Effectiveness of physiotherapy exercise following hip arthroplasty for osteoarthritis: a systematic review of clinical trials

Background: Physiotherapy has long been a routine component of patient rehabilitation following hip joint replacement. The purpose of this systematic review was to evaluate the effectiveness of physiotherapy exercise after discharge from hospital on function, walking, range of motion, quality of life and muscle strength, for osteoarthritic patients following elective primary total hip arthroplasty. Methods: Design: Systematic review, using the Cochrane Collaboration Handbook for Systematic Reviews of Interventions and the Quorom Statement. Database searches: AMED, CINAHL, EMBASE, KingsFund, MEDLINE, Cochrane library (Cochrane reviews, Cochrane Central Register of Controlled Trials, DARE), PEDro, The Department of Health National Research Register. Handsearches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings. No language restrictions were applied. Selection: Trials comparing physiotherapy exercise versus usual/standard care, or comparing two types of relevant exercise physiotherapy, following discharge from hospital after elective primary total hip replacement for osteoarthritis were reviewed. Outcomes: Functional activities of daily living, walking, quality of life, muscle strength and range of hip joint motion. Trial quality was extensively evaluated. Narrative synthesis plus meta-analytic summaries were performed to summarise the data. Results: 8 trials were identified. Trial quality was mixed. Generally poor trial quality, quantity and diversity prevented explanatory meta-analyses. The results were synthesised and meta-analytic summaries were used where possible to provide a formal summary of results. Results indicate that physiotherapy exercise after discharge following total hip replacement has the potential to benefit patients. Conclusion: Insufficient evidence exists to establish the effectiveness of physiotherapy exercise following primary hip replacement for osteoarthritis. Further well designed trials are required to determine the value of post discharge exercise following this increasingly common surgical procedure

The psychiatric risk gene NT5C2 regulates adenosine monophosphate-activated protein kinase signaling and protein translation in human neural progenitor cells

Background The 5′-nucleotidase, cytosolic II gene (NT5C2, cN-II) is associated with disorders characterized by psychiatric and psychomotor disturbances. Common psychiatric risk alleles at the NT5C2 locus reduce expression of this gene in the fetal and adult brain, but downstream biological risk mechanisms remain elusive. Methods Distribution of the NT5C2 protein in the human dorsolateral prefrontal cortex and cortical human neural progenitor cells (hNPCs) was determined using immunostaining, publicly available expression data, and reverse transcriptase quantitative polymerase chain reaction. Phosphorylation quantification of adenosine monophosphate-activated protein kinase (AMPK) alpha (Thr172) and ribosomal protein S6 (Ser235/Ser236) was performed using Western blotting to infer the degree of activation of AMPK signaling and the rate of protein translation. Knockdowns were induced in hNPCs and Drosophila melanogaster using RNA interference. Transcriptomic profiling of hNPCs was performed using microarrays, and motility behavior was assessed in flies using the climbing assay. Results Expression of NT5C2 was higher during neurodevelopment and was neuronally enriched in the adult human cortex. Knockdown in hNPCs affected AMPK signaling, a major nutrient-sensing mechanism involved in energy homeostasis, and protein translation. Transcriptional changes implicated in protein translation were observed in knockdown hNPCs, and expression changes to genes related to AMPK signaling and protein translation were confirmed using reverse transcriptase quantitative polymerase chain reaction. The knockdown in Drosophila was associated with drastic climbing impairment. Conclusions We provide an extensive neurobiological characterization of the psychiatric risk gene NT5C2, describing its previously unknown role in the regulation of AMPK signaling and protein translation in neural stem cells and its association with Drosophila melanogaster motility behavior

The natural function of the malaria parasite’s chloroquine resistance transporter

Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediates multidrug resistance, but its natural function remains unclear. Here, Shafik et al. show that PfCRT transports host-derived peptides of 4-11 residues but not other ions or metabolites, and that drug-resistance-conferring PfCRT mutants have reduced peptide transport

Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite’s Chloroquine Resistance Transporter

<div><p>Mutations in the <i>Plasmodium falciparum</i> ‘chloroquine resistance transporter’ (PfCRT) confer resistance to chloroquine (CQ) and related antimalarials by enabling the protein to transport these drugs away from their targets within the parasite’s digestive vacuole (DV). However, CQ resistance-conferring isoforms of PfCRT (PfCRT^CQR) also render the parasite hypersensitive to a subset of structurally-diverse pharmacons. Moreover, mutations in PfCRT^CQR that suppress the parasite’s hypersensitivity to these molecules simultaneously reinstate its sensitivity to CQ and related drugs. We sought to understand these phenomena by characterizing the functions of PfCRT^CQR isoforms that cause the parasite to become hypersensitive to the antimalarial quinine or the antiviral amantadine. We achieved this by measuring the abilities of these proteins to transport CQ, quinine, and amantadine when expressed in <i>Xenopus</i> oocytes and complemented this work with assays that detect the drug transport activity of PfCRT in its native environment within the parasite. Here we describe two mechanistic explanations for PfCRT-induced drug hypersensitivity. First, we show that quinine, which normally accumulates inside the DV and therewithin exerts its antimalarial effect, binds extremely tightly to the substrate-binding site of certain isoforms of PfCRT^CQR. By doing so it likely blocks the normal physiological function of the protein, which is essential for the parasite’s survival, and the drug thereby gains an additional killing effect. In the second scenario, we show that although amantadine also sequesters within the DV, the parasite’s hypersensitivity to this drug arises from the PfCRT^CQR-mediated transport of amantadine from the DV into the cytosol, where it can better access its antimalarial target. In both cases, the mutations that suppress hypersensitivity also abrogate the ability of PfCRT^CQR to transport CQ, thus explaining why rescue from hypersensitivity restores the parasite’s sensitivity to this antimalarial. These insights provide a foundation for understanding clinically-relevant observations of inverse drug susceptibilities in the malaria parasite.</p></div

Kinetic parameters for the transport of CQ, quinine, and quinidine via variants of PfCRT^K1.

<p>Kinetic parameters for the transport of CQ, quinine, and quinidine via variants of PfCRT^K1.</p

Molecular mechanisms for the drug hypersensitivities induced by PfCRT isoforms in the malaria parasite.

<p>(A) The variants of PfCRT^K1 that contain 72R, 76K, 163R, 352K, or 352R (R/K) do not possess significant quinine (QN) transport activity. The drug would therefore remain in the parasite’s DV where it exerts an anti-hemozoin effect that kills the parasite, which is consistent with the QN-sensitive (S) status of the respective lines. PfCRT^K1 (76T) is able to transport QN out of the DV and thereby imparts low-level resistance (<i>low</i>-R) to QN. By contrast, 76I-PfCRT^K1 has an extremely high affinity for QN coupled with an extremely low maximum rate of transport. This causes QN to clog the binding site of 76I-PfCRT^K1, thereby blocking the transport of the natural substrate. Hence, the QN-hypersensitivity (<i>hyper</i>-S) observed in 106/1^76I parasites results from QN exerting two killing effects—anti-hemozoin and anti-PfCRT^CQR. The gain of a positively-charged residue at position 72 or 352 (76I R/K) prevents the interaction of the transporter with QN and returns the parasites to QN-sensitive status. (B) Amantadine (AMT) is a relatively poor inhibitor of both 76I-PfCRT^K1 and 76I,369F-PfCRT^K1, making it unlikely that the AMT-hypersensitivity of CQ-resistant parasites is due to an anti-PfCRT^CQR effect. The isoforms of PfCRT from AMT-hypersensitive parasites (PfCRT^K1 and 76I-PfCRT^K1) have the ability to transport this weak-base drug out of the DV (where it accumulates) whereas those from AMT-sensitive parasites either do not possess significant AMT transport activity (e.g., 76K-PfCRT^K1 and 163R,356V-PfCRT^K1; R/K) or transport AMT with low affinity and low capacity (76I,369F-PfCRT^K1). The data therefore converge on a scenario in which AMT exerts its main antimalarial activity in the cytosol and AMT-hypersensitivity arises from the redistribution of the drug from the DV into the cytosol via a PfCRT^CQR variant (e.g., PfCRT^K1 or 76I-PfCRT^K1).</p

<i>In vitro</i> antiplasmodial activities of CQ and amantadine against CQ-sensitive and CQ-resistant <i>P</i>. <i>falciparum</i> parasites.

<p><i>In vitro</i> antiplasmodial activities of CQ and amantadine against CQ-sensitive and CQ-resistant <i>P</i>. <i>falciparum</i> parasites.</p

The origins, drug susceptibilities, and PfCRT haplotypes of different 106/1 and K1 <i>P</i>. <i>falciparum</i> lines.

<p>The origins, drug susceptibilities, and PfCRT haplotypes of different 106/1 and K1 <i>P</i>. <i>falciparum</i> lines.</p