Design of a series visco-elastic actuator for multi-purpose rehabilitation haptic device

<p>Abstract</p> <p>Background</p> <p>Variable structure parallel mechanisms, actuated with low-cost motors with serially added elasticity (series elastic actuator - SEA), has considerable potential in rehabilitation robotics. However, reflected masses of a SEA and variable structure parallel mechanism linked with a compliant actuator result in a potentially unstable coupled mechanical oscillator, which has not been addressed in previous studies.</p> <p>Methods</p> <p>The aim of this paper was to investigate through simulation, experimentation and theoretical analysis the necessary conditions that guarantee stability and passivity of a haptic device (based on a variable structure parallel mechanism driven by SEA actuators) when in contact with a human. We have analyzed an equivalent mechanical system where a dissipative element, a mechanical damper was placed in parallel to a spring in SEA.</p> <p>Results</p> <p>The theoretical analysis yielded necessary conditions relating the damping coefficient, spring stiffness, both reflected masses, controller's gain and desired virtual impedance that needs to be fulfilled in order to obtain stable and passive behavior of the device when in contact with a human. The validity of the derived passivity conditions were confirmed in simulations and experimentally.</p> <p>Conclusions</p> <p>These results show that by properly designing variable structure parallel mechanisms actuated with SEA, versatile and affordable rehabilitation robotic devices can be conceived, which may facilitate their wide spread use in clinical and home environments.</p

Comparison between clinical grading and navigation data of knee laxity in ACL-deficient knees

<p>Abstract</p> <p>Background</p> <p>The latest version of the navigation system for anterior cruciate ligament (ACL) reconstruction has the supplementary ability to assess knee stability before and after ACL reconstruction. In this study, we compared navigation data between clinical grades in ACL-deficient knees and also analyzed correlation between clinical grading and navigation data.</p> <p>Methods</p> <p>150 ACL deficient knees that received primary ACL reconstruction using an image-free navigation system were included. For clinical evaluation, the Lachman, anterior drawer, and pivot shift tests were performed under general anesthesia and were graded by an examiner. For the assessment of knee stability using the navigation system, manual tests were performed again before ACL reconstruction. Navigation data were recorded as anteroposterior (AP) displacement of the tibia for the Lachman and anterior drawer tests, and both AP displacement and tibial rotation for the pivot shift test.</p> <p>Results</p> <p>Navigation data of each clinical grade were as follows; Lachman test grade 1+: 10.0 mm, grade 2+: 13.2 ± 3.1 mm, grade 3+: 14.5 ± 3.3 mm, anterior drawer test grade 1+: 6.8 ± 1.4 mm, grade 2+: 7.4 ± 1.8 mm, grade 3+: 9.1 ± 2.3 mm, pivot shift test grade 1+: 3.9 ± 1.8 mm/21.5° ± 7.8°, grade 2+: 4.8 ± 2.1 mm/21.8° ± 7.1°, and grade 3+: 6.0 ± 3.2 mm/21.1° ± 7.1°. There were positive correlations between clinical grading and AP displacement in the Lachman, and anterior drawer tests. Although positive correlations between clinical grading and AP displacement in pivot shift test were found, there were no correlations between clinical grading and tibial rotation in pivot shift test.</p> <p>Conclusions</p> <p>In response to AP force, the navigation system can provide the surgeon with correct objective data for knee laxity in ACL deficient knees. During the pivot shift test, physicians may grade according to the displacement of the tibia, rather than rotation.</p

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

We analysed the expression of microsatellite instability, p53, p21, vascular endothelial growth factor and thymidylate synthase (TS) in pretreatment biopsy specimens from 57 locally advanced rectal cancers. The aim of the study was to correlate the expression of these markers with pathological response. Nineteen patients were treated with preoperative concomitant radiotherapy (RT) and fluorouracil/oxaliplatin-based chemotherapy (RCT), while 38 had RT alone. Pathological complete remission (pCR) and microfoci residual tumour (micR) occurred more frequently in patients treated with RCT (P=0.002) and in N0 tumours (P=0.004). Among patients treated with RCT, high TS levels were associated with a higher response rate (pCR+micR; P=0.015). No such correlation was found in the RT group. The other molecular factors were of no predictive value. Multivariate analysis confirmed a significant interaction between nodal status and the probability of achieving a pathological response (P=0.023) and between TS expression and treatment, indicating that a high TS level is predictive of a higher pathological response in the RCT subset (P=0.007). This study shows that lymph node status is the most important predictive factor of tumour response to preoperative treatment. Thymidylate synthase expression assessed immunohistochemically from pretreatment tumour biopsies may be a useful predictive marker of rectal tumour response to preoperative RCT

Small molecule sensitization to TRAIL is mediated via nuclear localization, phosphorylation and inhibition of chaperone activity of Hsp27

10.1038/cddis.2013.413Cell Death and Disease410

Endotoxaemia in Haemodialysis: A Novel Factor in Erythropoetin Resistance?

Background/Objectives Translocated endotoxin derived from intestinal bacteria is a driver of systemic inflammation and oxidative stress. Severe endotoxaemia is an underappreciated, but characteristic finding in haemodialysis (HD) patients, and appears to be driven by acute repetitive dialysis induced circulatory stress. Resistance to erythropoietin (EPO) has been identified as a predictor of mortality risk, and associated with inflammation and malnutrition. This study aims to explore the potential link between previously unrecognised endotoxaemia and EPO Resistance Index (ERI) in HD patients. Methodology/Principal Findings 50 established HD patients were studied at a routine dialysis session. Data collection included weight, BMI, ultrafiltration volume, weekly EPO dose, and blood sampling pre and post HD. ERI was calculated as ratio of total weekly EPO dose to body weight (U/kg) to haemoglobin level (g/dL). Mean haemoglobin (Hb) was 11.3±1.3 g/dL with a median EPO dose of 10,000 [IQR 7,500–20,000] u/wk and ERI of 13.7 [IQR 6.9–23.3] ((U/Kg)/(g/dL)). Mean pre-HD serum ET levels were significantly elevated at 0.69±0.30 EU/ml. Natural logarithm (Ln) of ERI correlated to predialysis ET levels (r = 0.324, p = 0.03) with a trend towards association with hsCRP (r = 0.280, p = 0.07). Ln ERI correlated with ultrafiltration volume, a driver of circulatory stress (r = 0.295, p = 0.046), previously identified to be associated with increased intradialytic endotoxin translocation. Both serum ET and ultrafiltration volume corrected for body weight were independently associated with Ln ERI in multivariable analysis. Conclusions This study suggests that endotoxaemia is a significant factor in setting levels of EPO requirement. It raises the possibility that elevated EPO doses may in part merely be identifying patients subjected to significant circulatory stress and suffering the myriad of negative biological consequences arising from sustained systemic exposure to endotoxin

Acute neurological signs as the predominant clinical manifestation in four dogs with Angiostrongylus vasorum infections in Denmark

Four dogs with acute neurological signs caused by haemorrhages in the central nervous system were diagnosed with Angiostrongylus vasorum infection as the underlying aetiology. Two dogs presented with brain lesions, one dog with spinal cord lesions and one with lesions in both the brain and spinal cord. Only one dog presented with concurrent signs of classical pulmonary angiostrongylosis (respiratory distress, cough), and only two dogs displayed overt clinical signs of haemorrhages. Results of coagulation assays were inconsistent. Neurological signs reflected the site of pathology and included seizures, various cranial nerve deficits, vestibular signs, proprioceptive deficits, ataxia and paraplegia. One dog died and three were euthanised due to lack of improvement despite medical treatment. This emphasises canine angiostrongylosis as a potential cause of fatal lesions of the central nervous system and the importance of including A. vasorum as a differential diagnosis in young dogs with acute neurological signs in Denmark

Recombinant Mouse PAP Has pH-Dependent Ectonucleotidase Activity and Acts through A1-Adenosine Receptors to Mediate Antinociception

Prostatic acid phosphatase (PAP) is expressed in nociceptive neurons and functions as an ectonucleotidase. When injected intraspinally, the secretory isoforms of human and bovine PAP protein have potent and long-lasting antinociceptive effects that are dependent on A1-adenosine receptor (A1R) activation. In this study, we purified the secretory isoform of mouse (m)PAP using the baculovirus expression system to determine if recombinant mPAP also had antinociceptive properties. We found that mPAP dephosphorylated AMP, and to a much lesser extent, ADP at neutral pH (pH 7.0). In contrast, mPAP dephosphorylated all purine nucleotides (AMP, ADP, ATP) at an acidic pH (pH 5.6). The transmembrane isoform of mPAP had similar pH-dependent ectonucleotidase activity. A single intraspinal injection of mPAP protein had long-lasting (three day) antinociceptive properties, including antihyperalgesic and antiallodynic effects in the Complete Freund's Adjuvant (CFA) inflammatory pain model. These antinociceptive effects were transiently blocked by the A1R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (CPX), suggesting mPAP dephosphorylates nucleotides to adenosine to mediate antinociception just like human and bovine PAP. Our studies indicate that PAP has species-conserved antinociceptive effects and has pH-dependent ectonucleotidase activity. The ability to metabolize nucleotides in a pH-dependent manner could be relevant to conditions like inflammation where tissue acidosis and nucleotide release occur. Lastly, our studies demonstrate that recombinant PAP protein can be used to treat chronic pain in animal models

Evolution of Alternative Splicing Regulation: Changes in Predicted Exonic Splicing Regulators Are Not Associated with Changes in Alternative Splicing Levels in Primates

Alternative splicing is tightly regulated in a spatio-temporal and quantitative manner. This regulation is achieved by a complex interplay between spliceosomal (trans) factors that bind to different sequence (cis) elements. cis-elements reside in both introns and exons and may either enhance or silence splicing. Differential combinations of cis-elements allows for a huge diversity of overall splicing signals, together comprising a complex ‘splicing code’. Many cis-elements have been identified, and their effects on exon inclusion levels demonstrated in reporter systems. However, the impact of interspecific differences in these elements on the evolution of alternative splicing levels has not yet been investigated at genomic level. Here we study the effect of interspecific differences in predicted exonic splicing regulators (ESRs) on exon inclusion levels in human and chimpanzee. For this purpose, we compiled and studied comprehensive datasets of predicted ESRs, identified by several computational and experimental approaches, as well as microarray data for changes in alternative splicing levels between human and chimpanzee. Surprisingly, we found no association between changes in predicted ESRs and changes in alternative splicing levels. This observation holds across different ESR exon positions, exon lengths, and 5′ splice site strengths. We suggest that this lack of association is mainly due to the great importance of context for ESR functionality: many ESR-like motifs in primates may have little or no effect on splicing, and thus interspecific changes at short-time scales may primarily occur in these effectively neutral ESRs. These results underscore the difficulties of using current computational ESR prediction algorithms to identify truly functionally important motifs, and provide a cautionary tale for studies of the effect of SNPs on splicing in human disease

Global assessment of genomic variation in cattle by genome resequencing and high-throughput genotyping

<p>Abstract</p> <p>Background</p> <p>Integration of genomic variation with phenotypic information is an effective approach for uncovering genotype-phenotype associations. This requires an accurate identification of the different types of variation in individual genomes.</p> <p>Results</p> <p>We report the integration of the whole genome sequence of a single Holstein Friesian bull with data from single nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) array technologies to determine a comprehensive spectrum of genomic variation. The performance of resequencing SNP detection was assessed by combining SNPs that were identified to be either in identity by descent (IBD) or in copy number variation (CNV) with results from SNP array genotyping. Coding insertions and deletions (indels) were found to be enriched for size in multiples of 3 and were located near the N- and C-termini of proteins. For larger indels, a combination of split-read and read-pair approaches proved to be complementary in finding different signatures. CNVs were identified on the basis of the depth of sequenced reads, and by using SNP and CGH arrays.</p> <p>Conclusions</p> <p>Our results provide high resolution mapping of diverse classes of genomic variation in an individual bovine genome and demonstrate that structural variation surpasses sequence variation as the main component of genomic variability. Better accuracy of SNP detection was achieved with little loss of sensitivity when algorithms that implemented mapping quality were used. IBD regions were found to be instrumental for calculating resequencing SNP accuracy, while SNP detection within CNVs tended to be less reliable. CNV discovery was affected dramatically by platform resolution and coverage biases. The combined data for this study showed that at a moderate level of sequencing coverage, an ensemble of platforms and tools can be applied together to maximize the accurate detection of sequence and structural variants.</p