The Mini-BESTest - a clinically reproducible tool for balance evaluations in mild to moderate Parkinson’s disease?

Background

The Mini-BESTest is a clinical balance test that has shown a high sensitivity in detecting balance impairments in elderly with Parkinson's disease (PD). However, its reproducibility between different raters and between test occasions has yet to be investigated in a clinical context. Moreover, no one has investigated the reproducibility of the Mini-BESTest's subcomponents (i.e. anticipatory postural adjustments; postural responses; sensory orientation and dynamic gait).We aimed to investigate the inter-rater and test-retest reproducibility (reliability as well as agreement) of the Mini-BESTest, as well as its subcomponents, in elderly with mild to moderate PD, performed under conditions assimilating clinical practice.

Method

This was an observational measurement study with a test-retest design.Twenty-seven individuals with idiopathic PD (66 - 80 years, mean age: 73; Hoehn & Yahr: 2-3; 1-15 years since diagnosis) were included. Two test administrators, having different experiences with the Mini-BESTest, administered the test individually, in separate rooms in a hospital setting. For the test-retest assessment, all participants returned 7 days after the first test session to perform the Mini-BESTest under similar conditions. Intra-class correlation coefficients (ICC_2.1), standard error of measurement (SEM_agreement), and smallest real difference (SRD) were analyzed.

Results

The Mini-BESTest showed good reliability for both inter-rater and test-retest reproducibility (ICC = 0.72 and 0.80). Regarding agreement, the measurement error (SRD) was found to be 4.1 points (accounting for 15% of the maximal total score) for inter-rater reproducibility and 3.4 points (12% of the maximal total score) for test-retest reproducibility. The investigation of the Mini-BESTest's subcomponents showed a similar pattern for both inter-rater and test-retest reproducibility, where postural responses had the largest proportional measurement error, and sensory orientation showed the highest agreement.

Conclusions

Our findings indicate that the Mini-BESTest is able to distinguish between individuals with mild to moderate PD; however, when used in clinical balance assessments, the large measurement error needs to be accounted for.

     

A Revised Time Tree of the Asterids: Establishing a Temporal Framework For Evolutionary Studies of the Coffee Family (Rubiaceae)

Divergence time analyses in the coffee family (Rubiaceae) have all relied on the same Gentianales crown group age estimate, reported by an earlier analysis of the asterids, for defining the upper age bound of the root node in their analyses. However, not only did the asterid analysis suffer from several analytical shortcomings, but the estimate itself has been used in highly inconsistent ways in these Rubiaceae analyses. Based on the original data, we here reanalyze the divergence times of the asterids using relaxed-clock models and 14 fossil-based minimum age constraints. We also expand the data set to include an additional 67 taxa from Rubiaceae sampled across all three subfamilies recognized in the family. Three analyses are conducted: a separate analysis of the asterids, which completely mirrors the original asterid analysis in terms of taxon sample and data; a separate analysis of the Gentianales, where the result from the first analysis is used for defining a secondary root calibration point; and a combined analysis where all taxa are analyzed simultaneously. Results are presented in the form of a time-calibrated phylogeny, and age estimates for asterid groups, Gentianales, and major groups of Rubiaceae are compared and discussed in relation to previously published estimates. Our updated age estimates for major groups of Rubiaceae provide a significant step forward towards the long term goal of establishing a robust temporal framework for the divergence of this biologically diverse and fascinating group of plants.     

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

The expression of the tissue plasminogen activator (t-PA) gene appears to be under epigenetic control and can be affected by histone deacetylation inhibition. The study aimed to test if histone deacetalyase inhibitor treatment lead to increased t-PA release or reduced exhaustion in t-PA release in response to stimulation, as well as change in plasminogen activator inhibitor-1 (PAI-1) in subjects with coronary disease. In this clinical study, 16 post-myocardial infarction subjects, the perfused forearm model was used with isoprenaline provocation during 20 minutes, to stimulate local t-PA release. Each subject was measured twice on the same day (repeated stimuli sequences) as well as on two different occasions, without treatment and after four weeks of treatment with valproic acid (500 mg, twice daily). Net forearm release for t-PA in response to isoprenaline at minutes 1.5, 3, 6, 9, 12, 15 and 18 was measured, allowing assessment of cumulative t-PA release. There was a reduction in the exhaustion of cumulative t-PA release during repeated and prolonged stimulation with valproic acid treatment compared to non-treatment. Plasma PAI-1 antigen was decreased following treatment compared to non-treatment (18.4 ± 10.0 vs. 11.0 ± 7.1 nanograms/ml respectively, mean with 95% confidence interval). These findings demonstrate that histone deacetylation inhibition increases the capacity for endogenous t-PA release in subjects with vascular disease. Furthermore, the fibrinolytic balance is favored with suppressed PAI-1 levels. More studies are needed to establish the clinical relevance of these findings.

Trial registration

EU Clinical Trials Register 2012-004950-27     

Time Trends in Incidence and Mortality of Acute Myocardial Infarction,and All-Cause Mortality following a Cardiovascular Prevention Program in Sweden

Background

In 1988, a cardiovascular prevention program which combined an individual and a population-based strategy was launched within primary health-care in Sollentuna, a municipality in Stockholm County. The aim of this study was to investigate time trends in the incidence of and mortality from acute myocardial infarction and all-cause mortality in Sollentuna compared with the rest of Stockholm County during a period of two decades following the implementation of a cardiovascular prevention program.

Materials and Methods

The average population in Sollentuna was 56,589 (49% men) and in Stockholm County (Sollentuna included) 1,795,504 (49% men) during the study period of 1987–2010. Cases of hospitalized acute myocardial infarction and death were obtained for the population of Sollentuna and the rest of Stockholm County using national registries of hospital discharges and deaths. Acute myocardial infarction incidence and mortality were estimated using the average population of Sollentuna and Stockholm in 1987–2010.

Results

During the observation period, the incidence of acute myocardial infarction decreased more in Sollentuna compared with the rest of Stockholm County in women (-22% vs. -7%; for difference in slope <0.05). There was a trend towards a greater decline in Sollentuna compared to the rest of Stockholm County in the incidence of acute myocardial infarction (in men), acute myocardial mortality, and all-cause mortality but the differences were not significant.

Conclusion

During a period of steep decline in acute myocardial infarction incidence and mortality in Stockholm County the municipality of Sollentuna showed a stronger trend in women possibly compatible with favorable influence of a cardiovascular prevention program.

Trial Registration

ClinicalTrials.gov NCT02212145     

Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents

Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn²⁺ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn²⁺ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.     

Proteomic and functional analysis of the mitotic Drosophila centrosome

Regulation of centrosome structure, duplication and segregation is integrated into cellular pathways that control cell cycle progression and growth. As part of these pathways, numerous proteins with well‐established non‐centrosomal localization and function associate with the centrosome to fulfill regulatory functions. In turn, classical centrosomal components take up functional and structural roles as part of other cellular organelles and compartments. Thus, although a comprehensive inventory of centrosome components is missing, emerging evidence indicates that its molecular composition reflects the complexity of its functions. We analysed the Drosophila embryonic centrosomal proteome using immunoisolation in combination with mass spectrometry. The 251 identified components were functionally characterized by RNA interference. Among those, a core group of 11 proteins was critical for centrosome structure maintenance. Depletion of any of these proteins in Drosophila SL2 cells resulted in centrosome disintegration, revealing a molecular dependency of centrosome structure on components of the protein translation machinery, actin‐ and RNA‐binding proteins. In total, we assigned novel centrosome‐related functions to 24 proteins and confirmed 13 of these in human cells.     

Design and synthesis of macrocyclic indoles targeting blood coagulation cascade Factor XIa

The synthesis of a series of novel macrocyclic compounds designed to target blood coagulation Factor XIa is described. The compounds were evaluated for their inhibition of a small set of serine proteases. Several compounds displayed modest activity and good selectivity for Factor XIa. Within the series, a promising lead structure for developing novel macrocyclic inhibitors of thrombin was identified.     

Structural basis of successive adenosine modifications by the conserved ribosomal methyltransferase KsgA

Biogenesis of ribosomal subunits involves enzymatic modifications of rRNA that fine-tune functionally important regions. The universally conserved prokaryotic dimethyltransferase KsgA sequentially modifies two universally conserved adenosine residues in helix 45 of the small ribosomal subunit rRNA, which is in proximity of the decoding site. Here we present the cryo-EM structure of Escherichia coli KsgA bound to an E. coli 30S at a resolution of 3.1 Å. The high-resolution structure reveals how KsgA recognizes immature rRNA and binds helix 45 in a conformation where one of the substrate nucleotides is flipped-out into the active site. We suggest that successive processing of two adjacent nucleotides involves base-flipping of the rRNA, which allows modification of the second substrate nucleotide without dissociation of the enzyme. Since KsgA is homologous to the essential eukaryotic methyltransferase Dim1 involved in 40S maturation, these results have also implications for understanding eukaryotic ribosome maturation.     

CONSTANCY OF RELATIVE VOLUMES OF ZONES IN SHOOT APICAL MERISTEMS IN CACTACEAE: IMPLICATIONS CONCERNING MERISTEM SIZE,SHAPE, AND METABOLISM

The volumes and dimensions of shoot apical meristem zones were determined for 21 species in 10 genera of the Cactaceae. If the volumes of the central-mother-cell zone (CMCZ), the peripheral zone (PZ), and the pith-rib meristem (PRM) are expressed as percentages of the total volume of the corpus, then they are remarkably constant (CMCZ = 11.1% of the volume of the corpus, PZ = 61.2% and PRM = 27.1%) regardless of the relative size of the apical meristems. The relative volume of the tunica decreases, however, as the whole apex increases. The zones have variable shapes, and whereas the PZ and PRM are always trapezoidal in longitudinal section, in apices with large volumes, these zones have a flatter, more flaring shape than they have in smaller apices. Thus large apices are flatter and less hemispherical than are small apices. The CMCZ, however, maintains a constant shape and is always relatively hemispherical regardless of its volume. A hypothesis that relates all of these shape and volume relationships as an integrated growth sequence is proposed.