A grounded theory study on the influence of sleep on Parkinson’s symptoms

Contains fulltext : 167717.pdf (publisher's version ) (Open Access)BACKGROUND: Upon awaking, many Parkinson's patients experience an improved mobility, a phenomenon known as 'sleep benefit'. Despite the potential clinical relevance, no objective correlates of sleep benefit exist. The discrepancy between the patients' subjective experience of improvement in absence of objective changes is striking, and raises questions about the nature of sleep benefit. We aimed to clarify what patients reporting subjective sleep benefit, actually experience when waking up. Furthermore, we searched for factors associated with subjective sleep benefit. METHODS: Using a standardized topic list, we interviewed 14 Parkinson patients with unambiguous subjective sleep benefit, selected from a larger questionnaire-based cohort. A grounded theory approach was used to analyse the data. RESULTS: A subset of the participants described a temporary decrease in their Parkinson motor symptoms after sleep. Others did experience beneficial effects which were, however, non-specific for Parkinson's disease (e.g. feeling 'rested'). The last group misinterpreted the selection questionnaire and did not meet the definition of sleep benefit for various reasons. There were no general sleep-related factors that influenced the presence of sleep benefit. Factors mentioned to influence functioning at awakening were mostly stress related. CONCLUSIONS: The group of participants convincingly reporting sleep benefit in the selection questionnaire appeared to be very heterogeneous, with only a portion of them describing sleep benefit on motor symptoms. The group of participants actually experiencing motor sleep benefit may be much smaller than reported in the literature so far. Future studies should employ careful inclusion criteria, which could be based on our reported data

Fibroid explants reveal a higher sensitivity against MDM2-inhibitor nutlin-3 than matching myometrium

<p>Abstract</p> <p>Background</p> <p>Spontaneous cessation of growth is a frequent finding in uterine fibroids. Increasing evidence suggests an important role of cellular senescence in this growth control. Deciphering the underlying mechanisms of growth control that can be expected not only to shed light on the biology of the tumors but also to identify novel therapeutic targets.</p> <p>Methods</p> <p>We have analyzed uterine leiomyomas and matching normal tissue for the expression of p14^Arfand used explants to see if reducing the MDM2 activity using the small-molecule inhibitor nutlin-3 can induce p53 and activate genes involved in senescence and/or apoptosis. For these studies quantitative real-time RT-PCR, Western blots, and immunohistochemistry were used. Statistical analyses were performed using the student's <it>t </it>test.</p> <p>Results</p> <p>An in depth analysis of 52 fibroids along with matching myometrium from 31 patients revealed in almost all cases a higher expression of p14^Arfin the tumors than in the matching normal tissue. In tissue explants, treatment with the MDM2 inhibitor nutlin-3 induced apoptosis as well as senescence as revealed by a dose-dependent increase of the expression of <it>BAX </it>as well as of <it>p21</it>, respectively. Simultaneously, the expression of the proliferation marker Ki-67 drastically decreased. Western-blot analysis identified an increase of the p53 level as the most likely reason for the increased activity of its downstream markers <it>BAX </it>and <it>p21</it>. Because as a rule fibroids express much higher levels of p14^Arf, a major negative regulator of MDM2, than matching myometrium it was then analyzed if fibroids are more sensitive against nutlin-3 treatment than matching myometrium. We were able to show that in most fibroids analyzed a higher sensibility than that of matching myometrium was noted with a corresponding increase of the p53 immunopositivity of the fibroid samples compared to those from myometrium.</p> <p>Conclusions</p> <p>The results show that uterine fibroids represent a cell population of advanced cellular age compared to matching myometrium. Moreover, the data point to members of the p53-network as to potential novel therapeutic targets for the treatment of uterine fibroids.</p

Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers

Background Plant-based diets rich in fruit and vegetables can prevent development of several chronic age-related diseases. However, the mechanisms behind this protective effect are not elucidated. We have tested the hypothesis that intake of antioxidant-rich foods can affect groups of genes associated with cellular stress defence in human blood cells. Trial registration number: NCT00520819 http://clinicaltrials.gov. Methods In an 8-week dietary intervention study, 102 healthy male smokers were randomised to either a diet rich in various antioxidant-rich foods, a kiwifruit diet (three kiwifruits/d added to the regular diet) or a control group. Blood cell gene expression profiles were obtained from 10 randomly selected individuals of each group. Diet-induced changes on gene expression were compared to controls using a novel application of the gene set enrichment analysis (GSEA) on transcription profiles obtained using Affymetrix HG-U133-Plus 2.0 whole genome arrays. Results Changes were observed in the blood cell gene expression profiles in both intervention groups when compared to the control group. Groups of genes involved in regulation of cellular stress defence, such as DNA repair, apoptosis and hypoxia, were significantly upregulated (GSEA, FDR q-values < 5%) by both diets compared to the control group. Genes with common regulatory motifs for aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (AhR/ARNT) were upregulated by both interventions (FDR q-values < 5%). Plasma antioxidant biomarkers (polyphenols/carotenoids) increased in both groups. Conclusions The observed changes in the blood cell gene expression profiles suggest that the beneficial effects of a plant-based diet on human health may be mediated through optimization of defence processes

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure &lt;= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Characterization of a replicating expanded tropism oncolytic reovirus carrying the adenovirus E4orf4 gene

While the mammalian orthoreovirus type 3 dearing (reovirus T3D) infects many different tumour cells, various cell lines resist the induction of reovirus-mediated cell death. In an effort to increase the oncolytic potency, we introduced transgenes into the S1 segment of reovirus T3D. The adenovirus E4orf4 gene was selected as transgene since the encoded E4orf4 protein induces cell death in transformed cells. The induction of cell death by E4orf4 depends in part on its binding to phosphatase 2A (PP2A). In addition to the S1-E4orf4 reovirus, two other reoviruses were employed in our studies. The reovirus rS1-RFA encodes an E4orf4 double-mutant protein that cannot interact with PP2A and the rS1-iLOV virus encoding the fluorescent marker iLOV as a reporter. The replacement of the codons for the junction adhesion molecule-A (JAM-A) binding head domain of the truncated spike protein blocks the entry of these recombinant viruses via the reovirus receptor JAM-A. Instead these viruses rely on internalization via binding to sialic acids on the cell surface. This expands their tropism and allows infection of JAM-A-deficient tumour cells. Here we not only demonstrate the feasibility of this approach but also established that the cytolytic activity of these recombinant viruses is largely transgene independent

Hallucinations after Cardiac Surgery: A Prospective Observational Study

Background and Objective: Hallucinations after cardiac surgery can be a burden, but their prevalence and phenomenology have not been studied well. Risk factors for postoperative hallucinations, as well as their relation to delirium are unclear. We aimed to study the prevalence and phenomenology of hallucinations after cardiac surgery, and to study the association between hallucinations and delirium in this population. Materials and Methods: We used the Questionnaire for Psychotic Experiences to detect hallucinations in cardiac surgery patients and a control group of cardiology outpatients. We assessed postoperative delirium with validated instruments. Risk factors for postoperative hallucinations and the association between hallucinations and delirium were analysed using logistic regression. Results: We included 201 cardiac surgery patients and 99 cardiology outpatient controls. Forty-four cardiac surgery patients (21.9%) experienced postoperative hallucinations in the first four postoperative days. This was significantly higher compared to cardiology outpatient controls (n = 4, 4.1%, p <0.001). Visual hallucinations were the most common type of hallucinations in cardiac surgery patients, and less common in outpatient controls. Cardiac surgery patients who experienced hallucinations were more likely to also have delirium (10/44, 22.7%) compared to patients without postoperative hallucinations (16/157, 10.2% p = 0.03). However, the majority of patients with postoperative hallucinations (34/44, 77.3%) did not develop delirium. Conclusion: After cardiac surgery, hallucinations occurred more frequently than in outpatient controls. Hallucinations after cardiac surgery were most often visual in character. Although postoperative hallucinations were associated with delirium, most patients with hallucinations did not develop delirium