Towards a pathway definition of Parkinson’s disease: a complex disorder with links to cancer, diabetes and inflammation

We have previously established a first whole genome transcriptomic profile of sporadic Parkinson’s disease (PD). After extensive brain tissue-based validation combined with cycles of iterative data analysis and by focusing on the most comparable cases of the cohort, we have refined our analysis and established a list of 892 highly dysregulated priority genes that are considered to form the core of the diseased Parkinsonian metabolic network. The substantia nigra pathways, now under scrutiny, contain more than 100 genes whose association with PD is known from the literature. Of those, more than 40 genes belong to the highly significantly dysregulated group identified in our dataset. Apart from the complete list of 892 priority genes, we present pathways revealing PD ‘hub’ as well as ‘peripheral’ network genes. The latter include Lewy body components or interact with known PD genes. Biological associations of PD with cancer, diabetes and inflammation are discussed and interactions of the priority genes with several drugs are provided. Our study illustrates the value of rigorous clinico-pathological correlation when analysing high-throughput data to make optimal use of the histopathological phenome, or morphonome which currently serves as the key diagnostic reference for most human diseases. The need for systematic human tissue banking, following the highest possible professional and ethical standard to enable sustainability, becomes evident

Injection therapy and denervation procedures for chronic low-back pain: a systematic review

Injection therapy and denervation procedures are commonly used in the management of chronic low-back pain (LBP) despite uncertainty regarding their effectiveness and safety. To provide an evaluation of the current evidence associated with the use of these procedures, a systematic review was performed. Existing systematic reviews were screened, and the Cochrane Back Review Group trial register was searched for randomized controlled trials (RCTs) fulfilling the inclusion criteria. Studies were included if they recruited adults with chronic LBP, evaluated the use of injection therapy or denervation procedures and measured at least one clinically relevant outcome (such as pain or functional status). Two review authors independently assessed studies for eligibility and risk of bias (RoB). A meta-analysis was performed with clinically homogeneous studies, and the GRADE approach was used to determine the quality of evidence. In total, 27 RCTs were included, 14 on injection therapy and 13 on denervation procedures. 18 (66%) of the studies were determined to have a low RoB. Because of clinical heterogeneity, only two comparisons could be pooled. Overall, there is only low to very low quality evidence to support the use of injection therapy and denervation procedures over placebo or other treatments for patients with chronic LBP. However, it cannot be ruled out that in carefully selected patients, some injection therapy or denervation procedures may be of benefit

The search for stable prognostic models in multiple imputed data sets

<p>Abstract</p> <p>Background</p> <p>In prognostic studies model instability and missing data can be troubling factors. Proposed methods for handling these situations are bootstrapping (B) and Multiple imputation (MI). The authors examined the influence of these methods on model composition.</p> <p>Methods</p> <p>Models were constructed using a cohort of 587 patients consulting between January 2001 and January 2003 with a shoulder problem in general practice in the Netherlands (the Dutch Shoulder Study). Outcome measures were persistent shoulder disability and persistent shoulder pain. Potential predictors included socio-demographic variables, characteristics of the pain problem, physical activity and psychosocial factors. Model composition and performance (calibration and discrimination) were assessed for models using a complete case analysis, MI, bootstrapping or both MI and bootstrapping.</p> <p>Results</p> <p>Results showed that model composition varied between models as a result of how missing data was handled and that bootstrapping provided additional information on the stability of the selected prognostic model.</p> <p>Conclusion</p> <p>In prognostic modeling missing data needs to be handled by MI and bootstrap model selection is advised in order to provide information on model stability.</p

Elevated Plasma Corticosterone Decreases Yolk Testosterone and Progesterone in Chickens: Linking Maternal Stress and Hormone-Mediated Maternal Effects

Despite considerable research on hormone-mediated maternal effects in birds, the underlying physiology remains poorly understood. This study investigated a potential regulation mechanism for differential accumulation of gonadal hormones in bird eggs. Across vertebrates, glucocorticoids can suppress reproduction by downregulating gonadal hormones. Using the chicken as a model species, we therefore tested whether elevated levels of plasma corticosterone in female birds influence the production of gonadal steroids by the ovarian follicles and thus the amount of reproductive hormones in the egg yolk. Adult laying hens of two different strains (ISA brown and white Leghorn) were implanted subcutaneously with corticosterone pellets that elevated plasma corticosterone concentrations over a period of nine days. Steroid hormones were subsequently quantified in plasma and yolk. Corticosterone-implanted hens of both strains had lower plasma progesterone and testosterone levels and their yolks contained less progesterone and testosterone. The treatment also reduced egg and yolk mass. Plasma estrogen concentrations decreased in white Leghorns only whereas in both strains yolk estrogens were unaffected. Our results demonstrate for the first time that maternal plasma corticosterone levels influence reproductive hormone concentrations in the yolk. Maternal corticosterone could therefore mediate environmentally induced changes in yolk gonadal hormone concentrations. In addition, stressful situations experienced by the bird mother might affect the offspring via reduced amounts of reproductive hormones present in the egg as well as available nutrients for the embryo

Apoptosis- and necrosis-induced changes in light attenuation measured by optical coherence tomography

Optical coherence tomography (OCT) was used to determine optical properties of pelleted human fibroblasts in which necrosis or apoptosis had been induced. We analysed the OCT data, including both the scattering properties of the medium and the axial point spread function of the OCT system. The optical attenuation coefficient in necrotic cells decreased from 2.2 ± 0.3 mm−1 to 1.3 ± 0.6 mm−1, whereas, in the apoptotic cells, an increase to 6.4 ± 1.7 mm−1 was observed. The results from cultured cells, as presented in this study, indicate the ability of OCT to detect and differentiate between viable, apoptotic, and necrotic cells, based on their attenuation coefficient. This functional supplement to high-resolution OCT imaging can be of great clinical benefit, enabling on-line monitoring of tissues, e.g. for feedback in cancer treatment

The Streptococcus pneumoniae Pilus-1 Displays a Biphasic Expression Pattern

The Streptococcus pneumoniae pilus-1 is encoded by pilus islet 1 (PI-1), which has three clonal variants (clade I, II and III) and is present in about 30% of clinical pneumococcal isolates. In vitro and in vivo assays have demonstrated that pilus-1 is involved in attachment to epithelial cells and virulence, as well as protection in mouse models of infection. Several reports suggest that pilus-1 expression is tightly regulated and involves the interplay of numerous genetic regulators, including the PI-1 positive regulator RlrA. In this report we provide evidence that pilus expression, when analyzed at the single-cell level in PI-1 positive strains, is biphasic. In fact, the strains present two phenotypically different sub-populations of bacteria, one that expresses the pilus, while the other does not. The proportions of these two phenotypes are variable among the strains tested and are not influenced by genotype, serotype, growth conditions, colony morphology or by the presence of antibodies directed toward the pilus components. Two sub-populations, enriched in pilus expressing or not expressing bacteria were obtained by means of colony selection and immuno-detection methods for five strains. PI-1 sequencing in the two sub-populations revealed the absence of mutations, thus indicating that the biphasic expression observed is not due to a genetic modification within PI-1. Microarray expression profile and western blot analyses on whole bacterial lysates performed comparing the two enriched sub-populations, revealed that pilus expression is regulated at the transcriptional level (on/off regulation), and that there are no other genes, in addition to those encoded by PI-1, concurrently regulated across the strains tested. Finally, we provide evidence that the over-expression of the RrlA positive regulator is sufficient to induce pilus expression in pilus-1 negative bacteria. Overall, the data presented here suggest that the observed biphasic pilus expression phenotype could be an example of bistability in pneumococcus

Late Window Imaging Selection for Endovascular Therapy of Large Vessel Occlusion Stroke: An International Survey

Background Current stroke guidelines recommend advanced imaging (computed tomography [CT] perfusion or magnetic resonance imaging) prior to endovascular therapy (EVT) in patients with late presentation of large vessel occlusion. Adherence to guidelines may be constrained by resources or timely access to imaging. We sought to understand the factors which influence late window imaging selection for EVT candidates with large vessel occlusion. Methods We conducted an international survey from January to May 2022. The questions aimed to identify advanced imaging and treatment decisions based on access to imaging, time delays, and simulated patient scenarios. Results There were 3000 invited participants and 1506 respondents, the majority (89.6%) from comprehensive stroke centers in high‐income countries. Neurointerventionalists comprised 31.8% and noninterventionalists 68.2% of respondents. Overall, 70.7% reported routine use of advanced imaging for late EVT selection, and 63.6% reported its usage in every case. There was greater availability of advanced imaging in comprehensive stroke centers versus primary stroke centers (67.0% versus 33.7%; P<0.0001), and high‐ versus low‐middle income countries (70.5% versus 44.5%; P<0.0001). When presented with a late window patient, 41.6% would complete CT perfusion or magnetic resonance imaging prior to EVT, 25.4% would perform CT perfusion or magnetic resonance imaging prior to IVT and EVT, and 25.8% would refer to EVT without advanced imaging. If advanced imaging was not readily available, 70.1% would refer a patient to EVT based on CT in the late window. Additional time delay within 20 minutes to obtain advanced imaging was considered acceptable in 77.7% of respondents. Conclusion Current guidelines for imaging late window EVT candidates are inconsistent with imaging decisions by physicians. Most respondents consider an imaging delay of greater than 20 minutes unacceptable. Access to advanced imaging was greater in comprehensive stroke centers and high‐income countries. In the case of limited access most respondents would consider EVT based on CT only

Root-emitted volatile organic compounds: can they mediate belowground plant-plant interactions?

peer reviewedBackground Aboveground, plants release volatile organic compounds (VOCs) that act as chemical signals between neighbouring plants. It is now well documented that VOCs emitted by the roots in the plant rhizosphere also play important ecological roles in the soil ecosystem, notably in plant defence because they are involved in interactions between plants, phytophagous pests and organisms of the third trophic level. The roles played by root-emitted VOCs in between- and within-plant signalling, however, are still poorly documented in the scientific literature. Scope Given that (1) plants release volatile cues mediating plant-plant interactions aboveground, (2) roots can detect the chemical signals originating from their neighbours, and (3) roots release VOCs involved in biotic interactions belowground, the aim of this paper is to discuss the roles of VOCs in between- and within-plant signalling belowground. We also highlight the technical challenges associated with the analysis of root-emitted VOCs and the design of experiments targeting volatile-mediated root-root interactions. Conclusions We conclude that root-root interactions mediated by volatile cues deserve more research attention and that both the analytical tools and methods developed to study the ecological roles played by VOCs in interplant signalling aboveground can be adapted to focus on the roles played by root-emitted VOCs in between- and within-plant signalling