Primary cilia disassembly down-regulates mechanosensitive hedgehog signalling: a feedback mechanism controlling ADAMTS-5 expression in chondrocytes

SummaryObjectiveHedgehog signalling is mediated by the primary cilium and promotes cartilage degeneration in osteoarthritis. Primary cilia are influenced by pathological stimuli and cilia length and prevalence are increased in osteoarthritic cartilage. This study aims to investigate the relationship between mechanical loading, hedgehog signalling and cilia disassembly in articular chondrocytes.MethodsPrimary bovine articular chondrocytes were subjected to cyclic tensile strain (CTS; 0.33 Hz, 10% or 20% strain). Hedgehog pathway activation (Ptch1, Gli1) and A Disintegrin And Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS-5) expression were assessed by real-time PCR. A chondrocyte cell line generated from the Tg737ORPK mouse was used to investigate the role of the cilium in this response. Cilia length and prevalence were quantified by immunocytochemistry and confocal microscopy.ResultsMechanical strain upregulates Indian hedgehog expression and activates hedgehog signalling. Ptch1, Gli1 and ADAMTS-5 expression were increased following 10% CTS, but not 20% CTS. Pathway activation requires a functioning primary cilium and is not observed in Tg737ORPK cells lacking cilia. Mechanical loading significantly reduced cilium length such that cilia became progressively shorter with increasing strain magnitude. Inhibition of histone deacetylase 6 (HDAC6), a tubulin deacetylase, prevented cilia disassembly and restored mechanosensitive hedgehog signalling and ADAMTS-5 expression at 20% CTS.ConclusionsThis study demonstrates for the first time that mechanical loading activates primary cilia-mediated hedgehog signalling and ADAMTS-5 expression in adult articular chondrocytes, but that this response is lost at high strains due to HDAC6-mediated cilia disassembly. The study provides new mechanistic insight into the role of primary cilia and mechanical loading in articular cartilage

Overcoming barriers to effective early parenting interventions for attention-deficit hyperactivity disorder (ADHD): parent and practitioner views

BackgroundThe importance of early intervention approaches for the treatment of attention-deficit hyperactivity disorder (ADHD) has been increasingly acknowledged. Parenting programmes (PPs) are recommended for use with preschool children with ADHD. However, low take-up' and high drop-out' rates compromise the effectiveness of such programmes within the community. MethodsThis qualitative study examined the views of 25 parents and 18 practitioners regarding currently available PPs for preschool children with ADHD-type problems in the UK. Semi-structured interviews were undertaken to identify both barriers and facilitators associated with programme access, programme effectiveness, and continued engagement. Results and conclusionsMany of the themes mirrored previous accounts relating to generic PPs for disruptive behaviour problems. There were also a number of ADHD-specific themes. Enhancing parental motivation to change parenting practice and providing an intervention that addresses the parents' own needs (e.g. in relation to self-confidence, depression or parental ADHD), in addition to those of the child, were considered of particular importance. Comparisons between the views of parents and practitioners highlighted a need to increase awareness of parental psychological barriers among practitioners and for better programme advertising generally. Clinical implications and specific recommendations drawn from these findings are discussed and presented

An enhanced SWAT wetland module to quantify hydraulic interactions between riparian depressional wetlands, rivers and aquifers

This study develops a modified version of the Soil and Water Assessment Tool (SWAT) designed to better represent riparian depressional wetlands (SWATrw). It replaces existing unidirectional hydrological interactions between a wetland and a river/aquifer with a more robust bidirectional approach based on hydraulic principles. SWATrw incorporates a more flexible wetland morphometric formula and a connecting channel concept to model wetland-river interactions. SWAT and SWATrw were tested for the Barak-Kushiyara River Basin (Bangladesh and India). Although the two models showed small differences in simulated stream flow, SWATrw outperformed SWAT in reproducing river stages and the pre-monsoon river-spills into riparian wetlands. SWATrw showed that the observed presence of dry season water in the wetland was due to reduced seepage to the local groundwater table whilst continuous seepage simulated by SWAT resulted in the wetland drying out completely. The new model therefore more closely simulates the hydrological interactions between wetlands, rivers and groundwater

Using multiple classifiers for predicting the risk of endovascular aortic aneurysm repair re-intervention through hybrid feature selection.

Feature selection is essential in medical area; however, its process becomes complicated with the presence of censoring which is the unique character of survival analysis. Most survival feature selection methods are based on Cox's proportional hazard model, though machine learning classifiers are preferred. They are less employed in survival analysis due to censoring which prevents them from directly being used to survival data. Among the few work that employed machine learning classifiers, partial logistic artificial neural network with auto-relevance determination is a well-known method that deals with censoring and perform feature selection for survival data. However, it depends on data replication to handle censoring which leads to unbalanced and biased prediction results especially in highly censored data. Other methods cannot deal with high censoring. Therefore, in this article, a new hybrid feature selection method is proposed which presents a solution to high level censoring. It combines support vector machine, neural network, and K-nearest neighbor classifiers using simple majority voting and a new weighted majority voting method based on survival metric to construct a multiple classifier system. The new hybrid feature selection process uses multiple classifier system as a wrapper method and merges it with iterated feature ranking filter method to further reduce features. Two endovascular aortic repair datasets containing 91% censored patients collected from two centers were used to construct a multicenter study to evaluate the performance of the proposed approach. The results showed the proposed technique outperformed individual classifiers and variable selection methods based on Cox's model such as Akaike and Bayesian information criterions and least absolute shrinkage and selector operator in p values of the log-rank test, sensitivity, and concordance index. This indicates that the proposed classifier is more powerful in correctly predicting the risk of re-intervention enabling doctor in selecting patients' future follow-up plan

Hydrological impacts of climate change on rice cultivated riparian wetlands in the Upper Meghna River Basin (Bangladesh and India)

Riparian depressional wetlands (haors) in the Upper Meghna River Basin of Bangladesh are invaluable agricultural resources. They are completely flooded between June and November and planted with Boro rice when floodwater recedes in December. However, early harvest period (April/May) floods frequently damage ripening rice. A calibrated/validated Soil and Water Assessment Tool for riparian wetland (SWATrw) model is perturbed with bias free (using an improved quantile mapping approach) climate projections from 17 general circulation models (GCMs) for the period 2031–2050. Projected mean annual rainfall increases (200–500 mm or 7–10%). However, during the harvest period lower rainfall (21–75%) and higher evapotranspiration (1–8%) reduces river discharge (5–18%) and wetland inundation (inundation fraction declines of 0.005–0.14). Flooding risk for Boro rice consequently declines (rationalized flood risk reductions of 0.02–0.12). However, the loss of cultivable land (15.3%) to increases in permanent haor inundation represents a major threat to regional food security

A combinatorial approach to angiosperm pollen morphology

Angiosperms (flowering plants) are strikingly diverse. This is clearly expressed in the morphology of their pollen grains, which are characterized by enormous variety in their shape and patterning. In this paper, I approach angiosperm pollen morphology from the perspective of enumerative combinatorics. This involves generating angiosperm pollen morphotypes by algorithmically combining character states and enumerating the results of these combinations. I use this approach to generate 3 643 200 pollen morphotypes, which I visualize using a parallel-coordinates plot. This represents a raw morphospace. To compare real-world and theoretical morphologies, I map the pollen of 1008 species of Neotropical angiosperms growing on Barro Colorado Island (BCI), Panama, onto this raw morphospace. This highlights that, in addition to their well-documented taxonomic diversity, Neotropical rainforests also represent an enormous reservoir of morphological diversity. Angiosperm pollen morphospace at BCI has been filled mostly by pollen morphotypes that are unique to single plant species. Repetition of pollen morphotypes among higher taxa at BCI reflects both constraint and convergence. This combinatorial approach to morphology addresses the complexity that results from large numbers of discrete character combinations and could be employed in any situation where organismal form can be captured by discrete morphological characters

Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling

This work was supported in part by funding from the AO Foundation (project S-12-15K) and the Medical Research Council (Swindon, United Kingdom) (MR/L002876/1). C.A.P. was supported by the Royal Society of New Zealand through a James Cook Research Fellowshi

Value of risk scores in the decision to palliate patients withruptured abdominal aortic aneurysm

Background: The aim of this study was to develop a 48‐h mortality risk score, which included morphology data, for patients with ruptured abdominal aortic aneurysm presenting to an emergency department, and to assess its predictive accuracy and clinical effectiveness in triaging patients to immediate aneurysm repair, transfer or palliative care. Methods: Data from patients in the IMPROVE (Immediate Management of the Patient With Ruptured Aneurysm: Open Versus Endovascular Repair) randomized trial were used to develop the risk score. Variables considered included age, sex, haemodynamic markers and aortic morphology. Backwards selection was used to identify relevant predictors. Predictive performance was assessed using calibration plots and the C‐statistic. Validation of the newly developed and other previously published scores was conducted in four external populations. The net benefit of treating patients based on a risk threshold compared with treating none was quantified. Results: Data from 536 patients in the IMPROVE trial were included. The final variables retained were age, sex, haemoglobin level, serum creatinine level, systolic BP, aortic neck length and angle, and acute myocardial ischaemia. The discrimination of the score for 48‐h mortality in the IMPROVE data was reasonable (C‐statistic 0·710, 95 per cent c.i. 0·659 to 0·760), but varied in external populations (from 0·652 to 0·761). The new score outperformed other published risk scores in some, but not all, populations. An 8 (95 per cent c.i. 5 to 11) per cent improvement in the C‐statistic was estimated compared with using age alone. Conclusion: The assessed risk scores did not have sufficient accuracy to enable potentially life‐saving decisions to be made regarding intervention. Focus should therefore shift to offering repair to more patients and reducing non‐intervention rates, while respecting the wishes of the patient and family

Mechanical Stimulation: A Crucial Element of Organ-on-Chip Models

Organ-on-chip (OOC) systems recapitulate key biological processes and responses in vitro exhibited by cells, tissues, and organs in vivo. Accordingly, these models of both health and disease hold great promise for improving fundamental research, drug development, personalized medicine, and testing of pharmaceuticals, food substances, pollutants etc. Cells within the body are exposed to biomechanical stimuli, the nature of which is tissue specific and may change with disease or injury. These biomechanical stimuli regulate cell behavior and can amplify, annul, or even reverse the response to a given biochemical cue or drug candidate. As such, the application of an appropriate physiological or pathological biomechanical environment is essential for the successful recapitulation of in vivo behavior in OOC models. Here we review the current range of commercially available OOC platforms which incorporate active biomechanical stimulation. We highlight recent findings demonstrating the importance of including mechanical stimuli in models used for drug development and outline emerging factors which regulate the cellular response to the biomechanical environment. We explore the incorporation of mechanical stimuli in different organ models and identify areas where further research and development is required. Challenges associated with the integration of mechanics alongside other OOC requirements including scaling to increase throughput and diagnostic imaging are discussed. In summary, compelling evidence demonstrates that the incorporation of biomechanical stimuli in these OOC or microphysiological systems is key to fully replicating in vivo physiology in health and disease

Indications for Catheter-Directed Thrombolysis in the Management of Acute Proximal Deep Venous Thrombosis

Deep vein thromboses (DVTs) cause significant morbidity and mortality in the general population. Oral anticoagulation therapy may reduce thrombus propagation but does not cause clot lysis and therefore does not prevent postthrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) can be used to treat DVTs as an adjunct to medical therapy, but there is no consensus defining exact indications. Current evidence suggests that CDT can reduce clot burden and DVT recurrence and consequently prevents the formation of PTS compared with systemic anticoagulation. Appropriate indications include younger individuals with acute proximal thromboses, a long life expectancy, and relatively few comorbidities. Limb-threatening thromboses may also be treated with CDT, although the subsequent mortality remains high. A number of randomized controlled trials are currently under way comparing the longer-term outcomes of CDT compared with anticoagulation alone. Initial reports suggest that venous patency and valvular function are better maintained after CDT. The effectiveness of combined pharmacomechanical thrombectomy and the role of vena cava filters need to be investigated further before strong recommendations can be made. The reported short-term outcomes following catheter-based intervention for DVT are encouraging in selected patients. Further evidence is required to establish long-term benefits and cost-effectiveness