Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression

Background: The objective of this study was to assess neurofilament light chain as a Parkinson’s disease biomarker. Methods: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson’s disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson’s disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. Results: In the Parkinson’s Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson’s disease patients (13 � 7.2 pg/mL) than in controls (12 � 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson’s disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. Conclusions: Neurofilament light chain in serum samples is increased in Parkinson’s disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson’s disease severity. Although the specificity of neurofilament light chain for Parkinson’s disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson’s disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed

Effects of Ambulant Myofeedback Training and Ergonomic Counselling in Female Computer Workers with Work-Related Neck-Shoulder Complaints: A Randomized Controlled Trial

Objective: To investigate the effects of ambulant myofeedback training including ergonomic counselling (Mfb) and ergonomic counselling alone (EC), on work-related neck-shoulder pain and disability. Methods: Seventy-nine female computer workers reporting neck-shoulder complaints were randomly assigned to Mfb or EC and received four weeks of intervention. Pain intensity in neck, shoulders, and upper back, and pain disability, were measured at baseline, immediately after intervention, and at three and six months follow-up. Results: Pain intensity and disability had significantly decreased immediately after four weeks Mfb or EC, and the effects remained at follow up. No differences were observed between the Mfb and EC group for outcome and subjects in both intervention groups showed comparable chances for improvement in pain intensity and disability. Conclusions: Pain intensity and disability significantly reduced after both interventions and this effect remained at follow-up. No differences were observed between the two intervention groups

Course and prognosis of recovery for chronic non-specific low back pain: design, therapy program and baseline data of a prospective cohort study

Background: There has been increasing focus on factors predicting the development of chronic musculoskeletal disorders. For patients already experiencing chronic non-specific low back pain it is also relevant to investigate which prognostic factors predict recovery. We present the design of a cohort study that aims to determine the course and prognostic factors for recovery in patients with chronic non-specific low back pain. Methods/Design. All participating patients were recruited (Jan 2003-Dec 2008) from the same rehabilitation centre and were evaluated by means of (postal) questionnaires and physical examinations at baseline, during the 2-month therapy program, and at 5 and 12 months after start of therapy. The therapy protocol at the rehabilitation centre used a bio-psychosocial approach to stimulate patients to adopt adequate (movement) behaviour aimed at physical and functional recovery. The program is part of regular care and consists of 16 sessions of 3 hours each, over an 8-week period (in total 48 hours), followed by a 3-month self-management program. The primary outcomes are low back pain intensity, disability, quality of life, patient's global perceived effect of recovery, and participation in work. Baseline characteristics include information on socio-demographics, low back pain, employment status, and additional clinical items status such as fatigue, duration of activities, and fear of kinesiophobia. Prognostic variables are determined for recovery at short-term (5 months) and long-term (12 months) follow-up after start of therapy. Discussion. In a routine clinical setting it is important to provide patients suffering from chronic non-specific low back pain with adequate information about the prognosis of their complaint

GpaXItarl originating from Solanum tarijense is a major resistance locus to Globodera pallida and is localised on chromosome 11 of potato

Resistance to Globodera pallida Rookmaker (Pa3), originating from wild species Solanum tarijense was identified by QTL analysis and can be largely ascribed to one major QTL. GpaXItarl explained 81.3% of the phenotypic variance in the disease test. GpaXItarl is mapped to the long arm of chromosome 11. Another minor QTL explained 5.3% of the phenotypic variance and mapped to the long arm of chromosome 9. Clones containing both QTL showed no lower cyst counts than clones with only GpaXItarl. After Mendelising the phenotypic data, GpaXItarl could be more precisely mapped near markers GP163 and FEN427, thus anchoring GpaXItarl to a region with a known R-gene cluster containing virus and nematode resistance genes

Formation of Trans-Activation Competent HIV-1 Rev:RRE Complexes Requires the Recruitment of Multiple Protein Activation Domains

The HIV-1 Rev trans-activator is a nucleocytoplasmic shuttle protein that is essential for virus replication. Rev directly binds to unspliced and incompletely spliced viral RNA via the cis-acting Rev Response Element (RRE) sequence. Subsequently, Rev oligomerizes cooperatively and interacts with the cellular nuclear export receptor CRM1. In addition to mediating nuclear RNA export, Rev also affects the stability, translation and packaging of Rev-bound viral transcripts. Although it is established that Rev function requires the multimeric assembly of Rev molecules on the RRE, relatively little is known about how many Rev monomers are sufficient to form a trans-activation competent Rev:RRE complex, or which specific activity of Rev is affected by its oligomerization. We here analyzed by functional studies how homooligomer formation of Rev affects the trans-activation capacity of this essential HIV-1 regulatory protein. In a gain-of-function approach, we fused various heterologous dimerization domains to an otherwise oligomerization-defective Rev mutant and were able to demonstrate that oligomerization of Rev is not required per se for the nuclear export of this viral trans-activator. In contrast, however, the formation of Rev oligomers on the RRE is a precondition to trans-activation by directly affecting the nuclear export of Rev-regulated mRNA. Moreover, experimental evidence is provided showing that at least two protein activation domains are required for the formation of trans-activation competent Rev:RRE complexes. The presented data further refine the model of Rev trans-activation by directly demonstrating that Rev oligomerization on the RRE, thereby recruiting at least two protein activation domains, is required for nuclear export of unspliced and incompletely spliced viral RNA

Relationship between psychological factors and performance-based and self-reported disability in chronic low back pain

Cross sectional study, performed in an outpatient university based pain rehabilitation setting. To analyze the relationship between psychological factors (psychosocial distress, depression, self efficacy, self-esteem, fear of movement, pain cognitions and coping reactions) and performance-based and self-reported disability, as measured with a Functional Capacity Evaluation (FCE) and the Roland Morris Disability Questionnaire (RMDQ), in patients with chronic low back pain (CLBP). It has been suggested that a strong relationship exists between psychological factors and disability in patients with CLBP. In former research disability was often measured by self-report and seldom performance-based. Study sample consisted of 92 patients with CLBP admitted for multidisciplinary rehabilitation. Prior to treatment, all patients completed questionnaires to measure psychological factors and self-reported disability, and performed an FCE to measure performance-based disability. Correlation coefficients between psychological variables and FCE and self-reported disability were calculated. Multivariate linear regression analyses were performed with self-reported or performance based disability measures as outcome variables, and psychological measures as predictor variables. Out of 42 relations analyzed, 5 were statistically significant. This concerned one significant correlation between kinesiophobia and a subtest of FCE, and four correlations between psychological factors and RMDQ. No correlation was significant after the Bonferroni correction was applied (P < 0.001). The strength of significant correlations ranged from r = −0.33 to r = 0.25. The multivariate analysis revealed that psychological variables measured in this study could explain 19% of the variance of self-reported disability, with kinesiophobia being the only psychological variable that contributed significantly. The suggested strong relationship between psychological factors and performance-based and self-reported disability could not be confirmed in this study. This may implicate that the relationship between psychological factors and disability in patients with CLBP is not as unambiguous as suggested

SUMO regulates p21Cip1 intracellular distribution and with p21Cip1 facilitates multiprotein complex formation in the nucleolus upon DNA damage

We previously showed that p21Cip1 transits through the nucleolus on its way from the nucleus to the cytoplasm and that DNA damage inhibits this transit and induces the formation of p21Cip1-containing intranucleolar bodies (INoBs). Here, we demonstrate that these INoBs also contain SUMO-1 and UBC9, the E2 SUMO-conjugating enzyme. Furthermore, whereas wild type SUMO-1 localized in INoBs, a SUMO-1 mutant, which is unable to conjugate with proteins, does not, suggesting the presence of SUMOylated proteins at INoBs. Moreover, depletion of the SUMO-conjugating enzyme UBC9 or the sumo hydrolase SENP2 changed p21Cip1 intracellular distribution. In addition to SUMO-1 and p21Cip1, cell cycle regulators and DNA damage checkpoint proteins, including Cdk2, Cyclin E, PCNA, p53 and Mdm2, and PML were also detected in INoBs. Importantly, depletion of UBC9 or p21Cip1 impacted INoB biogenesis and the nucleolar accumulation of the cell cycle regulators and DNA damage checkpoint proteins following DNA damage. The impact of p21Cip1 and SUMO-1 on the accumulation of proteins in INoBs extends also to CRM1, a nuclear exportin that is also important for protein translocation from the cytoplasm to the nucleolus. Thus, SUMO and p21Cip1 regulate the transit of proteins through the nucleolus, and that disruption of nucleolar export by DNA damage induces SUMO and p21Cip1 to act as hub proteins to form a multiprotein complex in the nucleolus

A systematic review on the effectiveness of physical and rehabilitation interventions for chronic non-specific low back pain

Low back pain (LBP) is a common and disabling disorder in western society. The management of LBP comprises a range of different intervention strategies including surgery, drug therapy, and non-medical interventions. The objective of the present study is to determine the effectiveness of physical and rehabilitation interventions (i.e. exercise therapy, back school, transcutaneous electrical nerve stimulation (TENS), low level laser therapy, education, massage, behavioural treatment, traction, multidisciplinary treatment, lumbar supports, and heat/cold therapy) for chronic LBP. The primary search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to 22 December 2008. Existing Cochrane reviews for the individual interventions were screened for studies fulfilling the inclusion criteria. The search strategy outlined by the Cochrane Back Review Groups (CBRG) was followed. The following were included for selection criteria: (1) randomized controlled trials, (2) adult (≥18 years) population with chronic (≥12 weeks) non-specific LBP, and (3) evaluation of at least one of the main clinically relevant outcome measures (pain, functional status, perceived recovery, or return to work). Two reviewers independently selected studies and extracted data on study characteristics, risk of bias, and outcomes at short, intermediate, and long-term follow-up. The GRADE approach was used to determine the quality of evidence. In total 83 randomized controlled trials met the inclusion criteria: exercise therapy (n = 37), back school (n = 5), TENS (n = 6), low level laser therapy (n = 3), behavioural treatment (n = 21), patient education (n = 1), traction (n = 1), and multidisciplinary treatment (n = 6). Compared to usual care, exercise therapy improved post-treatment pain intensity and disability, and long-term function. Behavioural treatment was found to be effective in reducing pain intensity at short-term follow-up compared to no treatment/waiting list controls. Finally, multidisciplinary treatment was found to reduce pain intensity and disability at short-term follow-up compared to no treatment/waiting list controls. Overall, the level of evidence was low. Evidence from randomized controlled trials demonstrates that there is low quality evidence for the effectiveness of exercise therapy compared to usual care, there is low evidence for the effectiveness of behavioural therapy compared to no treatment and there is moderate evidence for the effectiveness of a multidisciplinary treatment compared to no treatment and other active treatments at reducing pain at short-term in the treatment of chronic low back pain. Based on the heterogeneity of the populations, interventions, and comparison groups, we conclude that there are insufficient data to draw firm conclusion on the clinical effect of back schools, low-level laser therapy, patient education, massage, traction, superficial heat/cold, and lumbar supports for chronic LBP

Observation of the Gamma-Ray Binary HESS J0632+057 with the HESS, MAGIC, and VERITAS Telescopes

The results of gamma-ray observations of the binary system HESS J0632 + 057 collected during 450 hr over 15 yr, between 2004 and 2019, are presented. Data taken with the atmospheric Cherenkov telescopes H.E.S.S., MAGIC, and VERITAS at energies above 350 GeV were used together with observations at X-ray energies obtained with Swift-XRT, Chandra, XMM-Newton, NuSTAR, and Suzaku. Some of these observations were accompanied by measurements of the H alpha emission line. A significant detection of the modulation of the very high-energy gamma-ray fluxes with a period of 316.7 +/- 4.4 days is reported, consistent with the period of 317.3 +/- 0.7 days obtained with a refined analysis of X-ray data. The analysis of data from four orbital cycles with dense observational coverage reveals short-timescale variability, with flux-decay timescales of less than 20 days at very high energies. Flux variations observed over a timescale of several years indicate orbit-to-orbit variability. The analysis confirms the previously reported correlation of X-ray and gamma-ray emission from the system at very high significance, but cannot find any correlation of optical H alpha parameters with fluxes at X-ray or gamma-ray energies in simultaneous observations. The key finding is that the emission of HESS J0632 + 057 in the X-ray and gamma-ray energy bands is highly variable on different timescales. The ratio of gamma-ray to X-ray flux shows the equality or even dominance of the gamma-ray energy range. This wealth of new data is interpreted taking into account the insufficient knowledge of the ephemeris of the system, and discussed in the context of results reported on other gamma-ray binary systems