Shedding light on the clinical recognition process of transient global amnesia.

BACKGROUND AND PURPOSE: Diagnostic uncertainty is common in the emergency evaluation of neurological conditions such as acute confusional states, particularly for non-neurologists. We aimed to investigate the clinical recognition process of transient global amnesia (TGA) before arrival at the hospital and in the emergency department (ED). METHODS: In this retrospective observational study, medical records of 365 patients with TGA were analysed concerning mode of arrival, symptoms and suspected diagnosis made by pre-hospital medical care providers and the ED neurologist. RESULTS: More than half of the 248 patients who were evaluated before arrival at the hospital (N = 157, 63.3%) received a diagnosis of suspected stroke, whereas TGA was considered in only 16 patients (6.5%), with recognition of acute amnesia in 150 patients (60.5%) and disturbed orientation in 86 patients (34.7%). Repetitive questions by the patient were noted in 28 patients (11.3%). In contrast, in 355 patients (97.3%), TGA was considered the primary diagnosis by the ED neurologist. Diagnosis in the ED was achieved by documenting ongoing impairment of episodic verbal memory (100.0%), repetitive questions as a prominent ancillary finding (95.5%) and the lack of focal neurological symptoms (100.0%) or by carefully obtaining collateral history suggestive of anterograde memory disturbance (89.9%) and/or repetitive questions (85.7%). CONCLUSION: Recognizing TGA crucially depends on identifying isolated anterograde episodic long-term memory disturbance or its observable effects such as repetitive questions and actions.

Use of analgesics in acute stroke patients with inability to self-report pain: a retrospective cohort study.

BACKGROUND: Pain is a common and burdensome complication in patients with acute stroke. We assessed the impact of impaired communication in stroke patients on pain assessment and treatment. METHODS: We included 909 (507 male, mean age 71.8 years) patients admitted to our stroke unit from 01/2015 to 12/2015 in the analysis. Patients were assigned to four groups: able to communicate (AC), not able to communicate prior to index stroke (P-NAC), due to focal symptoms of index stroke (S-NAC), due to a reduced level of consciousness (C-NAC). Pain prevalence, documentation of pain and use of analgesics were evaluated. C-NAC patients were excluded from analyses regarding analgesic treatment due to relevant differences in patient characteristics. RESULTS: 746 patients (82.1%) were classified as AC, 25 (2.8%) as P-NAC, 90 (9.9%) as S-NAC and 48 (5.3%) as C-NAC. Pain was documented on the Numeric Rating Scale and in form of free text by nurses and physicians. Nurses documented pain more frequently than physicians (p < 0.001). Pain prevalence was 47.0% (n.s. between groups). The use of analgesic medication increased from 48.7% in the AC group, to 76.0% in the P-NAC group, and 77.8% in the S-NAC group (p < 0.001). Opioid use was significantly more frequent in NAC patients (p < 0.001). The response to the treatment was poorly documented with significantly lowest rates in S-NAC patients (p < 0.001). CONCLUSIONS: Our study suggests that post-stroke pain in patients with inability to communicate is not attended enough, not systematically assessed and therefore not sufficiently treated.

Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis.

BACKGROUND: The term "aseptic meningitis" encompasses cases of meningitis with negative bacterial CSF culture, which predominantly are of viral etiology. While the clinical course is usually benign, complications such as encephalitic involvement resulting in a more severe clinical course may occur. Dysfunction of the blood-brain-barrier (BBB), which is a prerequisite for viral entry into the brain parenchyma, can be approximated using the CSF/serum albumin ratio, readily obtainable in routine CSF analysis. OBJECITVES: Analysis of CSF patterns in patients with aseptic meningitis/meningoencephalitis with a focus on BBB dysfunction as a marker for encephalitic involvement. STUDY DESIGN: Retrospective chart review of patients admitted to our hospital between 2004 and 2016 with a diagnosis of aseptic meningitis/meningoencephalitis. RESULTS: Patients with aseptic meningitis displaying clinical, MR-tomographic or electroencephalographic signs of encephalitic involvement were significantly older than patients without these features (47.4 vs. 35.5 yrs., p=0.002). In patients with meningoencephalitis, CSF analysis revealed a more severe disruption of BBB, approximated by the CSF/serum albumin ratio (p=0.002). Compromised BBB function correlated positively with length of hospitalization (p=0.007), indicative of a more severe clinical course. The number of CSF lymphocytes was found to predict the severity of the BBB disruption, which additionally was more frequently observed when herpesviridae were identified as infectious agents. CONCLUSIONS: We suggest that the CSF/serum albumin ratio as an estimate for BBB function should be attended to in the evaluation of patients with aseptic meningitis. Severe BBB dysfunction, older age and infection with herpesviridae appear to raise the risk for encephalitic involvement.

Reliability of laser Doppler flowmetry curve reading for measurement of toe and ankle pressures: intra- and inter-observer variation.

OBJECTIVES: To assess the intra- and inter-observer variation in laser Doppler flowmetry curve reading for measurement of toe and ankle pressures. METHODS: A prospective single blinded diagnostic accuracy study was conducted on 200 patients with known or suspected peripheral arterial disease (PAD), with a total of 760 curve sets produced. The first curve reading for this study was performed by laboratory technologists blinded to clinical clues and previous readings at least 3 months after the primary data sampling. The pressure curves were later reassessed following another period of at least 3 months. Observer agreement in diagnostic classification according to TASC-II criteria was quantified using Cohen's kappa. Reliability was quantified using intra-class correlation coefficients, coefficients of variance, and Bland-Altman analysis. RESULTS: The overall agreement in diagnostic classification (PAD/not PAD) was 173/200 (87%) for intra-observer (κ = .858) and 175/200 (88%) for inter-observer data (κ = .787). Reliability analysis confirmed excellent correlation for both intra- and inter-observer data (ICC all ≥.931). The coefficients of variance ranged from 2.27% to 6.44% for intra-observer and 2.39% to 8.42% for inter-observer data. Subgroup analysis showed lower observer-variation for reading of toe pressures in patients with diabetes and/or chronic kidney disease than patients not diagnosed with these conditions. Bland-Altman plots showed higher variation in toe pressure readings than ankle pressure readings. CONCLUSIONS: This study shows substantial intra- and inter-observer agreement in diagnostic classification and reading of absolute pressures when using laboratory technologists as observers. The study emphasises that observer variation for curve reading is an important factor concerning the overall reproducibility of the method. Our data suggest diabetes and chronic kidney disease have an influence on toe pressure reproducibility.

Number of distal limb and brachial pressure measurements required when diagnosing peripheral arterial disease by laser Doppler flowmetry.

We examine the reliability of single and repeated blood pressure measurements at ankle, toe, and arm levels for the diagnosis of peripheral arterial disease (PAD) by laser Doppler flowmetry. Segmental pressures were measured in 200 patients with known or suspected PAD. Segmental indices were calculated using (1) one measurement [M-1], two measurements [M-2], or by a predefined reproducibility criterion (RC) as well as (2) by using one brachial blood-pressure (BBP-one) or correspondent to each segmental pressure (BBP-all) as reference. The agreement in diagnosis of PAD by Cohen's Kappa was κ = 0.930 when comparing RC to M-1, and κ = 0.977 when comparing RC to M-2. The same comparison showed excellent relative reliability for segmental indices (all intra-class correlation coefficients (ICC) ≥ 0.980). Diagnostic classification agreement for BBP-all versus BBP-one were κ = 0.831 for RC, κ = 0.804 for M-1, and κ = 0.847 for M-2. The relative reliability analysis showed excellent correlation in segmental indices (all ICC ≥ 0.957). The study shows minimal difference in segmental indices and diagnostic classification when comparing calculations based on the listed strategies. However, the study indicated that it is important to measure BBPs correspondent to each segmental pressure.

Bispectral index monitoring and seizure quality optimization in electroconvulsive therapy.

In ECT, the relative timing of seizure induction and anesthesia may critically impact on seizure quality when anesthetic agents with anticonvulsive properties such as barbiturates or propofol are used. Measuring the depth of anesthesia by bispectral index (BIS) monitoring and thereby identifying the optimal moment for seizure induction might enhance seizure quality.Seizures from 869 individual ECT -sessions with thiopental anesthetic from 118 patients were examined in this retrospective study. The associations of the BIS value at the moment of seizure induction with 7 established seizure parameters and with a novel model of seizure quality were tested by regression analyses.BIS value at induction correlated positively with seizure duration, central inhibition, coherence and maximal heart rate, but not with midictal amplitude. Higher seizure quality was related with a higher BIS value at the moment of seizure induction.The BIS value at seizure induction serves as an independent predictor of seizure quality, influencing most other established markers. BIS monitoring appears as a simple tool to identify the optimal moment for seizure induction.

Randomised diagnostic accuracy study of a fully automated portable device for diagnosing peripheral arterial disease by measuring the toe-brachial index.

OBJECTIVE: To assess the accuracy of a fully automated portable device (APD) for diagnosing peripheral arterial disease (PAD) by measuring the toe-brachial index (TBI) and using mercury-in-silastic, strain-gauge plethysmography (SGP) as reference. DESIGN: Prospective, randomised, double-blinded diagnostic accuracy study. MATERIALS AND METHODS: A total of 204 consecutive patients with known or suspected PAD were randomly assigned to measurement of TBI by the portable device followed by the SGP technique or the opposite sequence. Finally, ankle-brachial index (ABI) was assessed by SGP. RESULTS: The APD showed a sensitivity of 98.8%, a specificity of 61.0%, a positive predictive value of 91.0% and a negative predictive value of 92.6% for detecting PAD compared to a full SGP test comprised of ABI and TBI. According to the SGP test, 35 patients (17.2%) had an ABI > 0.90 but a TBI < 0.70. Correlation analysis of the absolute toe pressures by the two methods showed an intraclass correlation coefficient of 0.937 (95% confidence interval (CI) 0.887-0.962) for right toe pressures and 0.939 (95% CI 0.908-0.958) for the left toe pressures. CONCLUSIONS: The APD showed excellent diagnostic test characteristics for detecting PAD compared to SGP. Furthermore, the APD had a good correlation in absolute toe pressures with SGP.

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

HMG CoA reductase inhibition and left ventricular mass in hypertrophic cardiomyopathy: a randomized placebo-controlled pilot study.

BACKGROUND: Statins reduce cardiomyocyte hypertrophy in animal models of hypertrophic cardiomyopathy, aortic banding and heart failure after myocardial infarction. We investigated the effect of the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin on left ventricular (LV) mass in patients with hypertrophic cardiomyopathy in a randomized placebo-controlled double-blind pilot study. MATERIALS AND METHODS: Patients with hypertrophic cardiomyopathy were randomized to be treated once daily by atorvastatin 80 mg or placebo for nine months. LV mass was assessed by serial cardiac magnetic resonance imaging. LV systolic and diastolic function was determined by echocardiography. Markers of collagen metabolism and inflammation were also assessed. RESULTS: Out of 78 screened patients with hypertrophic cardiomyopathy 28 (2 x 14) patients were eligible for randomization. Eleven patients in each group completed the study with cardiac magnetic resonance imaging assessments meeting the evaluation standards at baseline and at follow-up. Low-density lipoprotein cholesterol levels in the atorvastatin group decreased from 3.24 +/- 1.14 mmol L(-1) (125 +/- 44 mg dL(-1)) at baseline to 1.37 +/- 0.49 mmol L(-1) (53 +/- 19 mg dL(-1)) at follow-up (P < 0.001), but were unchanged in the placebo group. Baseline LV mass was 228 +/- 51 g in the placebo and 232 +/- 67 g in the atorvastatin group. The primary endpoint of change in LV mass from baseline to follow-up was 2 +/- 10% in the atorvastatin group versus 0 +/- 13% in the placebo group (P = NS). Parameters of LV volumes and diameters, systolic and diastolic function, and markers of collagen metabolism were also unchanged in both groups. CONCLUSION: In patients with hypertrophic cardiomyopathy, this randomized placebo-controlled double-blind pilot study did not demonstrate an effect of 9-month treatment with atorvastatin 80 mg on LV mass reduction.

Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression.

The human endogenous cannabinoid system is an appealing target in the investigation of psychiatric disorders. In schizophrenia, endocannabinoids and their receptors are involved in the pathology of the disease. Previous studies reported an increased radioligand binding to cannabinoid receptors 1 (CB(1)) in schizophrenia, both in the dorsolateral prefrontal cortex and in the anterior cingulate cortex (ACC). We analyzed the expression of the CB(1) receptors in the ACC at the protein level using immunohistochemistry. In a quantitative postmortem study, 60 patients suffering from schizophrenia, bipolar disorder, major depression and controls were included. Numerical densities of neurons and glial cells immunopositive for CB(1) receptors were evaluated. No evidence of an increased or decreased density of CB(1) receptor immunopositive cells in schizophrenia or bipolar disorder was found. In major depression, CB(1) receptor immunopositive glial cells in the grey matter were decreased. Furthermore, our data show that different medications have an impact on the expression of CB(1) receptors in the ACC.

On-scene time in advanced trauma life support by anaesthesiologists.

OBJECTIVES: Severe injury is the leading cause of death among the young. Trauma systems have improved management of the severely injured and increased survival rates, but there is no level-1 evidence of advanced prehospital trauma care. Advanced prehospital trauma care prolongs on-scene time, which may imply a risk of significant delay in definitive trauma care. The aim of this study was to evaluate on-scene time and influence of (1) the presence of an anaesthesiologist on-scene, (2) prehospital intubation, (3) entrapment, and (4) injury severity. METHODS: A cohort of registry-based patients brought to Aarhus Trauma Centre. Data were consecutively reported. On-scene time was defined as the time from vehicle arrival to departure. Severe injury is defined by an injury severity score >15. The study was conducted over the period 1998-2000; only patients brought primarily to the trauma centre were included. Statistical tests used include chi, Kruskal-Wallis, Wilcoxon's rank sum and Spearman's rho. RESULTS: Seven hundred and forty-one patients triaged to Aarhus Trauma Centre from which we obtained all information in 596 cases constituted the study group. In 472 cases, an anaesthesiologist was present. On-scene times, median and 95% confidence interval, were as follows: entire study group (n=596) 15.5 min (15-17); ambulance only: 14.0 min (12-15); anaesthesiologist present, no intubation, no entrapment: 15.0 min (14-16); intubation, no entrapment: 21.5 min (16-27); entrapment, no intubation: 21.5 min (17-25); both intubation and entrapment: 22.0 min (16-36). CONCLUSION: The presence of an anaesthesiologist prolonged the median on-scene time by 1 min and in cases of prehospital intubation by 7.5 min. This result was no different from the prolongation caused by entrapment.

[Differential diagnosis of dyspnea - significance of clinic aspects, imaging and biomarkers for the diagnosis of heart failure]. / Abklärung von Luftnot: Bedeutung von Klinik, Bildgebung und Biomarkern in der Diagnostik der Herzinsuffizienz.

Dyspnea is a frequent reason for emergency consultations in hospitals or community medical facilities. Besides heart failure, a wide variety of other disorders may cause this symptom. Thus, early and accurate differential diagnosis is mandatory in order to facilitate rapid institution of appropriate therapy. This CME article elaborates on the specific usefulness of traditional diagnostic tools as history, symptomatology and physical signs along with chest X-ray and ECG and the more recently introduced natriuretic peptides to discriminate heart failure from other causes of dyspnea in the emergency setting. According to a systematic search and meta-analysis of the respective literature, several features from history and physical examination as well as pulmonary congestion on chest X-ray, atrial fibrillation and a high level of confidence of the initial clinical judgment indicate a cardiac cause of dyspnea with high specificity, but less sensitivity. Thus, in patients presenting with one or several of these characteristic features, little further diagnostic yield is to be expected from natriuretic peptides. If, however, the suspicion of heart failure remains unsettled by these means, determination of biomarkers may be helpful, although it needs to be considered that moderately elevated levels have only a limited specificity in particular in elderly patients with comorbidities. As also recognized by the European Guidelines for diagnosis and treatment of chronic heart failure, a BNP level of <100 pg/ml has proven particularly useful for excluding heart failure. Thus, a directed history, symptoms, physical findings, chest-X-ray and ECG remain the diagnostic mainstay. If the diagnosis cannot be established by these traditional tools, BNP or NT-proBNP testing may be very helpful, especially for ruling out heart failure.

Use of genetic complementation to identify gene(s) which specify species-specific organ tropism of Leishmania.

We have employed a genetic complementation screening to identify genetic markers of heat stress tolerance and visceralisation of Leishmania infection. Leishmania major, which has a low thermotolerance and which causes cutaneous lesions, was transfected with a cosmid library of L. donovani DNA. The recombinant parasites were then screened either for thermotolerance or selected by repeated passage in BALB/c mice. Cosmids which conferred selective advantage were isolated. Several strategies were tested to identify the gene(s) within the cosmids responsible for the observed selective advantages. Of the approaches tested, the complete sequence analysis of the cosmids and subsequent screening of defined candidate ORFs proved to be the method of choice. Other approaches, such as creation of sub-libraries or transposon insertion strategies proved to be unsuccessful.

Expression and subcellular localization of cpn60 protein family members in Leishmania donovani.

We have identified two diverged members of the cpn60 gene family in Leishmania donovani, causative agent of Indian Kala Azar. One of the genes, cpn60.1, although actively transcribed, is not expressed to detectable levels of protein in cultured L. donovani. The other gene, cpn60.2, which, compared with cpn60.1, shows a higher sequence conservation with the hsp60 genes from Trypanosoma brucei and Trypanosoma cruzi is expressed constitutively in cultured promastigotes. The abundance of the gene product, Cpn60.2, increases by 2.5-fold under heat stress and in axenic amastigotes of L. donovani. Cpn60.2 is also found enriched in mitochondrial cell fractions and localizes to the mitochondrial matrix. We conclude that Cpn60.2 is the major mitochondrial chaperonin in Leishmania.

Leishmania donovani heat shock protein 100. Characterization and function in amastigote stage differentiation.

We report the cloning and molecular analysis of the Leishmania donovani clpB gene. The protein-coding region is highly conserved compared with its L. major homologue, while 5'- and 3'-flanking DNA sequences display considerable divergence. The encoded mRNA has an unusually long 5'-leader sequence typical for RNAs, which are translated preferentially under heat stress. The gene product, a 100-kDa heat shock protein, Hsp100, becomes abundant only during sustained heat stress, but not under common chemical stresses. Hsp100 associates into trimeric complexes and is found mostly in a cytoplasmic, possibly membrane-associated, localization as determined by immune electron microscopy. Hsp100 shows immediate early expression kinetics during axenic amastigote development. In its absence, expression of at least one amastigote stage-specific protein family is impaired.

Chemical Stress does not Induce Heat Shock Protein Synthesis in Leishmania donovani.

The cellular heat shock response in kinetoplastid protozoa is regulated exclusively at a post-transcriptional level. The heat-inducibility of heat shock protein synthesis is retained under actinomycin C(1) which indicates an inducible translation of heat shock mRNAs. We have also assessed the ability of various chemicals known to be effective triggers of the heat shock response in higher eukaryotes to induce heat shock protein synthesis in Leishmania donovani. None of the tested chemicals elicited a stress response. We propose that the lack of transcription regulation in the kinetoplastida precludes a stress response under chemical stress.

Sequence verification by hybridisation with fluorescent octanucleotides as a first step to a fluorescent sequencing by hybridisation protocol.

Three sets of partly overlapping octanucleotides are 5' labelled with derivates of the fluorescence dyes fluorescein-, coumarine- and rhodamine, respectively. Hybridisation conditions are determined, under which all octanucleotides hybridise correctly against complementary target sequences bound on nylon membranes. Target sequences are three synthetic 48-mer oligonucleotides and herring sperm DNA, a positive control containing almost all possible octanucleotides. None of the octanucleotides hybridised to incorrect target sequences. Analysing these results, a given sequence could be unambiguously verified. A feature critical for the accuracy of the hybridisation is the temperature during the last washing step. This temperature can be estimated using the equation T = 19 - 0.4(G + C) + 0.15(G + C)2. Using octanucleotides labelled with three different colors, three hybridisations can be performed simultaneously.