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Efforts aiming at identifying biomarkers and corresponding methods for early diagnosis of Alzheimer's disease (AD) might be the most appropriate strategy to initiate promising new treatments and/or prevention of AD
The aim of our study is to assess the association of DNA methylation pattern of various leucocyte genes with AD pathogenesis in order to find potential biomarkers and corresponding methods for molecular diagnosis of AD.
DNA methylation level of various genes in AD patients and normal population were compared by bisulphite sequencing PCR and methylation-specific PCR (MSP). Furthermore, real-time PCR was used to explore the effects of DNA methylation on the expression of target genes.
Results showed significant hypermethylation of mammalian orthologue of Sir2 (SIRT1) gene in AD patients compared with normal population. Meanwhile, changes in methylation level of SIRT1 gene between different severities of AD were also found. Specific primers were designed from the SIRT1 CpG islands to differentiate AD and control group by MSP method. Besides, significant demethylation of β-amyloid precursor protein (APP) gene was observed in AD patients, whereas no difference was observed in other AD-related genes. Moreover, significant decrease in expression of SIRT1 gene and increase in expression of APP gene were also found in AD patients. In addition, the expression level of SIRT1/APP genes was associated with the severity, but not with the age or gender, of AD patients.
Conclusion:SIRT1 and APP might be the interesting candidate biomarkers and valuable for clinical diagnosis or treatment of AD.
Selective serotonin reuptake inhibitors (SSRIs) have been widely used in the treatment of most anxiety disorders. In this study, to clarify the mechanism of the anxiolytic effect, we investigated the mechanism underlying the effect of the SSRI citalopram on rat contextual conditioned fear stress (CFS), an animal model of anxiety.
Rats individually received footshocks in a shock chamber. More than 1 day later, they were given citalopram and/or dl‐p‐chlorophenylalanine (PCPA), various subtype‐selective serotonin (5‐HT) receptor antagonists: the 5‐HT1A receptor antagonist WAY 100635, the 5‐HT2A receptor antagonist MDL 100907, the 5‐HT2C receptor antagonist SB 242084, the 5‐HT3 receptor antagonist tropisetron, the 5‐HT4 receptor antagonist GR 125487, the 5‐HT6 receptor antagonist SB 258585 or the 5‐HT7 receptor antagonist SB 269970. After drug administration, freezing behaviour, which was used as an index of anxiety, was analysed in the same shock chamber without shocks.
Citalopram dose dependently reduced conditioned freezing behaviour. The anxiolytic‐like effect of citalopram was prevented completely by pretreatment with the 5‐HT‐depleting agent PCPA, but not by the 5‐HT1A receptor antagonist WAY 100635. Furthermore, none of the subtype‐selective 5‐HT receptor antagonists significantly affected conditioned freezing or affected the anxiolytic‐like effect of citalopram.
The anxiolytic‐like effect of citalopram in contextual CFS model depends on 5‐HT availability. In addition, contextual CFS model is suggested to be completely different from conventional anxiety models in neural mechanism or manners of serotonergic involvement. However, further studies are needed to identify the pharmacological mechanisms responsible for the anxiolytic‐like effect of citalopram.
Paliperidone palmitate long‐acting injection (PP‐LAI) has recently been approved for treatment of chronic schizophrenia. Its cost‐effectiveness has not been established. The objective was to compare direct costs and outcomes between PP‐LAI and olanzapine pamoate (OLZ‐LAI) in treating chronic schizophrenia in Norway from the perspective of the government payer.
We used a decision analytic model over a 1‐year time horizon. Clinical inputs were derived from the literature and an expert panel; costs were taken from standard lists, adjusted to 2010 Norwegian kroner (NOK). Discounting was not done. Main outcomes included average cost per patient treated, hospitalisations, emergency room (ER) visits and quality‐adjusted life years (QALYs). The pharmacoeconomic outcome was the incremental cost per QALY. Robustness was examined using one‐way sensitivity analyses on critical variables and a 5000‐iteration probabilistic Monte Carlo sensitivity analysis with all variables included.
PP‐LAI generated 0.845 QALY at a cost of 151 336 NOK of which 23% was due to drugs; 25% of patients were hospitalised and another 12% required ER visits. OLZ‐LAI cost 174 351 NOK (21% due to drugs); patient outcomes included 0.844 QALY, 27% hospitalisations and 14% ER visits. PP‐LAI dominated OLZ‐LAI in the base case. The analysis was reasonably robust against variations in drug cost but sensitive to small changes in adherence and hospitalisation rates. Overall, PP‐LAI was dominant over OLZ‐LAI in 54.5% of simulations. Replacing OLZ‐LAI with PP‐LAI would be cost saving for the Norwegian healthcare system.
PP‐LAI was cost‐effective compared with OLZ‐LAI in treating patients with chronic schizophrenia in Norway but sensitive to changes in adherence and hospitalisation rates.
Bacterial meningitis is an infection of the central nervous system characterised by strong inflammatory response. The brain is highly dependent on ATP, and the cell energy is obtained through oxidative phosphorylation, a process which requires the action of various respiratory enzyme complexes and creatine kinase (CK) as an effective buffering system of cellular ATP levels in tissues that consume high energy.
Evaluate the activities of mitochondrial respiratory chain complexes I, II, III, IV and CK activity in hippocampus and cortex of the Wistar rat submitted to meningitis by Klebsiella pneumoniae.
Adult Wistar rats received either 10 µl of sterile saline as a placebo or an equivalent volume of K. pneumoniae suspension. The animals were killed in different times at 6, 12, 24 and 48 h after meningitis induction. Another group was treated with antibiotic, starting at 16 h and continuing daily until their decapitation at 24 and 48 h after induction.
In the hippocampus, the meningitis group without antibiotic treatment, the complex I was increased at 24 and 48 h, complex II was increased at 48 h, complex III was inhibited at 6, 12, 24 and 48 h and in complex IV all groups with or without antibiotic treatment were inhibited after meningitis induction, in the cortex there was no alteration.
Although descriptive, our results show that antibiotic prevented in part the changes of the mitochondrial respiratory chain. The meningitis model could be a good research tool to study the biological mechanisms involved in the pathophysiology of the K. pneumoniae meningitis.
To verify the prevalence and clinical impact of excessive daytime sleepiness (EDS) in outpatients with bipolar disorder.
Eighty‐one outpatients with bipolar disorder and 79 healthy control subjects were recruited. Patients were required not to be acutely manic or depressed. We used the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index and the Functioning Assessment Short Test to assess sleepiness, sleep problems and functioning, respectively.
Patients had a higher prevalence of sleepiness (40%) than the control group (18%). Sleepiness and sleep disturbance had independent impacts on disability in the multivariable model.
This study suggests that EDS is a relevant clinical dimension in patients with bipolar disorder. It is a frequent symptom that often overlaps with other sleep disturbances. This study also reveals that once present it has the potential to increase functional impairment.
The primary aim of this explorative study was to investigate the influence of the glutamatergic N‐methyl‐d‐aspartate (NMDA) receptor antagonist memantine on motor activity in healthy subjects. Secondarily, we wanted to compare these data to findings in a sample of schizophrenia patients.
The healthy subjects acted as their own controls in an open‐within‐subject design. Motor activity was recorded with an actigraph worn for 24 h in the drug‐free, and steady‐state memantine conditions, respectively. Motor activity levels for 1‐min intervals were analysed by means of both linear and nonlinear methods. The schizophrenia patients were monitored only once, without memantine manipulation.
The root mean square successive differences (RMSSD) and the RMSSD/SD ratio were increased by memantine, and memantine was also associated with lower autocorrelation (lag 1) but in recordings from the right arm only. These movement patterns partly corresponded to those found in a sample of drug‐treated schizophrenia patients. Total activity level, standard deviation (SD) and sample entropy were not significantly different in the memantine versus drug‐free condition.
The findings suggest a role for the NMDA receptor in the regulation of motor activity in healthy individuals as memantine increased the variability in the motor recordings and the alterations between adjacent motor recordings. It is suggested that the findings may be relevant to the role played by glutamate and the NMDA receptor functioning to the motor disturbances in schizophrenia.
To examine and record the clinical antidepressant effect of exogenous agmatine, an amino acid derived central glutamaergic modulator in endogenously depressed subjects. It was also the author's intention to examine the effects of parachlorophenylalanine (PCPA) in therapeutic responders to determine if serotonergic mechanisms mediate agmatine's antidepressant effect.
Exogenous agmatine was ingested in doses of 2‐3mg/day by depressed subjects with Major Depresssive Disorder (MDD), clinically assessed using the 21 item Hamilton Rating Scale for Depression (HAM‐D), the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS). Antidepressant responders volunteered to concommittantly ingest parachlorophenylalanine (PCPA) at starting doses of 250mg/day, and increased until depressive relapse, mitigating side effects, or a maximum dosage of 1250mg/day.
Three depressed subjects showing total illness remission with exogenous agmatine did not relapse after concomitantly adding PCPA. Effective in relieving both psychomotor agitation and retardation, the antidepressant effect was free of physical or behavioural side effects: gastrointestinal discomfort and loose stools in one subject resolved spontaneously within days. All three subjects refused to risk depressive relapse by temporarily stopping agmatine after PCPA was stopped.
The antidepressant effect of exogenous agmatine was documented in a small number of MDD subjects, and was not reversed/modified by PCPA confirming findings in animals that therapeutic response is not mediated by serotonergic mechanisms. A NAMDA (N‐methyl‐D‐aspartate) receptor antagonist, agmatine's recognized function in brain as inhibitory modulator of excitatory glutamatergic transmission suggests a pivotal role for brain glutamate, contributing to the ripening glutamatergic basis of depression, and a rational basis for future antidepressant pharmacotherapy.
Urgency, urinary incontinence and bowel disturbances are distressing side effects that have been observed during treatment with risperidone and other antipsychotics probably due to the receptor affinity profile. This occurrence can lead to poor compliance and therefore impair clinical outcome.
We report the case of a 50 year‐old lady, who experienced urinary incontinence and diarrhoea, when switching from oral to injectable risperidone, which ceased when discontinuing the drug.
Results and conclusions
It should be taken into account that some side effects can be revealed when switching from oral to depot formulations due to non‐compliance to orals; nevertheless dose‐dependent mechanisms and individual metabolic variability must be considered when observing idiosyncratic reactions to drugs.
Tardive Tourette‐like syndrome is recognised by the observation of several motor and vocal tics often in individuals receiving psychotropic medications and can happen within 1–3 months of treatment.
We report a case which is unique in its onset of Tardive Tourette‐like syndrome comprising of vocal, motor tics and coprolalia after more than three decades of treatment with combination depot and oral neuroleptics.
Use of the Naranjo Adverse Drug Reaction Probability Scale indicates a probable relationship between the onset of Tardive Tourettism and the antipsychotic therapy in this patient. This was in contrast to earlier reports which noted earlier onset and partial reversal with termination or change of medications. Clinicians need to pay heed to the emergence of late‐onset Tourettism in order to better manage its manifestation and prevent its worsening in the context of holistic care for patients with neuropsychiatric conditions including schizophrenia.