement on a probe stimulus after a jittered delay. We presented visual pattern masks at four SOAs after the offset of the memory array (100 ms, 200 ms, 400 ms, and 800 ms). Memory performance decreased with increased load and shortened SOA. Brain activation data showed significant effects of load (during encoding and retrieval), SOA (retrieval) and an interaction of load by SOA (encoding), mainly in frontal and parietal areas. There was also a direct relationship between successfully stored items and activation in the right inferior parietal lobule and the left middle frontal gyrus. The neurobehavioral results suggest that the frontal regions, together with the inferior parietal lobe, are associated with successful WM performance, especially under the most challenging conditions of high load and short SOAs.

The When and Where of Working Memory Dysfunction in Early-Onset Schizophrenia-A Functional Magnetic Resonance Imaging Study.

Behavioral evidence indicates that working memory (WM) in schizophrenia is already impaired at the encoding stage. However, the neurophysiological basis of this primary deficit remains poorly understood. Using event-related fMRI, we assessed differences in brain activation and functional connectivity during the encoding, maintenance and retrieval stages of a visual WM task with 3 levels of memory load in 17 adolescents with early-onset schizophrenia (EOS) and 17 matched controls. The amount of information patients could store in WM was reduced at all memory load levels. During encoding, activation in left ventrolateral prefrontal cortex (VLPFC) and extrastriate visual cortex, which in controls positively correlated with the amount of stored information, was reduced in patients. Additionally, patients showed disturbed functional connectivity between prefrontal and visual areas. During retrieval, right inferior VLPFC hyperactivation was correlated with hypoactivation of left VLPFC in patients during encoding. Visual WM encoding is disturbed by a failure to adequately engage a visual-prefrontal network critical for the transfer of perceptual information into WM. Prefrontal hyperactivation appears to be a secondary consequence of this primary deficit. Isolating the component processes of WM can lead to more specific neurophysiological markers for translational efforts seeking to improve the treatment of cognitive dysfunction in schizophrenia.

Association between symptoms of psychosis and reduced functional connectivity of auditory cortex.

We have previously reported altered functional asymmetry of the primary auditory cortex (Heschl's gyrus) of patients with schizophrenia (SZ) and their relatives during auditory processing. In this study, we investigated whether schizophrenia patients have altered intrinsic functional organization of Heschl's gyrus (HG) during rest. Using functional magnetic resonance imaging (fMRI), we measured functional connectivity between bilateral HG and the whole brain in 24 SZ patients, 22 unaffected first-degree relatives and 24 matched healthy controls. SZ patients and relatives showed altered functional asymmetry in HG and altered connectivity between temporal and limbic areas in the auditory network during resting-state in comparison with healthy controls. These changes in functional connectivity correlated with predisposition towards hallucinations in patients and relatives and with acute positive symptoms in patients. The results are in line with the results from task-related and symptom-mapping studies that investigated the neural correlates of positive symptoms, and suggest that individual psychopathology is associated with aberrant intrinsic organization of auditory regions in schizophrenia. This might be evidence that reduced hemispheric lateralization and reduced functional connectivity of the auditory network are trait markers of schizophrenia.

Systemic ropivacaine diminishes pain sensitization processes: a randomized, double-blinded, placebo-controlled, crossover study in healthy volunteers.

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.

A presenilin 1 mutation in the first case of Alzheimer's disease: revisited.

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.

Prevalence of medication overuse headache in an interdisciplinary pain clinic.

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.

Deficits in high- (>60 Hz) gamma-band oscillations during visual processing in schizophrenia.

Current theories of the pathophysiology of schizophrenia have focused on abnormal temporal coordination of neural activity. Oscillations in the gamma-band range (>25 Hz) are of particular interest as they establish synchronization with great precision in local cortical networks. However, the contribution of high gamma (>60 Hz) oscillations toward the pathophysiology is less established. To address this issue, we recorded magnetoencephalographic (MEG) data from 16 medicated patients with chronic schizophrenia and 16 controls during the perception of Mooney faces. MEG data were analysed in the 25-150 Hz frequency range. Patients showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces while responses to inverted stimuli were intact. Impaired processing of Mooney faces in schizophrenia patients was accompanied by a pronounced reduction in spectral power between 60-120 Hz (effect size: d = 1.26) which was correlated with disorganized symptoms (r = -0.72). Our findings demonstrate that deficits in high gamma-band oscillations as measured by MEG are a sensitive marker for aberrant cortical functioning in schizophrenia, suggesting an important aspect of the pathophysiology of the disorder.

Preconditioning depolarizing ramp currents enhance the effect of sodium channel blockers in primary sensory afferents.

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.

Sensitivities of rat primary sensory afferent nerves to magnesium: implications for differential nerve blocks.

CONTEXT: Contrasting findings have been published regarding the role of magnesium sulphate used as an additive to local anaesthetics in peripheral nerve blocks. OBJECTIVE: To clarify the effect of magnesium sulphate on nerve excitability. SETTING: C and Aß compound action potentials were recorded extracellularly in vitro in saphenous nerves from adult rats. ANIMALS: Saphenous nerves (n = 30) from male Wistar rats (n = 19), 12 to 16 weeks old. INTERVENTION: Primary sensory afferents were tested with a computerised threshold tracking program (QTRAC) with a supramaximal 1 ms current pulse either alone or after 300 ms of conditioning polarising ramp currents in the presence and absence of 10 mmol l magnesium sulphate, 80 µmol l lidocaine and a combination of both. MAIN OUTCOME MEASURES: Changes in current thresholds to elicit compound action potential amplitudes of 40% of the maximal response. RESULTS: Magnesium sulphate increased excitability thresholds to a greater extent in Aß fibres than in C fibres. It enhanced the effects of lidocaine in both Aß fibres [mixture 0.470 mA (SD 0.105) versus lidocaine 0.358 mA (SD 0.080), P < 0.001] and C fibres [mixture 2.531 mA (SD 0.752) versus lidocaine 2.385 mA (SD 0.656), P = 0.008]. Preconditioning experiments also showed that magnesium sulphate had an enhancing effect with lidocaine in Aß fibres [mixture 0.620 mA (SD 0.281) versus lidocaine 0.543 mA (SD 0.315), P = 0.005], but not in C fibres [mixture 2.412 mA (SD 0.641), lidocaine 2.461 mA (SD 0.693), P = 0.17]. CONCLUSION: These results suggest that the binding of magnesium ions depends on both the type and conformational state of voltage-gated sodium channels. They also may help to explain the conflicting reports regarding the clinical effects of magnesium sulphate as an additive to lidocaine in peripheral nerve blocks.

Predictive value of lidocaine for treatment success of oxcarbazepine in patients with neuropathic pain syndrome.

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.

Imaginative resonance training (IRT) achieves elimination of amputees' phantom pain (PLP) coupled with a spontaneous in-depth proprioception of a restored limb as a marker for permanence and supported by pre-post functional magnetic resonance imaging (fMRI).

Non-pharmacological approaches such as mirror therapy and graded motor imagery often provide amelioration of amputees' phantom limb pain (PLP), but elimination has proved difficult to achieve. Proprioception of the amputated limb has been noted in studies to be defective and/or distorted in the presence of PLP, but has not, apparently, been researched for various stages of amelioration up to the absence of PLP. Previous studies using functional magnetic resonance imaging (fMRI) suggested that pathological cortical reorganisation after amputation may be the underlying neurobiological correlate of PLP. We report two cases of permanent elimination of PLP after application of imaginative resonance training. The patients, 69 years and 84 years old, reported freedom from PLP together with in-depth achievement of proprioception of a restored limb at the end of the treatment, which may thus be taken as an indication of permanence. Pre/post fMRI for the first case showed, against a group of healthy controls, analogous changes of activation in the sensorimotor cortex.

Protons regulate the excitability properties of rat myelinated sensory axons in vitro through block of persistent sodium currents.

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.

Propofol decreases the axonal excitability in rat primary sensory afferents.

AIMS: The aim of this present study was to investigate the changes of peripheral sensory nerve excitability produced by propofol. MAIN METHODS: In a recently described in vitro model of rodent saphenous nerve we used the technique of threshold tracking (QTRAC®) to measure changes of axonal nerve excitability of Aß-fibres caused by propofol. Concentrations of 10 µMol, 100 µMol and 1000 µMol were tested. Latency, peak response, strength-duration time constant (τSD) and recovery cycle of the sensory neuronal action potential (SNAP) were recorded. KEY FINDINGS: Our results have shown that propofol decreases nerve excitability of rat primary sensory afferents in vitro. Latency increased with increasing concentrations (0µMol: 0.96 ± 0.07ms; 1000µMol 1.10 ± 0.06ms, P<0.01). Also, propofol prolonged the relative refractory period (0µMol: 1.79 ± 1.13ms; 100 µMol: 2.53 ± 1.38ms, P<0.01), and reduced superexcitability (0 µMol: -14.0±4.0%; 100µMol: -9.5 ± 5.5%) and subexcitability (0µMol: 7.5 ± 1.2%; 1000µMol: 3.6 ± 1.2) significantly during the recovery cycle (P<0.01). SIGNIFICANCE: Our results have shown that propofol decreases nerve excitability of primary sensory afferents. The technique of threshold tracking revealed that axonal voltage-gated ion channels are significantly affected by propofol and therefore might be at least partially responsible for earlier described analgesic effects.