Acute effects of an exercise based multimodal in-patient rehabilitation protocol in male knee osteoarthritis patients and the two years follow-up sustainability.

BACKGROUND: Working with lifting and carrying heavy loads and kneeling postures with crawling, squats or heel seat position lead to progressive cartilage wear with premature degenerative changes. OBJECTIVE: To investigate the effects of the exercise based multimodal 'knee college' and its sustainability in patients with knee osteoarthritis with data assessments before and after a starter course, before a 1-year and a 2-year follow-up refresher course in a retrospective observational study. METHODS: A sample of 401 male patients (ICD10: M17 [arthrosis of knee]/ICF: s75011 [knee joint]) from the construction industries were assessed with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), EuroQol (EQ-5D), Performance Assessment Capacity Testing (PACT), Isokinetic torque H/Q ratio and Physical Work Capacity Test (PWC). Retrospectively, after two years they were divided into three groups based on their intermediate sporting activity: gym (n = 194, age: 50.8±7.0, BMI: 28.8±4,3), home training (n = 110, age: 50.2±7.0, BMI: 28.4±4,2), no exercising (n = 97, age: 48.2±7.0, BMI: 29.2±4,6). RESULTS: Patients did not differ significantly in their demographic and anthropometric data prior to the rehab program. Significant interaction effects indicated group-dependent differing sustainability effects for the 2-year follow-up (all outcomes: p < 0.001, except for H/Q ratio: p = 0.03). Group-wise analyses revealed significant acute improvements (after 3-week in-patient starter rehab program: p < 0.05) for all groups in almost all outcomes (except the 'no sport' group, H/Q ratio p = 0.08). These effects remained significant (p < 0.001) only for the 'gym' group during the 1-year and 2-year follow-up. CONCLUSION: Our data indicate that 2-year sustainability of acute rehabilitation starter effects was demonstrated especially for patients with adherence and compliance to long-term gym based exercises.

Planning of gamma knife radiosurgery (GKR) for brain arteriovenous malformations using triple magnetic resonance angiography (triple-MRA).

PURPOSE: Intra-arterial Digital Subtraction Angiography (DSA) is the gold standard technique for radiosurgery target delineation in brain Arterio-Venous Malformations (AVMs). This study aims to evaluate whether a combination of three Magnetic Resonance Angiography sequences (triple-MRA) could be used for delineation of brain AVMs for Gamma Knife Radiosurgery (GKR). METHODS: Fifteen patients undergoing DSA for GKR targeting of brain AVMs also underwent triple-MRA: 4D Arterial Spin Labelling based angiography (ASL-MRA), Contrast-Enhanced Time-Resolved MRA (CE-MRA) and High Definition post-contrast Time-Of-Flight angiography (HD-TOF). The arterial phase of the AVM nidus was delineated on triple-MRA by an interventional neuroradiologist and a consultant neurosurgeon (triple-MRA volume). Triple-MRA volumes were compared to AVM targets delineated by the clinical team for delivery of GKR using the current planning paradigm, i.e., stereotactic DSA and volumetric MRI (DSA volume). Difference in size, degree of inclusion (DI) and concordance index (CcI) between DSA and triple-MRA volumes are reported. RESULTS: AVM target volumes delineated on triple-MRA were on average 9.8% smaller than DSA volumes (95%CI:5.6-13.9%; SD:7.14%; p = .003). DI of DSA volume in triple-MRA volume was on average 73.5% (95%CI:71.2-76; range: 65-80%). The mean percentage of triple-MRA volume not included on DSA volume was 18% (95%CI:14.7-21.3; range: 7-30%). CONCLUSION: The technical feasibility of using triple-MRA for visualisation and delineation of brain AVMs for GKR planning has been demonstrated. Tighter and more precise delineation of AVM target volumes could be achieved by using triple-MRA for radiosurgery targeting. However, further research is required to ascertain the impact this may have in obliteration rates and side effects.

Management of incidental aneurysms: comparison of single Centre multi-disciplinary team decision making with the unruptured incidental aneurysm treatment score.

OBJECTIVE: To compare multidisciplinary team (MDT) decision making at our centre with the suggested management from the recently published Unruptured Intracranial Aneurysm Treatment Score (UIATS), with particular focus on disagreements between the two bodies of expert opinion. DESIGN: A retrospective audit of local practice. SUBJECTS: Adult patients with incidental cerebral saccular aneurysms referred to The National Hospital for Neurology and Neurosurgery Neurovascular MDT. METHODS: Review of MDT records from 2010-2015 and collection of UIATS criteria. MDT decisions for each aneurysm were designated as conservative or treatment group, then assessed for correlation with the UIATS. RESULTS: Data was collected on 398 aneurysms from 296 patients. 57% of aneurysms were managed conservatively and 43% were treated with endovascular or open repair. Total follow up was 8409 aneurysm months (mean: 21 months per aneurysm). The overall proportion of agreement (p0) was 66.6% (95% CI: 61.9-71.2). Cohen's Kappa (k) was 0.325 suggesting only a "fair" level of agreement between the two raters. Absolute agreement rates increased from 60% in 2010 to 74% in 2015. Aneurysm size was an important factor for disagreement, 77% of aneurysms treated following MDT, but not in agreement with the UIATS, were >7 mm, compared with only 70.5% in those treated following MDT and in agreement with UIATS. CONCLUSION: There was disagreement between the two expert opinions analysed in this study. A key factor was aneurysm size, with decision making at our centre seemingly more guided by older landmark papers such as work by the International Study of Unruptured Intracranial Aneurysms (ISUIA) group. However, agreement was at its highest at the end of the study period, suggesting increasing convergence between the two bodies of expert opinion. The reasons for disagreement and particularly clinicians' reliance on aneurysm size in decision making is something that needs consideration when planning and auditing aneurysm services.

Organic cation transporter 3: expression in failing and nonfailing human heart and functional characterization.

The organic cation transporter 3 (OCT3, SLC22A3) contributes to the control of cardiac catecholamine concentrations and is important for the disposition and action of cationic drugs, such as metformin, in the myocardium. We sought to characterize the regulation of OCT3 in failing human hearts and to study commonly prescribed drugs for their potential to interact with OCT3-dependent uptake of metformin. SLC22A3 was expressed high in the human heart with strongest OCT3 immunoreactivity in vascular endothelial cells. SLC22A3/OCT3 expression was not changed in failing human left ventricular myocardium compared with nonfailing control tissues and thus is not involved in altered catecholamine homeostasis generally observed in failing hearts. Michaelis-Menten kinetics of OCT3-mediated uptake of prototypical OCT substrates 1-methyl-4-phenylpyridinium and metformin were studied in human embryonic kidney 293 cells stably overexpressing OCT3. The affinity of 1-methyl-4-phenylpyridinium for OCT3 was much higher (Km 157 ± 16 µM) than the affinity of metformin (Km 2.46 ± 0.36 mM; P < 0.01), whereas maximum transport rate of 1-methyl-4-phenylpyridinium was significantly lower than that of metformin. Verapamil, carvedilol, imipramine, and cimetidine were competitive inhibitors of OCT3-mediated metformin uptake (Ki 3.6-15.8 µM). Altogether, OCT3 might be important for the cardiac disposition of cationic drugs, and OCT3-dependent interaction with concomitantly administered compounds may limit their disposition and effect.

Call-fleming syndrome: an extraordinary complication of tonsillectomy.

A 36 years old woman underwent tonsillectomy for recurrent tonsillitis. At about one week in the postoperative period, she developed sudden onset severe ("thunderclap"), recurrent headaches and focal neurological signs including visual disturbances, ataxia and myoclonic jerks. Serial imaging with MRI, MRA and CT angiography revealed reversible white matter focal edema and segmental cerebral vasoconstriction. A diagnosis of Call-Fleming syndrome was made based on her symptoms and imaging findings, and she was started on nimodipine. She made a slow recovery but still has slight unilateral foot drop even 12 months since the initial event. This is the first case of Call-Fleming syndrome occurring following an ENT procedure.

Functional characterization of the human organic cation transporter 2 variant p.270Ala>Ser.

The organic cation transporter 2 (OCT2, SLC22A2) plays an important role for renal drug elimination. Recent clinical studies indicate an impact of the frequent nonsynonymous c.808G>T (p.270Ala>Ser) polymorphism on renal clearance of metformin and the extent of the metformin-cimetidine interaction. The role of this polymorphism for renal disposition of endogenous compounds and drugs other than metformin has not been investigated. In addition, it is unclear whether the observed genotype dependence of an OCT2-mediated drug-drug interaction might occur also with other OCT inhibitors. To address these issues, we generated human embryonic kidney cells stably expressing wild-type OCT2 or the p.270Ala>Ser variant. No differences in protein expression levels and membrane incorporation pattern were observed between the two cell lines. The p.270Ala>Ser variant significantly impaired uptake kinetics of 1-methyl-4-phenylpyridinium, dopamine, norepinephrine, and propranolol. V(max) values were significantly reduced for uptake of all four compounds mediated by the p.270Ala>Ser variant compared with wild-type OCT2. In addition, a significant difference in the affinity to wild-type and mutant OCT2 was observed for dopamine (K(m) dopamine: 932 +/- 77 versus 1285 +/- 132 microM). Moreover, out of a set of 27 compounds p.270Ala>Ser OCT2 was significantly less sensitive to inhibition by cimetidine, flurazepam, metformin, mexiletine, propranolol, and verapamil than wild-type OCT2 (e.g., for propranolol: IC(50) wild type versus p.270Ala>Ser 189 versus 895 microM, P < 0.001). Our results indicate that the common OCT2 c.808G>T single nucleotide polymorphism significantly alters uptake of endogenous compounds and drugs. Moreover, for selected compounds the extent of OCT2-mediated drug interactions could depend on OCT2 c.808G>T genotype.

Structural determinants of inhibitor interaction with the human organic cation transporter OCT2 (SLC22A2).

The organic cation transporter 2 (OCT2) provides an important pathway for the uptake of cationic compounds in the kidney, which is the essential step in their elimination from the organism. Although many drugs have been identified which interact with human OCT2, structural elements required for an interaction with OCT2 are not well defined. To address this issue, HEK293 cells stably expressing human OCT2 were generated. IC(50) values of commonly used drugs for inhibition of [(3)H]MPP(+) uptake were determined and correlated with physicochemical descriptors. We found only a significant correlation between the topological polar surface area (TPSA) and IC(50) values (r = 0.71, p < 0.0001). Structural alignment of most potent inhibitor drugs of OCT2-mediated MPP(+) uptake was used to construct a two-point pharmacophore consisting of an ion-pair interaction site and a hydrophobic aromatic site separated by 5.0 A. Taken together, our data identify structural determinants for inhibitor interactions with OCT2.

Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure.

The hypoxia-inducible transcription factor HIF is induced early in acute myocardial ischemia in humans, but it is unknown whether this activation of HIF persists during chronic heart failure. The HIF system was characterized in left ventricular myocardia from 18 explanted failing hearts and 11 non-failing donor hearts by quantitative RT-PCR and Western analysis. HIF-1alpha mRNA levels were significantly decreased while its natural antisense transcript aHIF was nearly twofold higher (p<0.01) in failing myocardia than in control hearts. Moreover, compared to donor hearts a significantly increased expression of HIF-3alpha, which may act as a competitive inhibitor of HIF-1/2alpha activity, and PHD3, which upon hydroxylation of prolyl residues directs HIF-alpha subunits towards proteasomal degradation, was observed in the failing myocardium. Although negative regulators of HIF were induced, the HIF pathway obviously remains activated in chronic human heart failure, because prototype HIF target genes, such as ABCG2, VEGF, and BNIP3, were significantly induced.

ATP-binding cassette transporters in human heart failure.

Adenosine triphosphate-binding cassette (ABC) transporters are involved in energy-dependent transport of substrates across biological membranes. We hypothesized that their expression is altered during human heart failure, suggesting a pathophysiologic basis. Messenger ribonucleic acid quantification of all known ABC transporters revealed multiple alterations in ABC transporter expression in failing human hearts (New York Heart Association classification III-IV) compared to nonfailing controls. These include a loss of ABCC7 chloride channels and an increased expression of the K(ATP) channel regulatory subunits ABCC8. Moreover, ABCG2, an efflux pump for xenobiotics/drugs, was expressed at much higher levels in failing hearts compared to nonfailing control hearts. ABCG2 was found in cardiac capillary endothelial cells and cardiomyocytes. Experiments in cells stably transfected with human ABCG2 revealed that the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone was transported by ABCG2 but also inhibited the export of the prototypical ABCG2 substrate pheophorbide A (IC(50) 25 microM). These results suggest that altered ABC transporter expression in failing hearts might contribute to impaired channel conductance or might affect the cardiac disposition of drugs.

ATP-binding cassette transporters in the heart.

Members of the ATP-binding cassette (ABC) protein superfamily are integral membrane proteins involved in energy-dependent transport of a wide variety of substrates across biologic membranes. ATP-binding cassette transporters serve as functional barriers against the entry of xenobiotics, for example, in the intestine or at the blood-brain barrier, or contribute to drug excretion, for example, in the kidney or the liver. Many human ABC transporters, such as ABCB1 (P-glycoprotein), ABCC5 (MRP5), or ABCC9 (SUR2), are expressed in the heart, suggesting an important role of these transporters in cardiac drug effects or physiology. Interestingly, mutations in ABCC9, a constituent of cardiac K(ATP) channels, can cause dilated cardiomyopathy in humans, providing evidence that dysfunction of cardiac ABC transporters might have clinical implications. This review aims to give insights into the possible functions of ABC transporters in the heart, their role in drug disposition, as well as control of intracellular cyclic nucleotide levels or regulation of K(ATP) channel conductivity.