Sensori-motor adaptation to knee osteoarthritis during stepping-down before and after total knee replacement

BACKGROUND: Stepping-down is preceded by a shift of the center of mass towards the supporting side and forward. The ability to control both balance and lower limb movement was investigated in knee osteoarthritis patients before and after surgery. It was hypothesized that pain rather than knee joint mobility affects the coordination between balance and movement control. METHODS: The experiment was performed with 25 adult individuals. Eleven were osteoarthritic patients with damage restricted to one lower limb (8 right leg and 3 left leg). Subjects were recruited within two weeks before total knee replacement by the same orthopedic surgeon using the same prosthesis and technics of surgery. Osteoarthritic patients were tested before total knee replacement (pre-surgery session) and then, 9 of the 11 patients were tested one year after the surgery when re-educative training was completed (post-surgery session). 14 adult individuals (men: n = 7 and women: n = 7) were tested as the control group. RESULTS: The way in which the center of mass shift forward and toward the supporting side is initiated (timing and amplitude) did not vary within patients before and after surgery. In addition knee joint range of motion of the leading leg remained close to normal before and after surgery. However, the relative timing between both postural and movement phases was modified for the osteoarthritis supporting leg (unusual strategy for stepping-down) before surgery. The "coordinated" control of balance and movement turned to be a "sequential" mode of control; once the body weight transfer has been completed, the movement onset is triggered. This strategy could be aimed at shortening the duration-time supporting on the painful limb. However no such compensatory response was observed. CONCLUSION: The change in the strategy used when supporting on the arthritis and painful limb could result from the action of nociceptors that lead to increased proprioceptor thresholds, thus gating the proprioceptive inputs that may be the critical afferents in controlling the timing of the coordination between balance and movement initiation control

Bmcc1s, a Novel Brain-Isoform of Bmcc1, Affects Cell Morphology by Regulating MAP6/STOP Functions

The BCH (BNIP2 and Cdc42GAP Homology) domain-containing protein Bmcc1/Prune2 is highly enriched in the brain and is involved in the regulation of cytoskeleton dynamics and cell survival. However, the molecular mechanisms accounting for these functions are poorly defined. Here, we have identified Bmcc1s, a novel isoform of Bmcc1 predominantly expressed in the mouse brain. In primary cultures of astrocytes and neurons, Bmcc1s localized on intermediate filaments and microtubules and interacted directly with MAP6/STOP, a microtubule-binding protein responsible for microtubule cold stability. Bmcc1s overexpression inhibited MAP6-induced microtubule cold stability by displacing MAP6 away from microtubules. It also resulted in the formation of membrane protrusions for which MAP6 was a necessary cofactor of Bmcc1s. This study identifies Bmcc1s as a new MAP6 interacting protein able to modulate MAP6-induced microtubule cold stability. Moreover, it illustrates a novel mechanism by which Bmcc1 regulates cell morphology

Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion

The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis in vivo is unclear. Here we identify an RTK of the Eph family, EphA2, to be a cargo of an RCP-regulated endocytic pathway which controls cell:cell repulsion and metastasis in vivo. Phosphorylation of RCP at Ser435 by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser897 by Akt are both necessary to promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 which generates cell:cell repulsion events that drive tumour cells apart. Genetic disruption of RCP or EphA2 opposes cell:cell repulsion and metastasis in an autochthonous mouse model of pancreatic adenocarcinoma—whereas conditional knockout of another RCP cargo, α5 integrin, does not suppress pancreatic cancer metastasis—indicating a role for RCP-dependent trafficking of an Eph receptor to drive tumour dissemination in vivo

The effectiveness of modern cardiac rehabilitation : A systematic review of recent observational studies in non-attenders versus attenders

BACKGROUND: The beneficial effects of cardiac rehabilitation (CR) have been challenged in recent years and there is now a need to investigate whether current CR programmes, delivered in the context of modern cardiology, still benefit patients. METHODS: A systematic review of non-randomised controlled studies was conducted. Electronic searches of Medline, Embase, CINAHL, science citation index (web of science), CIRRIE and Open Grey were undertaken. Non-randomised studies investigating the effects of CR were included when recruitment occurred from the year 2000 onwards in accordance with significant CR guidance changes from the late 1990's. Adult patients diagnosed with acute myocardial infarction (AMI) were included. Non-English articles were considered. Two reviewers independently screened articles according to pre-defined selection criteria as reported in the PROSPERO database (CRD42015024021). RESULTS: Out of 2,656 articles, 8 studies involving 9,836 AMI patients were included. Studies were conducted in 6 countries. CR was found to reduce the risk of all-cause and cardiac-related mortality and improve Health-Related Quality of Life (HRQOL) significantly in at least one domain. The benefits of CR in terms of recurrent MI were inconsistent and no significant effects were found regarding re-vascularisation or re-hospitalisation following AMI. CONCLUSION: Recent observational evidence draws different conclusions to the most current reviews of trial data with respect to total mortality and re-hospitalisation, questioning the representativeness of historic data in the modern cardiological era. Future work should seek to clarify which patient and service level factors determine the likelihood of achieving improved all-cause and cardiac mortality and reduced hospital re-admissions

Multiscale Simulations Suggest a Mechanism for the Association of the Dok7 PH Domain with PIP-Containing Membranes

Dok7 is a peripheral membrane protein that is associated with the MuSK receptor tyrosine kinase. Formation of the Dok7/MuSK/membrane complex is required for the activation of MuSK. This is a key step in the complex exchange of signals between neuron and muscle, which lead to neuromuscular junction formation, dysfunction of which is associated with congenital myasthenic syndromes. The Dok7 structure consists of a Pleckstrin Homology (PH) domain and a Phosphotyrosine Binding (PTB) domain. The mechanism of the Dok7 association with the membrane remains largely unknown. Using multi-scale molecular dynamics simulations we have explored the formation of the Dok7 PH/membrane complex. Our simulations indicate that the PH domain of Dok7 associates with membranes containing phosphatidylinositol phosphates (PIPs) via interactions of the β1/β2, β3/β4, and β5/β6 loops, which together form a positively charged surface on the PH domain and interact with the negatively charged headgroups of PIP molecules. The initial encounter of the Dok7 PH domain is followed by formation of additional interactions with the lipid bilayer, and especially with PIP molecules, which stabilizes the Dok7 PH/membrane complex. We have quantified the binding of the PH domain to the model bilayers by calculating a density landscape for protein/membrane interactions. Detailed analysis of the PH/PIP interactions reveal both a canonical and an atypical site to be occupied by the anionic lipid. PH domain binding leads to local clustering of PIP molecules in the bilayer. Association of the Dok7 PH domain with PIP lipids is therefore seen as a key step in localization of Dok7 to the membrane and formation of a complex with MuSK

The effectiveness and cost-evaluation of manual therapy and physical therapy in patients with sub-acute and chronic non specific neck pain. Rationale and design of a Randomized Controlled Trial (RCT)

Contains fulltext : 88910.pdf (publisher's version ) (Open Access)BACKGROUND: Manual Therapy applied to patients with non specific neck pain has been investigated several times. In the Netherlands, manual therapy as applied according to the Utrecht School of Manual Therapy (MTU) has not been the subject of a randomized controlled trial. MTU differs in diagnoses and treatment from other forms of manual therapy. METHODS/DESIGN: This is a single blind randomized controlled trial in patients with sub-acute and chronic non specific neck pain. Patients with neck complaints existing for two weeks (minimum) till one year (maximum) will participate in the trial. 180 participants will be recruited in thirteen primary health care centres in the Netherlands.The experimental group will be treated with MTU during a six week period. The control group will be treated with physical therapy (standard care, mainly active exercise therapy), also for a period of six weeks.Primary outcomes are Global Perceived Effect (GPE) and functional status (Neck Disability Index (NDI-DV)). Secondary outcomes are neck pain (Numeric Rating Scale (NRS)), Eurocol, costs and quality of life (SF36). DISCUSSION: This paper presents details on the rationale of MTU, design, methods and operational aspects of the trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00713843

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

A Concerted Kinase Interplay Identifies PPARγ as a Molecular Target of Ghrelin Signaling in Macrophages

The peroxisome proliferator-activator receptor PPARγ plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through transcriptional activation of PPARγ. Although the interplay between CD36 and PPARγ in atherogenesis is well recognized, the contribution of the ghrelin receptor to regulate PPARγ remains unknown. Here, we demonstrate that ghrelin triggers PPARγ activation through a concerted signaling cascade involving Erk1/2 and Akt kinases, resulting in enhanced expression of downstream effectors LXRα and ABC sterol transporters in human macrophages. These effects were associated with enhanced PPARγ phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was identified as being recruited to GHS-R1a in response to ghrelin, but failure of activated Fyn to enhance PPARγ Ser-84 specific phosphorylation relied on the concomitant recruitment of docking protein Dok-1, which prevented optimal activation of the Erk1/2 pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARγ activity and responsiveness to Src inhibition, supporting a mechanism independent of Ser-84 in PPARγ response to ghrelin. Consistent with this, we found that ghrelin promoted the PI3-K/Akt pathway in a Gαq-dependent manner, resulting in Akt recruitment to PPARγ, enhanced PPARγ phosphorylation and activation independently of Ser-84, and increased expression of LXRα and ABCA1/G1. Collectively, these results illustrate a complex interplay involving Fyn/Dok-1/Erk and Gαq/PI3-K/Akt pathways to transduce in a concerted manner responsiveness of PPARγ to ghrelin in macrophages