An alternative treatment for degenerative triangular fibrocartilage complex injuries with distal radioulnar joint instability: first experience with 48 patients.

Treatment of ulnar impaction syndrome combined with distal radioulnar joint instability due to irreparable degenerative triangular fibrocartilage complex injuries can be complex. We describe the outcomes of a novel technique for restoring distal radioulnar stability due to ulnar impaction syndrome using a distally based extensor carpi ulnaris tendon strip combined with ulnar shortening osteotomy in 48 patients. Patients were assessed using standardized outcome measurements. The patient-rated wrist/hand evaluation total score improved from 66 (SD 15) at intake to 40 (SD 25) at 3 months, and 28 (SD 23) at 12 months postoperatively (p < 0.001). Wrist extension and flexion improved significantly at 12 months from 53° (SD 11) to 65° (SD 8) (p < 0.001) and from 45° (SD 10) to 56° (SD 12) (p = 0.01), respectively. Adding a distally based longitudinal extensor carpi ulnaris strip to ulnar shortening osteotomy for restoring distal radioulnar joint stability seems to be an effective treatment in patients with irreparable degenerative triangular fibrocartilage complex injuries due to ulnar impaction syndrome. Level of evidence: IV.

Brain-wide electrical dynamics encode individual appetitive social behavior.

The architecture whereby activity across many brain regions integrates to encode individual appetitive social behavior remains unknown. Here we measure electrical activity from eight brain regions as mice engage in a social preference assay. We then use machine learning to discover a network that encodes the extent to which individual mice engage another mouse. This network is organized by theta oscillations leading from prelimbic cortex and amygdala that converge on the ventral tegmental area. Network activity is synchronized with cellular firing, and frequency-specific activation of a circuit within this network increases social behavior. Finally, the network generalizes, on a mouse-by-mouse basis, to encode individual differences in social behavior in healthy animals but fails to encode individual behavior in a 'high confidence' genetic model of autism. Thus, our findings reveal the architecture whereby the brain integrates distributed activity across timescales to encode an appetitive brain state underlying individual differences in social behavior.

Learning the dynamics of cell-cell interactions in confined cell migration.

The migratory dynamics of cells in physiological processes, ranging from wound healing to cancer metastasis, rely on contact-mediated cell-cell interactions. These interactions play a key role in shaping the stochastic trajectories of migrating cells. While data-driven physical formalisms for the stochastic migration dynamics of single cells have been developed, such a framework for the behavioral dynamics of interacting cells still remains elusive. Here, we monitor stochastic cell trajectories in a minimal experimental cell collider: a dumbbell-shaped micropattern on which pairs of cells perform repeated cellular collisions. We observe different characteristic behaviors, including cells reversing, following, and sliding past each other upon collision. Capitalizing on this large experimental dataset of coupled cell trajectories, we infer an interacting stochastic equation of motion that accurately predicts the observed interaction behaviors. Our approach reveals that interacting noncancerous MCF10A cells can be described by repulsion and friction interactions. In contrast, cancerous MDA-MB-231 cells exhibit attraction and antifriction interactions, promoting the predominant relative sliding behavior observed for these cells. Based on these experimentally inferred interactions, we show how this framework may generalize to provide a unifying theoretical description of the diverse cellular interaction behaviors of distinct cell types.

Area and Geometry Dependence of Cell Migration in Asymmetric Two-State Micropatterns.

Microstructured surfaces provide a unique framework to probe cell migration and cytoskeletal dynamics in a standardized manner. Here, we report on the steady-state occupancy probability of cells in asymmetric two-state microstructures that consist of two fibronectin-coated adhesion sites connected by a thin guidance cue. In these dumbbell-like structures, cells transition between the two sites in a repeated and stochastic manner, and average dwell times in the respective microenvironments are determined from the cell trajectories. We study the dynamics of human breast carcinoma cells (MDA-MB-231) in these microstructures as a function of area, shape, and orientation of the adhesion sites. On square adhesive sites with different areas, we find that the occupancy probability ratio is directly proportional to the ratio of corresponding adhesion site areas. These asymmetries are well captured by a simple model for the stochastic nonlinear dynamics of the cells, which reveals generic features of the motion. Sites of equal area but different shape lead to equal occupancy if shapes are isotropic (e.g., squared or circular). In contrast, an asymmetry in the occupancy is induced by anisotropic shapes like rhombi, triangles, or rectangles that enable motion in the direction perpendicular to the transition axis. Analysis of the two-dimensional motion of cells between two rectangles with orthogonal orientation suggests that cellular transition rates depend on the cell polarization induced by anisotropic micropatterns. Taken together, our results illustrate how two-state micropatterns provide a dynamic migration assay with distinct dwell times and relative cell occupancy as readouts, which may be useful to probe cell-microenvironment interactions.

The reliability and measurement error of protractor-based goniometry of the fingers: A systematic review.

STUDY DESIGN: Systematic review PURPOSE OF THE STUDY: The purpose was to review the available literature for evidence on the reliability and measurement error of protractor-based goniometry assessment of the finger joints. METHODS: Databases were searched for articles with key words "hand," "goniometry," "reliability," and derivatives of these terms. Assessment of the methodological quality was carried out using the Consensus-Based Standards for the Selection of Health Measurement Instruments checklist. Two independent reviewers performed a best evidence synthesis based on criteria proposed by Terwee et al (2007). RESULTS: Fifteen articles were included. One article was of fair methodological quality, and 14 articles were of poor methodological quality. An acceptable level for reliability (intraclass correlation coefficient > 0.70 or Pearson's correlation > 0.80) was reported in 1 study of fair methodological quality and in 8 articles of low methodological quality. Because the minimal important change was not calculated in the articles, there was an unknown level of evidence for the measurement error. DISCUSSION: Further research with adequate sample sizes should focus on reference outcomes for different patient groups. For valid therapy evaluation, it is important to know if the change in range of motion reflects a real change of the patient or if this is due to the measurement error of the goniometer. Until now, there is insufficient evidence to establish this cut-off point (the smallest detectable change). CONCLUSION: Following the Consensus-Based Standards for the Selection of Health Measurement Instruments criteria, there was limited level of evidence for an acceptable reliability in the dorsal measurement method and unknown level of evidence for the measurement error. LEVEL OF EVIDENCE: 2a.

Reproducibility of Ultrasonographic Measurements of the Ulnar Nerve at the Cubital Tunnel.

The cross-sectional area (CSA) of the ulnar nerve is thought to be indicative of ulnar nerve entrapment. The purpose of the study was to determine reproducibility of ultrasonographic measurements of CSA of the ulnar nerve at the cubital tunnel in healthy adults. Two sonographers tested 69 participants using a standardized protocol. The inter-rater reliability intra-class correlation coefficient was 0.63, and the intra-rater reliability intra-class correlation coefficient was 0.85 for sonographer 1 and 0.88 for sonographer 2. The smallest detectable changes were 2.47 and 2.63 mm2 (25% and 26% of the mean CSA). The mean difference and 95% limits of agreement for sonographers 1 and 2 were -0.13 (-2.56 to 2.29) and -0.38 (-2.93 to 2.18). Based on the fair to good inter-rater reliability, the excellent intra-rater reliability and the clinical applicable intra-rater agreement, ultrasonography seems to be a valuable tool with which to assess the CSA of the ulnar nerve for diagnostic and evaluative purposes.

Reliability and agreement of ultrasonographic thickness measurements of the common lateral extensors of the elbow.

In individuals with lateral elbow tendinopathy, the thickness of the common lateral extensors tendon can be evaluated by musculoskeletal ultrasonography (MSU) for diagnostic and evaluative purposes. The reproducibility of these thickness measurements should be established before integrating it into daily practice. A test-retest design was used to determine the reproducibility of these measurements in the longitudinal and transverse planes. Seventy-three healthy participants were measured two times by two raters. Intra-class correlation coefficient values for inter-rater reliability for the longitudinal and transverse planes were 0.67 and 0.49. Intra-class correlation coefficient values for intra-rater reliability varied between 0.73 and 0.92. The smallest detectable change ranged from 0.50 to 0.78 mm and comprised 9.8%-16.3% of the mean thickness. MSU thickness measurement of the common lateral extensors tendon of the elbow has fair to excellent intra- and inter-rater reliability. Additionally, agreement is acceptable, which makes MSU a valuable tool for the evaluation of tendon thickness over time.

4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.

Identification of non-furan containing A2A antagonists using database mining and molecular similarity approaches.

Database searching led to the identification of potent A(2A) antagonists which do not contain the privileged furan moiety and which show selectivity over A(1) receptors. Simple substructure searching on a proprietary database identified compounds with activities in the low nM range. A targeted approach to the identification of non-furan containing compounds resulted in the identification of two novel series, with potency, selectivity and directional SAR from screening 113 compounds.

4-Amino derivatives of the Hsp90 inhibitor CCT018159.

Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.

Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures.

Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated enzyme. Anti-tumour cell potency and mechanism of action data is also described for the most potent compounds. These data should enable the design of more potent Hsp90 inhibitors.