Use of antipsychotics and benzodiazepines in patients with psychiatric emergencies: Results of an observational trial

<p>Abstract</p> <p>Background</p> <p>Conventional antipsychotics augmented with benzodiazepines have been the standard acute treatment for psychiatric emergencies for more than 50 years. The inability of patients to give informed consent limits randomised, controlled studies. This observational study on immediate therapy for aggression and impulse control in acutely agitated patients (IMPULSE) evaluated the short-term effectiveness and tolerability of atypical and typical antipsychotic medications (AP) in a non-interventional setting.</p> <p>Methods</p> <p>This was a comparative, non-randomised, prospective, open-label, observational study. Treatment over the first 5 days was classified according to whether any olanzapine, risperidone, or haloperidol was included or not. Documentations (PANSS-excited component, CGI-aggression, CGI-suicidality, tranquilisation score) were at baseline (day 1) and days 2–6 after start of AP.</p> <p>Results</p> <p>During the short treatment-period, PANSS-EC and CGI-aggression scores improved in all cohorts. 68.7% of patients treated with olanzapine, 72.2% of patients treated with risperidone, and 83.3% of patients treated with haloperidol received concomitant benzodiazepines (haloperidol vs. non-haloperidol: p < 0.001). More patients treated with olanzapine (73.8%) were fully alert according to a tranquilisation score and active at day 2 than patients treated with risperidone (57.1%) or haloperidol (58.0%).</p> <p>Conclusion</p> <p>Current medication practices for immediate aggression control are effective with positive results present within a few days. In this study, concomitant benzodiazepine use was significantly more frequent in patients receiving haloperidol.</p

Altered Prion Protein Expression Pattern in CSF as a Biomarker for Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression

Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone

Differential diagnosis of suspected multiple sclerosis: a consensus approach

BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision

Methylphenidate during early consolidation affects long-term associative memory retrieval depending on baseline catecholamines

RATIONALE: Synaptic memory consolidation is thought to rely on catecholaminergic signaling. Eventually, it is followed by systems consolidation, which embeds memories in a neocortical network. Although this sequence was demonstrated in rodents, it is unclear how catecholamines affect memory consolidation in humans. OBJECTIVES: Here, we tested the effects of catecholaminergic modulation on synaptic and subsequent systems consolidation. We expected enhanced memory performance and increased neocortical engagement during delayed retrieval. Additionally, we tested if this effect was modulated by individual differences in a cognitive proxy measure of baseline catecholamine synthesis capacity. METHODS: Fifty-three healthy males underwent a between-subjects, double-blind, placebo-controlled procedure across 2 days. On day 1, subjects studied and retrieved object-location associations and received 20 mg of methylphenidate or placebo. Drug intake was timed so that methylphenidate was expected to affect early consolidation but not encoding or retrieval. Memory was tested again while subjects were scanned three days later. RESULTS: Methylphenidate did not facilitate memory performance, and there was no significant group difference in activation during delayed retrieval. However, memory representations differed between groups depending on baseline catecholamines. The placebo group showed increased activation in occipito-temporal regions but decreased connectivity with the hippocampus, associated with lower baseline catecholamine synthesis capacity. The methylphenidate group showed stronger activation in the postcentral gyrus, associated with higher baseline catecholamine synthesis capacity. CONCLUSIONS: Altogether, methylphenidate during early consolidation did not foster long-term memory performance, but it affected retrieval-related neural processes depending on individual levels of baseline catecholamines

Microbial diversity and biogeochemical cycling in soda lakes

Soda lakes contain high concentrations of sodium carbonates resulting in a stable elevated pH, which provide a unique habitat to a rich diversity of haloalkaliphilic bacteria and archaea. Both cultivation-dependent and -independent methods have aided the identification of key processes and genes in the microbially mediated carbon, nitrogen, and sulfur biogeochemical cycles in soda lakes. In order to survive in this extreme environment, haloalkaliphiles have developed various bioenergetic and structural adaptations to maintain pH homeostasis and intracellular osmotic pressure. The cultivation of a handful of strains has led to the isolation of a number of extremozymes, which allow the cell to perform enzymatic reactions at these extreme conditions. These enzymes potentially contribute to biotechnological applications. In addition, microbial species active in the sulfur cycle can be used for sulfur remediation purposes. Future research should combine both innovative culture methods and state-of-the-art ‘meta-omic’ techniques to gain a comprehensive understanding of the microbes that flourish in these extreme environments and the processes they mediate. Coupling the biogeochemical C, N, and S cycles and identifying where each process takes place on a spatial and temporal scale could unravel the interspecies relationships and thereby reveal more about the ecosystem dynamics of these enigmatic extreme environments