Classification of patients with knee osteoarthritis in clinical phenotypes: data from the osteoarthritis initiative

<div><p>Objectives</p><p>The existence of phenotypes has been hypothesized to explain the large heterogeneity characterizing the knee osteoarthritis. In a previous systematic review of the literature, six main phenotypes were identified: Minimal Joint Disease (MJD), Malaligned Biomechanical (MB), Chronic Pain (CP), Inflammatory (I), Metabolic Syndrome (MS) and Bone and Cartilage Metabolism (BCM). The purpose of this study was to classify a sample of individuals with knee osteoarthritis (KOA) into pre-defined groups characterized by specific variables that can be linked to different disease mechanisms, and compare these phenotypes for demographic and health outcomes.</p><p>Methods</p><p>599 patients were selected from the OAI database FNIH at 24 months’ time to conduct the study. For each phenotype, cut offs of key variables were identified matching the results from previous studies in the field and the data available for the sample. The selection process consisted of 3 steps. At the end of each step, the subjects classified were excluded from the further classification stages. Patients meeting the criteria for more than one phenotype were classified separately into a ‘complex KOA’ group.</p><p>Results</p><p>Phenotype allocation (including complex KOA) was successful for 84% of cases with an overlap of 20%. Disease duration was shorter in the MJD while the CP phenotype included a larger number of Women (81%). A significant effect of phenotypes on WOMAC pain (F = 16.736 p <0.001) and WOMAC physical function (F = 14.676, p < 0.001) was identified after controlling for disease duration.</p><p>Conclusion</p><p>This study signifies the feasibility of a classification of KOA subjects in distinct phenotypes based on subgroup-specific characteristics.</p></div

Minimal regulation of platelet activity by PECAM-1

PECAM-1 is a member of the superfamily of immunoglobulins (Ig) and is expressed on platelets at moderate level. PECAM-1 has been reported to have contrasting effects on platelet activation by the collagen receptor GPVI and the integrin, αIIbβ3, even though both receptors signal through Src-kinase regulation of PLCγ2. The present study compares the role of PECAM-1 on platelet activation by these two receptors and by the lectin receptor, CLEC-2, which also signals via PLCγ2. Studies using PECAM-1 knockout-mice and cross-linking of PECAM-1 using specific antibodies demonstrated a minor inhibitory role on platelet responses to the above three receptors and also under some conditions to the G-protein agonist thrombin. The degree of inhibition was considerably less than that produced by PGI2, which elevates cAMP. There was no significant difference in thrombus formation on collagen in PECAM-1-/- platelets relative to litter-matched controls. The very weak inhibitory effect of PECAM-1 on platelet activation relative to that of PGI2 indicate that the Ig-receptor is not a major regulator of platelet activation. PECAM-1 has been reported to have contrasting effects on platelet activation. The present study demonstrates a very mild or negligible effect on platelet activation in response to stimulation by a variety of agonists, thereby questioning the physiological role of the immunoglobulin receptor as a major regulator of platelet activation

Akt-Induced Phosphorylation of N-CoR at Serine 1450 Contributes to Its Misfolded Conformational Dependent Loss (MCDL) in Acute Myeloid Leukemia of the M5 Subtype

10.1371/journal.pone.0070891PLoS ONE88-POLN

Automated systems to identify relevant documents in product risk management

<p>Abstract</p> <p>Background</p> <p>Product risk management involves critical assessment of the risks and benefits of health products circulating in the market. One of the important sources of safety information is the primary literature, especially for newer products which regulatory authorities have relatively little experience with. Although the primary literature provides vast and diverse information, only a small proportion of which is useful for product risk assessment work. Hence, the aim of this study is to explore the possibility of using text mining to automate the identification of useful articles, which will reduce the time taken for literature search and hence improving work efficiency. In this study, term-frequency inverse document-frequency values were computed for predictors extracted from the titles and abstracts of articles related to three tumour necrosis factors-alpha blockers. A general automated system was developed using only general predictors and was tested for its generalizability using articles related to four other drug classes. Several specific automated systems were developed using both general and specific predictors and training sets of different sizes in order to determine the minimum number of articles required for developing such systems.</p> <p>Results</p> <p>The general automated system had an area under the curve value of 0.731 and was able to rank 34.6% and 46.2% of the total number of 'useful' articles among the first 10% and 20% of the articles presented to the evaluators when tested on the generalizability set. However, its use may be limited by the subjective definition of useful articles. For the specific automated system, it was found that only 20 articles were required to develop a specific automated system with a prediction performance (AUC 0.748) that was better than that of general automated system.</p> <p>Conclusions</p> <p>Specific automated systems can be developed rapidly and avoid problems caused by subjective definition of useful articles. Thus the efficiency of product risk management can be improved with the use of specific automated systems.</p

Impact of COVID-19 Nonpharmaceutical Interventions on Pneumococcal Carriage Prevalence and Density in Vietnam.

Nonpharmaceutical interventions (NPIs) implemented to contain SARS-CoV-2 have decreased invasive pneumococcal disease. Previous studies have proposed the decline is due to reduced pneumococcal transmission or suppression of respiratory viruses, but the mechanism remains unclear. We undertook a secondary analysis of data collected from a clinical trial to evaluate the impact of NPIs on pneumococcal carriage and density, drivers of transmission and disease, during the COVID-19 pandemic in Ho Chi Minh City, Vietnam. Nasopharyngeal samples from children aged 24 months were assessed in three periods - one pre-COVID-19 period (n = 1,537) and two periods where NPIs were implemented with increasing stringency (NPI period 1 [NPI-1, n = 307], and NPI period 2 [NPI-2, n = 262]). Pneumococci were quantified using lytA quantitative PCR and serotyped by DNA microarray. Overall, capsular, and nonencapsulated pneumococcal carriage and density were assessed in each NPI period compared with the pre-COVID-19 period using unadjusted log-binomial and linear regression. Pneumococcal carriage was generally stable after the implementation of NPIs. In contrast, overall pneumococcal carriage density decreased by 0.44 log10 genome equivalents/mL (95% confidence interval [CI]: 0.19 to 0.69) in NPI-1 and by 0.84 log10 genome equivalents/mL (95% CI: 0.55 to 1.13) in NPI-2 compared with the pre-COVID-19 period. Reductions in overall pneumococcal density were driven by reductions in capsular pneumococci, with no corresponding reduction in nonencapsulated density. As higher pneumococcal density is a risk factor for disease, the decline in density provides a plausible explanation for the reductions in invasive pneumococcal disease that have been observed in many countries in the absence of a substantive reduction in pneumococcal carriage. IMPORTANCE The pneumococcus is a major cause of mortality globally. Implementation of NPIs during the COVID-19 pandemic led to reductions in invasive pneumococcal disease in many countries. However, no studies have conducted a fully quantitative assessment on the impact of NPIs on pneumococcal carriage density, which could explain this reduction. We evaluated the impact of COVID-19 NPIs on pneumococcal carriage prevalence and density in 2,106 children aged 24 months in Vietnam and found pneumococcal carriage density decreased up to 91.5% after NPI introduction compared with the pre-COVID-19 period, which was mainly attributed to capsular pneumococci. Only a minor effect on carriage prevalence was observed. As respiratory viruses are known to increase pneumococcal carriage density, transmission, and disease, this work suggests that interventions targeting respiratory viruses may have the added benefit of reducing invasive pneumococcal disease and explain the reductions observed following NPI implementation

Functional Neuromuscular Junctions Formed by Embryonic Stem Cell-Derived Motor Neurons

A key objective of stem cell biology is to create physiologically relevant cells suitable for modeling disease pathologies in vitro. Much progress towards this goal has been made in the area of motor neuron (MN) disease through the development of methods to direct spinal MN formation from both embryonic and induced pluripotent stem cells. Previous studies have characterized these neurons with respect to their molecular and intrinsic functional properties. However, the synaptic activity of stem cell-derived MNs remains less well defined. In this study, we report the development of low-density co-culture conditions that encourage the formation of active neuromuscular synapses between stem cell-derived MNs and muscle cells in vitro. Fluorescence microscopy reveals the expression of numerous synaptic proteins at these contacts, while dual patch clamp recording detects both spontaneous and multi-quantal evoked synaptic responses similar to those observed in vivo. Together, these findings demonstrate that stem cell-derived MNs innervate muscle cells in a functionally relevant manner. This dual recording approach further offers a sensitive and quantitative assay platform to probe disorders of synaptic dysfunction associated with MN disease

Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis

Effects of a robot-assisted training of grasp and pronation/supination in chronic stroke: a pilot study

<p>Abstract</p> <p>Background</p> <p>Rehabilitation of hand function is challenging, and only few studies have investigated robot-assisted rehabilitation focusing on distal joints of the upper limb. This paper investigates the feasibility of using the <it>HapticKnob</it>, a table-top end-effector device, for robot-assisted rehabilitation of grasping and forearm pronation/supination, two important functions for activities of daily living involving the hand, and which are often impaired in chronic stroke patients. It evaluates the effectiveness of this device for improving hand function and the transfer of improvement to arm function.</p> <p>Methods</p> <p>A single group of fifteen chronic stroke patients with impaired arm and hand functions (Fugl-Meyer motor assessment scale (FM) 10-45/66) participated in a 6-week 3-hours/week rehabilitation program with the <it>HapticKnob</it>. Outcome measures consisted primarily of the FM and Motricity Index (MI) and their respective subsections related to distal and proximal arm function, and were assessed at the beginning, end of treatment and in a 6-weeks follow-up.</p> <p>Results</p> <p>Thirteen subjects successfully completed robot-assisted therapy, with significantly improved hand and arm motor functions, demonstrated by an average 3.00 points increase on the FM and 4.55 on the MI at the completion of the therapy (4.85 FM and 6.84 MI six weeks post-therapy). Improvements were observed both in distal and proximal components of the clinical scales at the completion of the study (2.00 FM wrist/hand, 2.55 FM shoulder/elbow, 2.23 MI hand and 4.23 MI shoulder/elbow). In addition, improvements in hand function were observed, as measured by the Motor Assessment Scale, grip force, and a decrease in arm muscle spasticity. These results were confirmed by motion data collected by the robot.</p> <p>Conclusions</p> <p>The results of this study show the feasibility of this robot-assisted therapy with patients presenting a large range of impairment levels. A significant homogeneous improvement in both hand and arm function was observed, which was maintained 6 weeks after end of the therapy.</p

How useful are systematic reviews for informing palliative care practice? Survey of 25 Cochrane systematic reviews

<p>Abstract</p> <p>Background</p> <p>In contemporary medical research, randomised controlled trials are seen as the gold standard for establishing treatment effects where it is ethical and practical to conduct them. In palliative care such trials are often impractical, unethical, or extremely difficult, with multiple methodological problems. We review the utility of Cochrane reviews in informing palliative care practice.</p> <p>Methods</p> <p>Published reviews in palliative care registered with the Cochrane Pain, Palliative and Supportive Care Group as of December 2007 were obtained from the Cochrane Database of Systematic Reviews, issue 1, 2008. We reviewed the quality and quantity of primary studies available for each review, assessed the quality of the review process, and judged the strength of the evidence presented. There was no prior intention to perform any statistical analyses.</p> <p>Results</p> <p>25 published systematic reviews were identified. Numbers of included trials ranged from none to 54. Within each review, included trials were heterogeneous with respect to patients, interventions, and outcomes, and the number of patients contributing to any single analysis was generally much lower than the total included in the review. A variety of tools were used to assess trial quality; seven reviews did not use this information to exclude low quality studies, weight analyses, or perform sensitivity analysis for effect of low quality. Authors indicated that there were frequently major problems with the primary studies, individually or in aggregate. Our judgment was that the reviewing process was generally good in these reviews, and that conclusions were limited by the number, size, quality and validity of the primary studies.</p> <p>We judged the evidence about 23 of the 25 interventions to be weak. Two reviews had stronger evidence, but with limitations due to methodological heterogeneity or definition of outcomes. No review provided strong evidence of no effect.</p> <p>Conclusion</p> <p>Cochrane reviews in palliative care are well performed, but fail to provide good evidence for clinical practice because the primary studies are few in number, small, clinically heterogeneous, and of poor quality and external validity. They are useful in highlighting the weakness of the evidence base and problems in performing trials in palliative care.</p

Ascorbic acid partly antagonizes resveratrol mediated heme oxygenase-1 but not paraoxonase-1 induction in cultured hepatocytes - role of the redox-regulated transcription factor Nrf2

<p>Abstract</p> <p>Background</p> <p>Both resveratrol and vitamin C (ascorbic acid) are frequently used in complementary and alternative medicine. However, little is known about the underlying mechanisms for potential health benefits of resveratrol and its interactions with ascorbic acid.</p> <p>Methods</p> <p>The antioxidant enzymes heme oxygenase-1 and paraoxonase-1 were analysed for their mRNA and protein levels in HUH7 liver cells treated with 10 and 25 μmol/l resveratrol in the absence and presence of 100 and 1000 μmol/l ascorbic acid. Additionally the transactivation of the transcription factor Nrf2 and paraoxonase-1 were determined by reporter gene assays.</p> <p>Results</p> <p>Here, we demonstrate that resveratrol induces the antioxidant enzymes heme oxygenase-1 and paraoxonase-1 in cultured hepatocytes. Heme oxygenase-1 induction by resveratrol was accompanied by an increase in Nrf2 transactivation. Resveratrol mediated Nrf2 transactivation as well as heme oxygenase-1 induction were partly antagonized by 1000 μmol/l ascorbic acid.</p> <p>Conclusions</p> <p>Unlike heme oxygenase-1 (which is highly regulated by Nrf2) paraoxonase-1 (which exhibits fewer ARE/Nrf2 binding sites in its promoter) induction by resveratrol was not counteracted by ascorbic acid. Addition of resveratrol to the cell culture medium produced relatively low levels of hydrogen peroxide which may be a positive hormetic redox-signal for Nrf2 dependent gene expression thereby driving heme oxygenase-1 induction. However, high concentrations of ascorbic acid manifold increased hydrogen peroxide production in the cell culture medium which may be a stress signal thereby disrupting the Nrf2 signalling pathway.</p